[{"id":"paper-ata-2015-thyroid-nodules-dtc-haugen-thyroid-2016","kind":"paper","name":"2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer","aka":[],"tldr":"The 2015 American Thyroid Association guideline moved differentiated thyroid cancer towards less treatment: lobectomy rather than total thyroidectomy for many low-risk cancers, selective rather than routine radioactive iodine, and active surveillance for small papillary cancers.","summary":"Comprehensive guideline covering evaluation of thyroid nodules, ultrasound risk stratification, molecular testing, extent of surgery, risk stratification for recurrence, radioactive iodine indications, TSH suppression, follow-up, and management of recurrent and metastatic differentiated thyroid cancer including kinase inhibitors.","asOf":"2026-09-17","links":[{"label":"Thyroid 2016","url":"https://doi.org/10.1089/thy.2015.0020"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26462967/"}],"tags":[],"related":[],"cancers":["follicular-thyroid-cancer","papillary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Thyroid","year":2016,"doi":"10.1089/thy.2015.0020","pmid":"26462967","authors":"Haugen BR, Alexander EK, Bible KC, et al.","paperType":"guideline","findings":[],"whatItMeans":"The follicular and papillary thyroid cancer pages' recommendations for lobectomy, selective iodine and surveillance of microcarcinoma follow this guideline.","caveats":["Under revision; ESTIMABL2 and IoN have since supported omitting iodine in low-risk disease."],"changedPractice":true},{"id":"paper-ata-anaplastic-thyroid-guideline-bible-thyroid-2021","kind":"paper","name":"2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer","aka":[],"tldr":"The updated American guideline for anaplastic thyroid cancer stresses molecular testing within days of diagnosis, BRAF-MEK inhibitors for BRAF-mutant disease including before surgery, multimodal therapy for resectable disease, and early goals-of-care discussions.","summary":"Evidence-based guideline covering rapid diagnosis and staging, airway management, molecular testing, surgery, radiotherapy with or without chemotherapy, BRAF-directed and other targeted therapy, immunotherapy, and palliative and supportive care for anaplastic thyroid cancer.","asOf":"2026-09-17","links":[{"label":"Thyroid 2021","url":"https://doi.org/10.1089/thy.2020.0944"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33728999/"}],"tags":[],"related":[],"cancers":["anaplastic-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Thyroid","year":2021,"doi":"10.1089/thy.2020.0944","pmid":"33728999","authors":"Bible KC, Kebebew E, Brierley J, et al.","paperType":"guideline","findings":[],"whatItMeans":"The anaplastic thyroid cancer page's emphasis on speed, BRAF testing and neoadjuvant targeted therapy follows this guideline.","caveats":["Evidence for most recommendations is from small series."],"changedPractice":true},{"id":"paper-rindi-common-classification-framework-mod-pathol-2018","kind":"paper","name":"A common classification framework for neuroendocrine neoplasms (IARC and WHO expert consensus)","aka":[],"tldr":"This consensus proposed a uniform way of classifying neuroendocrine neoplasms at every body site, separating well-differentiated neuroendocrine tumours (graded 1 to 3) from poorly differentiated neuroendocrine carcinomas, which became the basis of the WHO 2019 and 2022 classifications.","summary":"Expert consensus from the International Agency for Research on Cancer and WHO proposing that neuroendocrine neoplasms across organs be divided into well-differentiated neuroendocrine tumours graded 1 to 3 by proliferation and poorly differentiated small- and large-cell neuroendocrine carcinomas, with mixed neuroendocrine-non-neuroendocrine neoplasms as a third family.","asOf":"2026-09-17","links":[{"label":"Mod Pathol 2018","url":"https://doi.org/10.1038/s41379-018-0110-y"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30140036/"}],"tags":[],"related":[],"cancers":["extrapulmonary-nec","grade-3-net"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Modern Pathology","year":2018,"doi":"10.1038/s41379-018-0110-y","pmid":"30140036","authors":"Rindi G, Klimstra DS, Abedi-Ardekani B, et al.","paperType":"guideline","findings":[],"whatItMeans":"The grade 3 neuroendocrine tumour category, treated differently from neuroendocrine carcinoma, exists because of this framework.","caveats":["Lung neuroendocrine tumours retain older terminology (typical and atypical carcinoid) in the 2021 thoracic classification."],"changedPractice":true},{"id":"paper-pramesh-ncg-pooled-procurement-2023","kind":"paper","name":"A National Cancer Grid pooled procurement initiative, India","aka":[],"tldr":"When 23 Indian cancer centres bought 40 cancer drugs together instead of separately, prices fell by a median of 82%, saving about 13 billion rupees against list prices.","summary":"Report in the Bulletin of the World Health Organization of the National Cancer Grid's pooled procurement pilot: 40 anticancer drugs, pooled demand from 23 cancer centres worth about 15.6 billion Indian rupees (197 million dollars) at maximum retail price, and a negotiated cost reduction of about 13.2 billion rupees (166.7 million dollars). Savings ranged from 23% to 99% per drug (median 82%), larger for generics than for innovator or newly patented drugs, and were achieved through group negotiation of fixed prices and uniform contracts with standardised terms.","asOf":"2026-09-10","links":[{"label":"Bull WHO 2023","url":"https://doi.org/10.2471/BLT.23.289714"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["global-oncology-access"],"targets":[],"drugs":[],"companies":[],"institutions":["national-cancer-grid","tata-memorial"],"pathways":[],"terms":[],"trials":[],"people":["pramesh-c-s"],"bottlenecks":["b-drug-pricing","b-global-access"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Bulletin of the World Health Organization","year":2023,"doi":"10.2471/BLT.23.289714","authors":"Pramesh CS, Sengar M, Patankar S, et al.","paperType":"real-world","findings":["40 drugs, 23 centres, pooled demand of about 15.6 billion rupees at maximum retail price.","Cost reduction of about 13.2 billion rupees (166.7 million dollars).","Savings per drug 23% to 99%, median 82%; larger for generics than innovator drugs.","Mechanism: group negotiation, fixed prices, uniform contracts with standardised terms."],"whatItMeans":"Buying power, not new science, is the fastest lever on cancer drug prices in a decentralised, under-funded system. The Grid's model is being extended across its 360-plus centres and offers a template for other middle-income countries and for pooled buying of newer, patented drugs.","caveats":["Savings are measured against maximum retail price, which overstates the gain versus prices large centres already negotiated.","Innovator and patented drugs saw far smaller discounts; the model works best for generics.","Sustaining supply quality and adherence to contracts across many hospitals is an ongoing task."],"changedPractice":true},{"id":"paper-errani-wwtr1-camta1-ehe-gcc-2011","kind":"paper","name":"A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid haemangioendothelioma","aka":[],"tldr":"This study identified the WWTR1-CAMTA1 gene fusion in nearly every epithelioid haemangioendothelioma from any body site, giving this rare vascular tumour a defining molecular marker.","summary":"Molecular study identifying a t(1;3) translocation fusing WWTR1 (encoding TAZ) to CAMTA1 in epithelioid haemangioendothelioma of soft tissue, bone, liver and lung, present in almost all cases and absent from other vascular tumours.","asOf":"2026-09-17","links":[{"label":"Genes Chromosomes Cancer 2011","url":"https://doi.org/10.1002/gcc.20886"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21584898/"}],"tags":[],"related":[],"cancers":["epithelioid-haemangioendothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["genes-chromosomes-and-cancer"],"dependsOn":[],"notes":[],"journal":"Genes, chromosomes & cancer","year":2011,"doi":"10.1002/gcc.20886","pmid":"21584898","authors":"Errani C, Zhang L, Sung YS, et al.","paperType":"basic","findings":["WWTR1-CAMTA1 fusion in the vast majority of epithelioid haemangioendotheliomas across sites."],"whatItMeans":"CAMTA1 immunohistochemistry and fusion testing confirm the diagnosis, and the TAZ-CAMTA1 fusion protein's dependence on the Hippo pathway is guiding drug development.","caveats":["A minority of cases carry an alternative YAP1-TFE3 fusion."],"changedPractice":true},{"id":"paper-den-boer-bcr-abl1-like-all-lancet-oncol-2009","kind":"paper","name":"A subtype of childhood acute lymphoblastic leukaemia with poor outcome: genome-wide classification study (BCR-ABL1-like ALL)","aka":[],"tldr":"Gene expression profiling identified a group of childhood leukaemias that look like Philadelphia-positive disease without the fusion gene, later called Ph-like or BCR-ABL1-like ALL, with a high relapse rate and frequent IKZF1 deletions.","summary":"Genome-wide expression classification of 190 childhood B-ALL cases identifying a novel subtype in about 15 percent of B-other cases with a signature resembling BCR-ABL1-positive ALL, frequent IKZF1 deletions, and poor five-year disease-free survival (about 60 percent) validated in independent cohorts.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2009","url":"https://doi.org/10.1016/S1470-2045(08)70339-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19138562/"}],"tags":[],"related":[],"cancers":["all-ph-like"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2009,"doi":"10.1016/S1470-2045(08)70339-5","pmid":"19138562","authors":"Den Boer ML, van Slegtenhorst M, De Menezes RX, et al.","paperType":"translational","findings":["BCR-ABL1-like subtype in about 15 percent of B-other childhood ALL.","Five-year disease-free survival about 60 percent, similar to BCR-ABL1-positive ALL."],"whatItMeans":"This discovery, made simultaneously with the American Children's Oncology Group finding, created the Ph-like ALL category now screened for in high-risk protocols.","caveats":["Discovery study without kinase lesion characterisation, which came with later sequencing."],"changedPractice":true,"participants":190},{"id":"paper-a3961-intermediate-risk-neuroblastoma-baker-nejm-2010","kind":"paper","name":"A3961: outcome after reduced chemotherapy for intermediate-risk neuroblastoma","aka":[],"tldr":"Cutting chemotherapy to four or eight cycles based on tumour biology kept three-year survival above 96 percent in intermediate-risk neuroblastoma, showing these children could be safely treated with substantially less.","summary":"Children's Oncology Group prospective study of 479 children with intermediate-risk neuroblastoma treated with four cycles (favourable biology) or eight cycles (unfavourable biology) of carboplatin, etoposide, cyclophosphamide and doxorubicin, with surgery and no radiotherapy for most.\n\nThree-year event-free survival was 88 percent and overall survival 96 percent, similar to historical results with more intensive therapy, with excellent outcomes in the favourable biology group (96 percent overall survival).","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2010","url":"https://doi.org/10.1056/NEJMoa1001527"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20879880/"}],"tags":[],"related":[],"cancers":["neuroblastoma-intermediate-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa1001527","pmid":"20879880","authors":"Baker DL, Schmidt ML, Cohn SL, et al.","paperType":"observational","findings":["Three-year overall survival 96 percent; event-free survival 88 percent.","Four cycles sufficient for favourable biology."],"whatItMeans":"Biology-based reduction of chemotherapy is the standard for intermediate-risk neuroblastoma, and the successor trial ANBL0531 reduced it further.","caveats":["Non-randomised comparison with historical controls."],"changedPractice":true,"participants":479},{"id":"paper-aall0031-imatinib-ph-positive-all-schultz-jco-2009","kind":"paper","name":"AALL0031: imatinib with intensive chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukaemia in children","aka":[],"tldr":"Adding continuous imatinib to intensive chemotherapy more than doubled three-year event-free survival in childhood Philadelphia-positive leukaemia compared with historical controls and matched the results of transplant, changing the standard of care.","summary":"Children's Oncology Group study of 92 children with Ph-positive ALL treated with intensive chemotherapy plus imatinib for increasing durations across cohorts, with transplant for those with a sibling donor.\n\nThree-year event-free survival in the cohort with continuous imatinib was 80 percent, more than double the 35 percent of historical controls, and no worse than with sibling donor transplant; toxicity was not increased.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2009","url":"https://doi.org/10.1200/JCO.2008.21.2514"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19805687/"}],"tags":[],"related":[],"cancers":["all-paediatric-ph-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2009,"doi":"10.1200/JCO.2008.21.2514","pmid":"19805687","authors":"Schultz KR, Bowman WP, Aledo A, et al.","paperType":"observational","findings":["Three-year event-free survival 80 percent with continuous imatinib vs 35 percent in historical controls.","Chemotherapy plus imatinib comparable to sibling donor transplant."],"whatItMeans":"A tyrosine kinase inhibitor throughout chemotherapy is the standard for childhood Ph-positive ALL, and transplant in first remission is no longer routine.","caveats":["Non-randomised comparison with historical controls; small cohorts."],"changedPractice":true,"participants":92},{"id":"paper-aall0232-larsen-jco-2016","kind":"paper","name":"AALL0232: dexamethasone and high-dose methotrexate improve outcome in high-risk B-cell acute lymphoblastic leukaemia in children and young adults","aka":[],"tldr":"In high-risk childhood B-cell acute lymphoblastic leukaemia, high-dose methotrexate beat escalating-dose methotrexate, and dexamethasone beat prednisone in children under 10, defining the backbone still used in Children's Oncology Group trials.","summary":"Phase 3 factorial trial of 3,154 patients aged 1 to 30 with high-risk B-ALL randomised to dexamethasone or prednisone during induction and to high-dose methotrexate or Capizzi escalating methotrexate with asparaginase during interim maintenance.\n\nFive-year event-free survival was 79.6 percent with high-dose methotrexate against 75.2 percent with Capizzi methotrexate; dexamethasone improved event-free survival in patients under 10 (91.2 versus 83.2 percent) but increased osteonecrosis in older patients.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2016","url":"https://doi.org/10.1200/JCO.2015.62.4544"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27114587/"}],"tags":[],"related":[],"cancers":["all-paediatric-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["dexamethasone","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2016,"doi":"10.1200/JCO.2015.62.4544","pmid":"27114587","authors":"Larsen EC, Devidas M, Chen S, et al.","paperType":"rct","findings":["Five-year event-free survival 79.6 percent (high-dose methotrexate) vs 75.2 percent (Capizzi).","Dexamethasone benefit in patients under 10; more osteonecrosis in those 10 and over."],"whatItMeans":"High-dose methotrexate interim maintenance and age-adapted steroid choice are standard in high-risk paediatric B-ALL protocols.","caveats":["Large factorial design with interactions between the two randomisations."],"changedPractice":true,"participants":3154},{"id":"paper-aall0434-nelarabine-t-all-dunsmore-jco-2020","kind":"paper","name":"AALL0434: nelarabine in newly diagnosed T-cell acute lymphoblastic leukaemia in children and young adults","aka":[],"tldr":"Adding the T-cell-specific drug nelarabine to intensive chemotherapy improved disease-free survival in childhood T-cell acute lymphoblastic leukaemia and cut central nervous system relapses, in the largest T-ALL trial ever run.","summary":"Phase 3 trial of 1,895 patients with T-ALL of whom 1,562 were randomised in a factorial design to Capizzi or high-dose methotrexate and, for intermediate- and high-risk patients, to nelarabine or not.\n\nFive-year disease-free survival was 88.2 percent with nelarabine against 82.1 percent without, with fewer central nervous system relapses; Capizzi methotrexate was superior to high-dose methotrexate in this T-cell population, the opposite of B-ALL.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2020","url":"https://doi.org/10.1200/JCO.20.00256"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32813610/"}],"tags":[],"related":[],"cancers":["all-paediatric-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["nelarabine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["aall0434"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"doi":"10.1200/JCO.20.00256","pmid":"32813610","authors":"Dunsmore KP, Winter SS, Devidas M, et al.","paperType":"rct","findings":["Five-year disease-free survival 88.2 percent with nelarabine vs 82.1 percent without.","Overall five-year survival 90.2 percent for the whole T-ALL cohort."],"whatItMeans":"Nelarabine is part of standard therapy for intermediate- and high-risk childhood T-ALL, and Capizzi methotrexate is preferred in T-ALL.","caveats":["Neurotoxicity of nelarabine requires monitoring.","Cranial irradiation was still used for many patients; its omission was tested later."],"changedPractice":true,"participants":1562},{"id":"paper-aaml0531-gemtuzumab-gamis-jco-2014","kind":"paper","name":"AAML0531: gemtuzumab ozogamicin added to chemotherapy for children and adolescents with acute myeloid leukaemia","aka":[],"tldr":"Adding the CD33-targeted antibody-drug conjugate gemtuzumab ozogamicin to two courses of chemotherapy reduced relapses in childhood acute myeloid leukaemia, most clearly in the high-risk group, and it was later restored to the paediatric label.","summary":"Phase 3 trial of 1,022 children, adolescents and young adults with newly diagnosed AML randomised to standard chemotherapy with or without gemtuzumab ozogamicin in induction and intensification.\n\nEvent-free survival at three years was 53.1 versus 46.9 percent (hazard ratio 0.83) with relapse risk reduced from 41 to 33 percent; overall survival was not significantly different (69.4 versus 65.4 percent), and benefit was greatest in high-risk patients and those with high CD33 expression.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2014","url":"https://doi.org/10.1200/JCO.2014.55.3628"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25092781/"}],"tags":[],"related":[],"cancers":["aml-paediatric"],"sections":[],"technologies":[],"targets":[],"drugs":["gemtuzumab-ozogamicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["aaml0531"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2014,"doi":"10.1200/JCO.2014.55.3628","pmid":"25092781","authors":"Gamis AS, Alonzo TA, Meshinchi S, et al.","paperType":"rct","findings":["Three-year event-free survival 53.1 percent vs 46.9 percent; relapse risk 32.8 percent vs 41.3 percent.","Overall survival 69.4 percent vs 65.4 percent (not significant)."],"whatItMeans":"Gemtuzumab ozogamicin is part of standard induction for CD33-positive childhood AML in Children's Oncology Group protocols.","caveats":["Higher treatment-related mortality offset part of the relapse reduction.","Benefit depends on CD33 expression and splicing genotype."],"changedPractice":true,"participants":1022},{"id":"paper-aaml1031-sorafenib-flt3-pollard-jco-2022","kind":"paper","name":"AAML1031: sorafenib combined with chemotherapy for children with high allelic ratio FLT3-ITD acute myeloid leukaemia","aka":[],"tldr":"Adding the kinase inhibitor sorafenib to chemotherapy improved event-free survival in children with high allelic ratio FLT3-ITD acute myeloid leukaemia compared with matched historical controls, the first FLT3-targeted result in paediatric leukaemia.","summary":"Non-randomised cohort within the AAML1031 trial of 92 children with high allelic ratio FLT3-ITD AML treated with sorafenib during induction, consolidation and maintenance, compared with 76 concurrent and historical controls treated without sorafenib.\n\nThree-year event-free survival was 55.9 versus 31.9 percent and relapse risk lower with sorafenib; benefit was concentrated in patients who received it from the first induction course, and toxicity was mostly rash and hand-foot syndrome.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2022","url":"https://doi.org/10.1200/JCO.21.01612"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35349331/"}],"tags":[],"related":[],"cancers":["aml-paediatric"],"sections":[],"technologies":[],"targets":[],"drugs":["sorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2022,"doi":"10.1200/JCO.21.01612","pmid":"35349331","authors":"Pollard JA, Alonzo TA, Gerbing R, et al.","paperType":"observational","findings":["Three-year event-free survival 55.9 percent vs 31.9 percent.","Three-year relapse risk 22.8 percent vs 55.5 percent."],"whatItMeans":"FLT3 inhibitors are now incorporated into frontline paediatric AML therapy for FLT3-ITD, with gilteritinib being studied in the successor trial.","caveats":["Non-randomised comparison; sorafenib patients more often had haematopoietic stem cell transplant."],"changedPractice":true,"participants":92},{"id":"paper-aaronson-eortc-qlq-c30-jnci-1993","kind":"paper","name":"Aaronson 1993: the EORTC QLQ-C30 quality of life questionnaire","aka":[],"tldr":"The 30-question form that lets cancer trials measure how patients feel and function, tested first in lung cancer patients across 13 countries and now used in thousands of studies.","summary":"Aaronson and the EORTC Study Group on Quality of Life designed a core questionnaire for use in international cancer trials and tested it in 305 patients with non-resectable lung cancer in 13 countries before and during treatment. The QLQ-C30 covers five functioning scales (physical, role, cognitive, emotional and social), symptom scales for fatigue, pain and nausea and vomiting, single items for other common symptoms and financial impact, and a global health and quality of life scale. Its scales showed acceptable reliability, distinguished patients by performance status and weight loss, and changed with clinical status over time.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1093/jnci/85.5.365"},{"label":"EORTC Quality of Life Group","url":"https://qol.eortc.org/"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["quality-of-life","qol-pro"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":1993,"doi":"10.1093/jnci/85.5.365","authors":"Aaronson NK, Ahmedzai S, Bergman B, et al.","paperType":"methods","findings":["Field-tested in 305 lung cancer patients from 13 countries, before and during treatment.","Thirty items forming five functioning scales, three symptom scales, six single items and a global quality of life scale.","Scales were reliable, distinguished clinically distinct patient groups and responded to change in clinical status."],"whatItMeans":"The QLQ-C30 made patient-reported quality of life a standard trial endpoint and is the instrument behind many of the quality of life claims on drug labels and in health technology assessments. Cancer-specific modules were later added on top of the core questionnaire.","caveats":["Validated first in lung cancer; later modules extend it to other cancers.","Quality of life data in trials are often incomplete because sicker patients stop filling in forms."],"changedPractice":true},{"id":"paper-abc-02-gemcitabine-cisplatin-nejm-2010","kind":"paper","name":"ABC-02: cisplatin plus gemcitabine versus gemcitabine alone for biliary tract cancer","aka":[],"tldr":"Adding cisplatin to gemcitabine lengthened survival by more than three months in advanced bile duct and gallbladder cancer without extra serious toxicity, establishing the chemotherapy standard for the disease.","summary":"Phase 3 trial of 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder or ampullary cancer randomised to cisplatin plus gemcitabine or gemcitabine alone for up to 24 weeks.\n\nMedian overall survival was 11.7 versus 8.1 months (hazard ratio 0.64) and progression-free survival 8.0 versus 5.0 months, with similar rates of grade 3 to 4 adverse events.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2010","url":"https://doi.org/10.1056/NEJMoa0908721"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20375404/"}],"tags":[],"related":[],"cancers":["extrahepatic-cholangiocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","gemcitabine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["abc-02"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa0908721","pmid":"20375404","authors":"Valle J, Wasan H, Palmer DH, et al.","paperType":"rct","findings":["Median overall survival 11.7 vs 8.1 months; hazard ratio 0.64.","Median progression-free survival 8.0 vs 5.0 months."],"whatItMeans":"Gemcitabine-cisplatin is the backbone of first-line treatment for advanced biliary tract cancer, now combined with durvalumab or pembrolizumab.","caveats":["Treatment was capped at eight cycles.","Heterogeneous population across biliary sites."],"changedPractice":true,"participants":410},{"id":"paper-acns0331-michalski-jco-2021","kind":"paper","name":"ACNS0331: reduced-dose and reduced-volume radiotherapy with chemotherapy for average-risk medulloblastoma","aka":[],"tldr":"Reducing the radiotherapy boost to the tumour bed instead of the whole posterior fossa was safe in average-risk medulloblastoma, but lowering the craniospinal dose from 23.4 to 18 Gy in young children led to more relapses, so the standard dose was kept.","summary":"Children's Oncology Group phase 3 trial of 464 children with average-risk medulloblastoma randomised to involved-field (tumour bed) versus whole posterior fossa boost, and, for children aged 3 to 7, to low-dose (18 Gy) versus standard-dose (23.4 Gy) craniospinal irradiation.\n\nFive-year event-free survival was 82.5 percent with involved-field boost versus 80.5 percent with posterior fossa boost (non-inferior), but 71.4 percent with 18 Gy against 82.9 percent with 23.4 Gy craniospinal irradiation (inferior); WNT tumours did well regardless.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2021","url":"https://doi.org/10.1200/JCO.20.02730"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34110925/"}],"tags":[],"related":[],"cancers":["medulloblastoma-group-3-4","medulloblastoma-wnt"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["acns0331"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2021,"doi":"10.1200/JCO.20.02730","pmid":"34110925","authors":"Michalski JM, Janss AJ, Vezina LG, et al.","paperType":"rct","findings":["Involved-field boost non-inferior: five-year event-free survival 82.5 percent vs 80.5 percent.","18 Gy craniospinal irradiation inferior: 71.4 percent vs 82.9 percent."],"whatItMeans":"Tumour-bed boost is standard in average-risk medulloblastoma, while craniospinal dose reduction is reserved for the WNT-activated subgroup in trials.","caveats":["Molecular subgroup was determined retrospectively.","Neurocognitive outcomes were somewhat better with lower dose, highlighting the trade-off."],"changedPractice":true,"participants":464},{"id":"paper-acns0332-leary-jama-oncol-2021","kind":"paper","name":"ACNS0332: carboplatin during radiotherapy and isotretinoin maintenance in high-risk medulloblastoma","aka":[],"tldr":"Adding daily carboplatin during craniospinal radiotherapy improved event-free survival in children with high-risk group 3 medulloblastoma, but not in other subgroups, while isotretinoin maintenance did not help.","summary":"Children's Oncology Group phase 3 trial of 261 children with high-risk medulloblastoma randomised to 36 Gy craniospinal radiotherapy with or without daily carboplatin, and to maintenance isotretinoin or not (the isotretinoin randomisation was stopped early for futility).\n\nCarboplatin improved five-year event-free survival in group 3 tumours (73.2 versus 53.7 percent) but not overall or in group 4, and molecular subgroup was strongly prognostic.","asOf":"2026-09-17","links":[{"label":"JAMA Oncol 2021","url":"https://doi.org/10.1001/jamaoncol.2021.2224"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34292305/"}],"tags":[],"related":[],"cancers":["medulloblastoma-group-3-4"],"sections":[],"technologies":[],"targets":[],"drugs":["carboplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["acns0332"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2021,"doi":"10.1001/jamaoncol.2021.2224","pmid":"34292305","authors":"Leary SES, Packer RJ, Li Y, et al.","paperType":"rct","findings":["Group 3: five-year event-free survival 73.2 percent with carboplatin vs 53.7 percent without.","No benefit from isotretinoin maintenance."],"whatItMeans":"Carboplatin radiosensitisation is used for high-risk group 3 medulloblastoma, an example of subgroup-directed therapy.","caveats":["Subgroup analysis; overall effect of carboplatin was not significant."],"changedPractice":true,"participants":261},{"id":"paper-acns1123-germinoma-neuro-oncology-2022","kind":"paper","name":"ACNS1123: response-based reduced-dose whole-ventricular radiotherapy for localised germinoma","aka":[],"tldr":"In children with localised germinoma who responded completely to chemotherapy, lowering the whole-ventricular radiotherapy dose to 18 Gy kept cure rates above 90 percent, allowing less radiation to the developing brain.","summary":"Children's Oncology Group phase 2 trial of 137 patients with localised germinoma treated with carboplatin and etoposide induction; complete responders received reduced-dose whole-ventricular irradiation (18 Gy) with a 12 Gy boost, while partial responders received 24 Gy plus boost.\n\nThree-year progression-free survival was 94.5 percent in the reduced-dose group and overall survival 100 percent, with the trial meeting its goal of maintaining outcomes with less radiation.","asOf":"2026-09-17","links":[{"label":"Neuro Oncol 2022","url":"https://doi.org/10.1093/neuonc/noab270"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34850169/"}],"tags":[],"related":[],"cancers":["cns-germ-cell-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["neuro-oncology"],"dependsOn":[],"notes":[],"journal":"Neuro-Oncology","year":2022,"doi":"10.1093/neuonc/noab270","pmid":"34850169","authors":"Bartels U, Onar-Thomas A, Patel SK, et al.","paperType":"observational","findings":["Three-year progression-free survival 94.5 percent with 18 Gy whole-ventricular irradiation after complete response.","Overall survival 100 percent."],"whatItMeans":"Response-adapted, reduced-dose whole-ventricular radiotherapy after chemotherapy is now a standard for localised germinoma in North American protocols.","caveats":["Single-arm trial; late neurocognitive outcomes are still being followed.","The non-germinomatous stratum of the same trial had a different, less favourable result."],"changedPractice":true,"participants":137},{"id":"paper-ito-kuma-active-surveillance-microcarcinoma-thyroid-2014","kind":"paper","name":"Active surveillance of papillary thyroid microcarcinoma at Kuma Hospital: patient age and progression","aka":[],"tldr":"Following more than 1,200 patients with small papillary thyroid cancers under observation, the Kuma Hospital group found that only 8 percent grew and under 4 percent developed node metastases over ten years, with the lowest risk in older patients, establishing surveillance as a safe alternative to surgery.","summary":"Prospective observational cohort of 1,235 patients with low-risk papillary thyroid microcarcinoma managed by active surveillance between 1993 and 2011, analysing tumour enlargement and nodal metastasis by age.\n\nTen-year rates of tumour enlargement of 3 mm or more and of new node metastases were 8.0 and 3.8 percent; progression was most frequent in patients under 40 and rarest in those over 60, and no patient died of thyroid cancer or developed distant metastases.","asOf":"2026-09-17","links":[{"label":"Thyroid 2014","url":"https://doi.org/10.1089/thy.2013.0367"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24001104/"}],"tags":[],"related":[],"cancers":["papillary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Thyroid","year":2014,"doi":"10.1089/thy.2013.0367","pmid":"24001104","authors":"Ito Y, Miyauchi A, Kihara M, et al.","paperType":"observational","findings":["Ten-year tumour enlargement 8.0 percent; nodal metastasis 3.8 percent.","Progression more frequent under 40 (about 22 percent at ten years) than over 60 (about 3 percent)."],"whatItMeans":"Active surveillance is a guideline-endorsed option for papillary microcarcinoma, adopted in Japan, the United States and elsewhere, especially for older patients.","caveats":["Single-centre Japanese cohort with expert ultrasound; selection excluded tumours near the trachea or nerve."],"changedPractice":true,"participants":1235},{"id":"paper-sirolimus-ehe-stacchiotti-cancer-2021","kind":"paper","name":"Activity of sirolimus in progressive epithelioid haemangioendothelioma (Italian Rare Cancer Network)","aka":[],"tldr":"In patients with progressing epithelioid haemangioendothelioma, the mTOR inhibitor sirolimus stabilised the disease in most, with a median progression-free survival of about a year, but did not help patients who had developed serosal effusions.","summary":"Retrospective case series of 38 patients with progressive epithelioid haemangioendothelioma treated with sirolimus within the Italian Rare Cancer Network.\n\nBest response was partial response in 11 percent and stable disease in 71 percent, with median progression-free survival of 13 months and median overall survival of 19 months in patients with serosal effusions against not reached in those without.","asOf":"2026-09-17","links":[{"label":"Cancer 2021","url":"https://doi.org/10.1002/cncr.33247"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33107985/"}],"tags":[],"related":[],"cancers":["epithelioid-haemangioendothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-wiley"],"dependsOn":[],"notes":[],"journal":"Cancer","year":2021,"doi":"10.1002/cncr.33247","pmid":"33107985","authors":"Stacchiotti S, Simeone N, Lo Vullo S, et al.","paperType":"observational","findings":["Partial response 11 percent; stable disease 71 percent; median progression-free survival 13 months.","Poor outcome with serosal effusions."],"whatItMeans":"Sirolimus is the first-choice systemic therapy for progressing EHE, ideally started before pleural or peritoneal effusions develop.","caveats":["Retrospective series without a comparator."],"changedPractice":true,"participants":38},{"id":"paper-hunger-mullighan-all-children-nejm-2015","kind":"paper","name":"Acute lymphoblastic leukaemia in children (review)","aka":[],"tldr":"This review summarises how childhood acute lymphoblastic leukaemia became curable in nine of ten children through risk-adapted chemotherapy, and how genomic subtypes such as Ph-like and infant leukaemia are shaping the next generation of targeted treatment.","summary":"Review of the epidemiology, genomic classification (including Ph-like ALL, IKZF1 alterations, KMT2A rearrangements, hypodiploidy), risk stratification by measurable residual disease, treatment phases, outcomes approaching 90 percent survival, late effects, relapse and emerging immunotherapies for childhood ALL.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2015","url":"https://doi.org/10.1056/NEJMra1400972"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26465987/"}],"tags":[],"related":[],"cancers":["all-paediatric-high-risk","all-ph-like","all-infant"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMra1400972","pmid":"26465987","authors":"Hunger SP, Mullighan CG.","paperType":"review","findings":[],"whatItMeans":"The structure of the paediatric ALL subtype pages, from risk groups to new targeted and immune therapies, follows the framework in this review.","caveats":["Predates blinatumomab and CAR-T results in frontline therapy."],"changedPractice":false},{"id":"paper-adaura-nejm-2020","kind":"paper","name":"ADAURA: three years of osimertinib after surgery for EGFR-mutated lung cancer","aka":[],"tldr":"After surgery for early-stage EGFR-mutated lung cancer, three years of osimertinib cut recurrences by about 80% and later reduced deaths by half.","summary":"Double-blind, placebo-controlled phase 3 trial of 682 patients with completely resected stage IB-IIIA EGFR-mutated NSCLC, with or without adjuvant chemotherapy, randomised to three years of osimertinib or placebo. Primary endpoint was disease-free survival in stage II-IIIA.\n\nThe trial was unblinded early: DFS HR 0.17 in stage II-IIIA and 0.20 overall, with 24-month DFS 89% vs 52%. The 2023 overall survival report showed 5-year OS 88% vs 78% (HR 0.49). It made adjuvant osimertinib standard and established EGFR testing of resected tumours.","asOf":"2026-09-08","links":[{"label":"NEJM 2020","url":"https://doi.org/10.1056/NEJMoa2027071"},{"label":"ClinicalTrials.gov NCT02511106","url":"https://clinicaltrials.gov/study/NCT02511106"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["egfr"],"drugs":["osimertinib"],"companies":["astrazeneca"],"institutions":[],"pathways":[],"terms":["neoadjuvant-adjuvant","oncogene-addiction","mrd"],"trials":["adaura"],"people":["wu-yi-long","he-jie","lu-shun"],"bottlenecks":["b-dormancy-mrd","b-drug-pricing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2027071","authors":"Wu YL, Tsuboi M, He J, et al.","paperType":"rct","findings":["Stage II-IIIA: 24-month disease-free survival 90% vs 44%; HR 0.17 (99.06% CI 0.11-0.26).","Overall population (IB-IIIA): 24-month DFS 89% vs 52%; HR 0.20.","CNS recurrence or death HR 0.18.","Overall survival (2023): 5-year OS 88% vs 78% overall, HR 0.49; stage II-IIIA 85% vs 73%.","Benefit was seen with or without prior adjuvant chemotherapy."],"whatItMeans":"Every resected non-squamous lung cancer should be tested for EGFR mutations, because patients who carry one live longer if they take osimertinib for three years after surgery. The trial does not tell us whether adjuvant chemotherapy can be omitted, nor what happens on relapse after osimertinib, and the three-year duration was chosen empirically.","caveats":["Early unblinding after a dramatic DFS effect meant the trial was stopped before the planned analysis.","Recurrences resumed after osimertinib stopped, raising the question of whether it delays rather than prevents relapse in some patients; OS benefit argues it does more than delay.","Optimal duration (three years vs indefinite) is untested.","Cost of three years of therapy is very high."],"changedPractice":true,"participants":682},{"id":"paper-lian-adjuvant-temozolomide-cisplatin-mucosal-melanoma-ccr-2013","kind":"paper","name":"Adjuvant temozolomide plus cisplatin versus high-dose interferon versus observation in resected mucosal melanoma","aka":[],"tldr":"In this Chinese randomised trial, chemotherapy with temozolomide and cisplatin after surgery for mucosal melanoma lengthened relapse-free and overall survival compared with interferon or observation, the only positive adjuvant trial specific to mucosal disease.","summary":"Phase 2 randomised trial of 189 patients with resected mucosal melanoma assigned to observation, high-dose interferon alfa-2b for one year, or six cycles of temozolomide plus cisplatin.\n\nMedian relapse-free survival was 5.4 months with observation, 9.4 months with interferon and 20.8 months with chemotherapy, and median overall survival 21.2, 40.4 and 48.7 months respectively.","asOf":"2026-09-17","links":[{"label":"Clin Cancer Res 2013","url":"https://doi.org/10.1158/1078-0432.CCR-13-0739"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23833309/"}],"tags":[],"related":[],"cancers":["mucosal-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2013,"doi":"10.1158/1078-0432.CCR-13-0739","pmid":"23833309","authors":"Lian B, Si L, Cui C, et al.","paperType":"rct","findings":["Median relapse-free survival 20.8 months (chemotherapy) vs 9.4 (interferon) vs 5.4 (observation).","Median overall survival 48.7 vs 40.4 vs 21.2 months."],"whatItMeans":"Adjuvant temozolomide-cisplatin is used in China for resected mucosal melanoma; elsewhere anti-PD-1 therapy is extrapolated from cutaneous disease, and the two have since been compared directly.","caveats":["Single-country phase 2 trial in a largely Asian population.","Predates adjuvant immunotherapy."],"changedPractice":true,"participants":189},{"id":"paper-admiral-gilteritinib-flt3-nejm-2019","kind":"paper","name":"ADMIRAL: gilteritinib pills versus chemotherapy for relapsed FLT3-mutated acute myeloid leukaemia","aka":[],"tldr":"An oral FLT3 inhibitor extended survival compared with salvage chemotherapy in relapsed AML with a FLT3 mutation, doubling the remission rate.","summary":"ADMIRAL randomised 371 adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to gilteritinib 120 mg daily or investigator-chosen salvage chemotherapy (high- or low-intensity). Primary endpoints were overall survival and the rate of complete remission or remission with partial haematological recovery. Median OS was 9.3 versus 5.6 months (hazard ratio 0.64) and one-year survival 37.1% versus 16.7%; CR/CRh was 34.0% versus 15.3%. More patients on gilteritinib proceeded to transplant, and toxicity was lower than with chemotherapy. It established single-agent targeted therapy as a standard in relapsed FLT3-mutated AML.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1902688"},{"label":"ClinicalTrials.gov NCT02421939","url":"https://clinicaltrials.gov/study/NCT02421939"}],"tags":[],"related":["paper-quantum-first-quizartinib-lancet-2023"],"cancers":["aml"],"sections":[],"technologies":["allogeneic-hsct"],"targets":["flt3"],"drugs":["gilteritinib","midostaurin","quizartinib"],"companies":["astellas"],"institutions":[],"pathways":[],"terms":["os"],"trials":["admiral"],"people":[],"bottlenecks":["b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1902688","authors":"Perl AE, Martinelli G, Cortes JE, et al.","paperType":"rct","findings":["371 patients with relapsed/refractory FLT3-mutated AML; gilteritinib vs salvage chemotherapy (2:1).","Median OS 9.3 vs 5.6 months; hazard ratio 0.64.","1-year overall survival 37.1% vs 16.7%.","CR/CRh 34.0% vs 15.3%; complete remission 21.1% vs 10.5%.","Fewer grade 3 or higher adverse events per exposure-adjusted analysis with gilteritinib."],"whatItMeans":"ADMIRAL showed that a targeted oral drug can beat chemotherapy outright in relapsed AML, and made gilteritinib the standard bridge to transplant for FLT3-mutated relapse. Its success also underpinned FLT3 inhibitor use in first-line combinations. Resistance through FLT3-independent clones and RAS pathway mutations limits durability without transplant.","caveats":["Modest absolute survival gain; most patients not transplanted eventually relapsed.","Open-label with heterogeneous chemotherapy comparators.","Excluded patients previously treated with certain FLT3 inhibitors; prior midostaurin exposure was uncommon.","Differentiation syndrome and QT prolongation require monitoring."],"changedPractice":true,"participants":371},{"id":"paper-adriatic-nejm-2024","kind":"paper","name":"ADRIATIC: durvalumab after chemoradiotherapy for limited-stage small-cell lung cancer","aka":[],"tldr":"For small-cell lung cancer confined to the chest, adding two years of durvalumab after chemoradiotherapy extended median survival from under three years to over four and a half, the first advance in this setting in decades.","summary":"Double-blind, placebo-controlled phase 3 trial of 730 patients with limited-stage small-cell lung cancer who had not progressed after concurrent platinum-etoposide chemoradiotherapy, randomised to durvalumab, durvalumab plus tremelimumab, or placebo for up to 24 months. Primary endpoints were overall survival and PFS for durvalumab versus placebo.\n\nMedian overall survival was 55.9 vs 33.4 months (HR 0.73) and median PFS 16.6 vs 9.2 months (HR 0.76). It applied the PACIFIC consolidation model to small-cell lung cancer and became the new standard for limited-stage disease.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2404873"},{"label":"ClinicalTrials.gov NCT03703297","url":"https://clinicaltrials.gov/study/NCT03703297"}],"tags":[],"related":[],"cancers":["sclc"],"sections":[],"technologies":["checkpoint-inhibitor","imrt-igrt","platinum"],"targets":["pdl1"],"drugs":["durvalumab"],"companies":["astrazeneca"],"institutions":[],"pathways":[],"terms":["os","pfs","standard-of-care"],"trials":[],"people":["cho-byoung-chul"],"bottlenecks":["b-immunotherapy-response","b-surgery-radiation-innovation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2404873","authors":"Cheng Y, Spigel DR, Cho BC, et al.","paperType":"rct","findings":["Median overall survival 55.9 vs 33.4 months; HR 0.73 (98.321% CI 0.54-0.98); 36-month OS 56.5% vs 47.6%.","Median PFS 16.6 vs 9.2 months; HR 0.76; 24-month PFS 46.2% vs 34.2%.","Grade 3-4 adverse events 24.4% vs 24.2%; pneumonitis or radiation pneumonitis of any grade 38.2% vs 30.2%.","Benefit was consistent regardless of whether prophylactic cranial irradiation had been given."],"whatItMeans":"Patients with limited-stage small-cell lung cancer who complete chemoradiotherapy without progression should now be offered up to two years of durvalumab consolidation, which extends life by almost two years on average. This is the first survival improvement for limited-stage disease since twice-daily radiotherapy and prophylactic cranial irradiation, and small-cell lung cancer is no longer a disease where immunotherapy gives only marginal gains.","caveats":["The durvalumab plus tremelimumab arm has not shown clear additional benefit and its role is unclear.","Radiotherapy schedules varied (once or twice daily) and prophylactic cranial irradiation was optional, adding heterogeneity.","Only patients without progression after chemoradiotherapy were eligible, as in PACIFIC.","No biomarker predicts benefit; PD-L1 is not useful in small-cell lung cancer."],"changedPractice":true,"participants":730},{"id":"paper-agile-ivosidenib-azacitidine-nejm-2022","kind":"paper","name":"AGILE: ivosidenib plus azacitidine for newly diagnosed IDH1-mutated AML in patients unfit for intensive chemotherapy","aka":[],"tldr":"Adding the IDH1 inhibitor ivosidenib to azacitidine tripled median survival, from 7.9 to 24 months, in older patients with IDH1-mutated AML.","summary":"AGILE randomised 146 patients with newly diagnosed IDH1-mutated AML who were ineligible for intensive induction to ivosidenib plus azacitidine or placebo plus azacitidine. The primary endpoint was event-free survival. EFS favoured ivosidenib (hazard ratio 0.33), complete remission was 47% versus 15%, and median overall survival was 24.0 versus 7.9 months (hazard ratio 0.44). Differentiation syndrome occurred in 14% of ivosidenib patients; febrile neutropenia and infections were less frequent than with azacitidine alone, partly because of faster count recovery. The result established a mutation-directed doublet for this subgroup.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2117344"},{"label":"ClinicalTrials.gov NCT03173248","url":"https://clinicaltrials.gov/study/NCT03173248"}],"tags":[],"related":["paper-viale-a-venetoclax-azacitidine-nejm-2020"],"cancers":["aml"],"sections":[],"technologies":[],"targets":[],"drugs":["ivosidenib","azacitidine","venetoclax"],"companies":["servier"],"institutions":[],"pathways":[],"terms":["efs","os"],"trials":["agile"],"people":[],"bottlenecks":["b-rare-cancers","b-trial-enrolment"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2117344","authors":"Montesinos P, Recher C, Vives S, et al.","paperType":"rct","findings":["146 patients with untreated IDH1-mutated AML unfit for intensive chemotherapy; ivosidenib + azacitidine vs placebo + azacitidine.","Event-free survival hazard ratio 0.33.","Complete remission 47% vs 15%.","Median OS 24.0 vs 7.9 months; hazard ratio 0.44.","Differentiation syndrome 14%; fewer infections and febrile neutropenia than the control arm."],"whatItMeans":"AGILE showed that for the roughly 6-10% of AML patients with an IDH1 mutation, a targeted doublet produces survival in the range of two years, an outcome previously unimaginable in unfit patients. Ivosidenib-azacitidine is approved and is one option alongside venetoclax-azacitidine for these patients. Which regimen, or triplet, is best for IDH1-mutated disease has not been settled by a randomised trial.","caveats":["Small trial that stopped enrolment early; wide confidence intervals.","Enrolled before venetoclax-azacitidine became standard, so the comparator is azacitidine alone.","Restricted to IDH1; IDH2-mutated AML is treated with enasidenib or venetoclax-based regimens.","Differentiation syndrome needs prompt recognition."],"changedPractice":true,"participants":146},{"id":"paper-al-hajj-breast-cancer-stem-cells-pnas-2003","kind":"paper","name":"Al-Hajj 2003: prospective identification of tumorigenic breast cancer cells","aka":[],"tldr":"The first demonstration in a solid tumour that only a small, marker-defined fraction of breast cancer cells can regrow the cancer: a few hundred cells with one surface profile formed tumours in mice while tens of thousands of the other cells did not.","summary":"Al-Hajj, Wicha, Clarke and colleagues separated cells from human breast cancers, mostly metastatic fluid collections and one primary tumour, by surface markers and injected them into immunodeficient mice. Cells that were CD44-positive and CD24-negative or low, and lacked lineage markers, formed tumours from as few as 100 cells in eight of nine patients' samples, whereas tens of thousands of cells with other profiles did not. The resulting tumours reproduced the mixture of cell types of the original cancer and could be passaged serially, the defining behaviour of a cancer stem cell.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1073/pnas.0530291100"}],"tags":[],"related":["paper-reya-cancer-stem-cells-nature-2001"],"cancers":["breast-hr-positive","breast-her2-positive","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["michigan-rogel"],"pathways":[],"terms":["stem-cell","relapse-recurrence"],"trials":[],"people":["max-wicha"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Proceedings of the National Academy of Sciences","year":2003,"doi":"10.1073/pnas.0530291100","authors":"Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF.","paperType":"basic","findings":["Tumorigenic cells from human breast cancers were enriched in the CD44-positive, CD24-negative or low, lineage-negative fraction.","As few as 100 such cells formed tumours in NOD/SCID mice; tens of thousands of cells with other marker profiles did not.","Tumours from the sorted cells reproduced the original tumour's heterogeneity and could be passaged repeatedly."],"whatItMeans":"This paper extended the cancer stem cell concept from leukaemia to a common solid tumour and started the search for tumour-initiating cells across cancers. It underpins research on why cancers relapse after treatments that shrink them and on therapies aimed at the cells that regrow disease.","caveats":["Samples were mostly metastatic effusions rather than primary tumours.","Transplantation into mice measures what survives the assay and may not reflect behaviour in patients.","The markers are not universal across breast cancer subtypes."],"changedPractice":false},{"id":"paper-alcanza-brentuximab-vedotin-lancet-2017","kind":"paper","name":"ALCANZA: brentuximab vedotin versus physician's choice in CD30-positive cutaneous T-cell lymphoma","aka":[],"tldr":"In CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, the antibody-drug conjugate brentuximab vedotin produced lasting responses in more than half of patients, far more than methotrexate or bexarotene.","summary":"Phase 3 trial of 131 patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large cell lymphoma previously treated with systemic therapy, randomised to brentuximab vedotin or physician's choice of methotrexate or bexarotene.\n\nObjective response lasting at least four months was 56.3 versus 12.5 percent, median progression-free survival 16.7 versus 3.5 months, and peripheral neuropathy occurred in two thirds of brentuximab patients.","asOf":"2026-09-17","links":[{"label":"Lancet 2017","url":"https://doi.org/10.1016/S0140-6736(17)31266-7"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28600132/"}],"tags":[],"related":[],"cancers":["cutaneous-t-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["brentuximab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["alcanza"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2017,"doi":"10.1016/S0140-6736(17)31266-7","pmid":"28600132","authors":"Prince HM, Kim YH, Horwitz SM, et al.","paperType":"rct","findings":["Objective response lasting four months or more: 56.3 percent vs 12.5 percent.","Median progression-free survival 16.7 vs 3.5 months."],"whatItMeans":"Brentuximab vedotin is a standard for CD30-positive cutaneous T-cell lymphoma requiring systemic therapy, including large cell transformation.","caveats":["Peripheral neuropathy in 67 percent, mostly reversible.","CD30 expression threshold for benefit is low and variable."],"changedPractice":true,"participants":131},{"id":"paper-alcohol-cancer-burden-lancet-oncol-2021","kind":"paper","name":"Alcohol caused an estimated 741,000 cancers worldwide in 2020","aka":[],"tldr":"Building on the IARC classification of alcohol as a Group 1 carcinogen, this global modelling study attributed 4.1% of all new cancers in 2020 to drinking, three-quarters of them in men and the largest numbers in oesophageal, liver and breast cancer.","summary":"IARC Monographs volumes 44, 96 and 100E established alcoholic beverages, and the acetaldehyde derived from them, as Group 1 carcinogens with sufficient evidence for cancers of the oral cavity, pharynx, larynx, oesophagus (squamous), liver, colorectum and female breast. Rumgay and colleagues combined per-capita alcohol consumption estimates (with a 10-year lag) and relative risks from meta-analyses with GLOBOCAN 2020 incidence to estimate the attributable burden by country, sex and site.\n\nAn estimated 741,300 new cancers (4.1% of all cases) were attributable to alcohol in 2020; 76.7% were in men. Oesophageal (189,700), liver (154,700) and breast (98,300) cancers had the largest numbers. Heavy drinking accounted for most of the burden, but moderate drinking (up to two drinks a day) contributed around 100,000 cases.\n\nThe paper drove policy interest in alcohol labelling and pricing, and the 2023 WHO and 2025 US Surgeon General statements on alcohol and cancer.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S1470-2045(21)00279-5"},{"label":"IARC Monographs Volume 100E","url":"https://publications.iarc.who.int/122"}],"tags":[],"related":["idea-prev-alcohol-cancer-warning-labels","idea-prev-pharmacy-prevention-hub"],"cancers":["esophageal","hcc","breast-hr-positive","colorectal","head-and-neck"],"sections":["prevention"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-misinformation","b-incentive-misalignment"],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00279-5","pmid":"34270924","authors":"Rumgay H, Shield K, Charvat H, et al.","paperType":"observational","findings":["741,300 alcohol-attributable new cancers globally in 2020 (95% uncertainty interval 558,500-951,200), 4.1% of all cancers","76.7% of attributable cases were in men","Largest contributions: oesophagus 189,700; liver 154,700; female breast 98,300","Moderate drinking (less than 20 g/day) accounted for an estimated 103,100 cases (13.9% of the alcohol burden)"],"whatItMeans":"There is no safe level of alcohol for cancer risk, and the risk is highest for cancers of the mouth, throat, oesophagus, liver, bowel and breast. Public awareness is low; most people do not know alcohol causes breast cancer. Warning labels and minimum pricing are the policy levers being debated.","caveats":["Modelled estimates depend on consumption data of uneven quality and on relative risks from observational meta-analyses","Unrecorded alcohol consumption is poorly captured in many countries","Does not account for former drinkers or interactions with smoking","Population-level estimates say nothing about individual risk trajectories"],"changedPractice":false},{"id":"paper-allemani-concord-3-lancet-2018","kind":"paper","name":"Allemani 2018: CONCORD-3, global surveillance of cancer survival 2000 to 2014","aka":[],"tldr":"The largest comparison of cancer survival between countries, covering 37.5 million patients in 71 countries, found survival rising for most cancers but with very wide gaps between countries, especially for children's cancers and cancers that depend on early diagnosis and good treatment access.","summary":"CONCORD-3 analysed individual records for 37.5 million patients diagnosed with one of 18 cancers between 2000 and 2014, supplied by 322 population-based registries in 71 countries and territories, and estimated five-year net survival by country and period. Survival was rising for most cancers in most countries, including steep rises for liver and lung cancers in some countries, but international differences remained very wide. The paper documented, for example, breast cancer survival in the high 80s and 90s of percent in Australia and the United States against the mid-60s in India, and childhood brain tumour survival ranging from under 40% to over 80%.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/S0140-6736(17)33326-3"},{"label":"CONCORD programme","url":"https://csg.lshtm.ac.uk/research/themes/concord-programme/"}],"tags":[],"related":["paper-bray-globocan-2018-cacancer-2018"],"cancers":["breast-hr-positive","colorectal","nsclc","hcc","pancreatic"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["prognosis","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2018,"doi":"10.1016/S0140-6736(17)33326-3","authors":"Allemani C, Matsuda T, Di Carlo V, et al.","paperType":"observational","findings":["37.5 million patient records for 18 cancers from 322 registries in 71 countries, diagnosed 2000 to 2014.","Five-year net survival increased for most cancers in most countries over the period.","Five-year breast cancer survival about 90% in the United States and Australia versus about 66% in India; childhood brain tumour survival ranged from under 40% to over 80% between countries.","Survival for oesophageal, liver, lung and pancreatic cancers remained low almost everywhere."],"whatItMeans":"CONCORD is the evidence base for national cancer plans and for the statement that where you live changes your chance of surviving cancer. Its country tables are the benchmark health systems use to judge early diagnosis and treatment access.","caveats":["Registry coverage and data quality vary widely; some countries contributed only regional registries.","Net survival compares against general population mortality and is affected by screening-detected, slow-growing cancers."],"changedPractice":false},{"id":"paper-alliance-n0574-brown-jama-2016","kind":"paper","name":"Alliance N0574: radiosurgery alone versus radiosurgery plus whole-brain radiotherapy for one to three brain metastases","aka":[],"tldr":"Adding whole-brain radiotherapy to focused radiosurgery for a few brain metastases caused more memory and thinking problems without lengthening life, so radiosurgery alone became standard for limited brain metastases.","summary":"Phase 3 trial of 213 patients with one to three brain metastases randomised to stereotactic radiosurgery alone or radiosurgery plus whole-brain radiotherapy, with cognitive decline at three months as the primary endpoint.\n\nCognitive deterioration was more frequent with whole-brain radiotherapy (91.7 versus 63.5 percent) despite better intracranial control, and median overall survival did not differ (10.4 versus 7.4 months, not significant).","asOf":"2026-09-17","links":[{"label":"JAMA 2016","url":"https://doi.org/10.1001/jama.2016.9839"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27458945/"}],"tags":[],"related":[],"cancers":["secondary-brain-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["alliance-n0574"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2016,"doi":"10.1001/jama.2016.9839","pmid":"27458945","authors":"Brown PD, Jaeckle K, Ballman KV, et al.","paperType":"rct","findings":["Cognitive deterioration at three months 91.7 percent vs 63.5 percent.","Intracranial control at one year better with whole-brain radiotherapy (85 vs 51 percent) without a survival difference."],"whatItMeans":"Patients with a limited number of brain metastases are treated with radiosurgery alone and surveillance, accepting more new brain lesions in return for preserved cognition.","caveats":["Cognitive testing only assessed to three months in the primary endpoint.","Modern hippocampal-avoidance whole-brain radiotherapy was not used."],"changedPractice":true,"participants":213},{"id":"paper-alphafold2-jumper-nature-2021","kind":"paper","name":"AlphaFold 2: predicting protein structures to near-experimental accuracy","aka":[],"tldr":"DeepMind's neural network predicted protein structures at CASP14 with a median backbone error of under 1 angstrom, comparable to experimental methods, and the team released predicted structures for essentially every human protein within a year.","summary":"AlphaFold 2 combines multiple-sequence alignments, an attention-based Evoformer network and an equivariant structure module trained end to end on the Protein Data Bank. At the blind CASP14 assessment in 2020 it achieved a median GDT of about 92 and a median backbone RMSD95 of 0.96 angstrom on the hardest targets, versus 2.8 angstrom for the next-best method.\n\nThe model provides per-residue confidence estimates (pLDDT), enabling users to distinguish reliable regions from disordered or uncertain ones. The accompanying AlphaFold Protein Structure Database, built with EMBL-EBI, released predicted structures for the human proteome and later for more than 200 million proteins.\n\nFor cancer drug discovery, AlphaFold accelerated structure-based design for targets without crystal structures and, with AlphaFold 3 (2024) extending to protein-ligand and protein-nucleic acid complexes, is now a routine part of the target-to-lead pipeline.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1038/s41586-021-03819-2"},{"label":"AlphaFold Protein Structure Database","url":"https://alphafold.ebi.ac.uk"}],"tags":[],"related":["alphafold3","de-novo-protein-design","idea-multimodal-foundation-model"],"cancers":[],"sections":["drug-discovery","ai-computation"],"technologies":["ai-drug-design","structural-biology-infrastructure"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-translational-valley","b-ai-validation"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2021,"doi":"10.1038/s41586-021-03819-2","pmid":"34265844","authors":"Jumper J, Evans R, Pritzel A, et al.","paperType":"methods","findings":["CASP14: median backbone RMSD95 of 0.96 angstrom (95% CI 0.85-1.16) vs 2.8 angstrom for the next-best method","Median GDT score around 92 across CASP14 targets, the first time a computational method reached experimental-grade accuracy","Per-residue confidence (pLDDT) reliably flags disordered and low-confidence regions","Predicted structures for the entire human proteome released in 2021; over 200 million proteins by 2022"],"whatItMeans":"The shape of nearly every protein is now available to any researcher in seconds instead of years, which shortens the path from a cancer target to a designed molecule. It does not by itself produce drugs: binding pockets, dynamics and cellular context still need experiment.","caveats":["Predicts single static conformations; many drug targets (kinases, GPCRs, KRAS) move between states","Accuracy is lower for proteins without evolutionary homologues, disordered regions and multi-protein complexes","Does not predict effects of point mutations or ligand binding (AlphaFold 3 and other tools partly address this)","The 2021 model was released with a non-commercial licence for weights, later loosened"],"changedPractice":false},{"id":"paper-alsympca-radium-223-nejm-2013","kind":"paper","name":"ALSYMPCA: alpha emitter radium-223 and survival in metastatic prostate cancer with bone metastases","aka":[],"tldr":"Radium-223, an injected alpha-emitting radioisotope that homes to bone, lengthened survival and delayed skeletal complications in men with castration-resistant prostate cancer that had spread to bone but not to organs.","summary":"Phase 3 placebo-controlled trial of 921 men with castration-resistant prostate cancer, symptomatic bone metastases and no visceral disease, randomised 2:1 to six injections of radium-223 or placebo with best standard of care.\n\nMedian overall survival was 14.9 versus 11.3 months (hazard ratio 0.70), time to first symptomatic skeletal event was delayed (15.6 versus 9.8 months) and myelosuppression was mild.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2013","url":"https://doi.org/10.1056/NEJMoa1213755"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23863050/"}],"tags":[],"related":[],"cancers":["prostate-mcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["alsympca"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2013,"doi":"10.1056/NEJMoa1213755","pmid":"23863050","authors":"Parker C, Nilsson S, Heinrich D, et al.","paperType":"rct","findings":["Median overall survival 14.9 vs 11.3 months; hazard ratio 0.70.","Time to first symptomatic skeletal event 15.6 vs 9.8 months."],"whatItMeans":"Radium-223 is an option for symptomatic bone-predominant castration-resistant prostate cancer, now less used since lutetium-PSMA, and should not be combined with abiraterone after the ERA 223 fracture signal.","caveats":["No effect on PSA or soft tissue disease.","Combination with abiraterone increased fractures and deaths in ERA 223."],"changedPractice":true,"participants":921},{"id":"paper-ampect-nab-sirolimus-pecoma-wagner-jco-2021","kind":"paper","name":"AMPECT: nab-sirolimus for malignant perivascular epithelioid cell tumours","aka":[],"tldr":"Albumin-bound sirolimus shrank tumours in about four in ten patients with malignant PEComa, with responses lasting years and best results in tumours with TSC2 mutations, and became the first approved treatment for the disease.","summary":"Phase 2 study of 34 patients with malignant PEComa treated with intravenous nab-sirolimus weekly for two of every three weeks.\n\nObjective response by independent review was 39 percent with a median duration of response not reached (over 2.5 years), median progression-free survival 10.6 months; 89 percent of TSC2-mutant tumours responded. Stomatitis, myelosuppression and hyperglycaemia were manageable.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2021","url":"https://doi.org/10.1200/JCO.21.01728"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34637337/"}],"tags":[],"related":[],"cancers":["pecoma"],"sections":[],"technologies":[],"targets":[],"drugs":["sirolimus-albumin-bound"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ampect"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2021,"doi":"10.1200/JCO.21.01728","pmid":"34637337","authors":"Wagner AJ, Ravi V, Riedel RF, et al.","paperType":"observational","findings":["Objective response 39 percent; 89 percent in TSC2-mutant tumours.","Median duration of response not reached at 2.5 years."],"whatItMeans":"Nab-sirolimus is the approved first-line treatment for advanced malignant PEComa, and TSC1/TSC2 testing helps predict response.","caveats":["Single-arm study in a rare tumour; comparison with oral mTOR inhibitors is indirect."],"changedPractice":true,"participants":34},{"id":"paper-amplify-acalabrutinib-venetoclax-nejm-2025","kind":"paper","name":"AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients","aka":[],"tldr":"In AMPLIFY, an all-oral, 14-month course of acalabrutinib plus venetoclax beat FCR or BR chemo-immunotherapy in fit CLL patients, offering a time-limited alternative to indefinite pills.","summary":"AMPLIFY randomised 867 fit, previously untreated patients with CLL without del(17p) or TP53 mutation to acalabrutinib plus venetoclax (AV), acalabrutinib plus venetoclax plus obinutuzumab (AVO), or investigator's choice of FCR or bendamustine-rituximab. The primary endpoint was PFS for AV versus chemo-immunotherapy. Estimated 36-month PFS was 76.5% with AV, 83.1% with AVO and 66.5% with chemo-immunotherapy (hazard ratios 0.65 and 0.42 respectively). Overall survival favoured AV, driven largely by deaths from COVID-19 in the chemo-immunotherapy arm during the pandemic. AVO produced the deepest MRD responses but more infections and neutropenia.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=AMPLIFY%20acalabrutinib%20venetoclax%20obinutuzumab%20Brown%20NEJM%202025"},{"label":"ClinicalTrials.gov NCT03836261","url":"https://clinicaltrials.gov/study/NCT03836261"}],"tags":[],"related":["btki-plus-venetoclax-fixed-duration"],"cancers":["cll"],"sections":[],"technologies":[],"targets":["btk","bcl2","cd20"],"drugs":["acalabrutinib","venetoclax","obinutuzumab"],"companies":["astrazeneca","abbvie"],"institutions":[],"pathways":[],"terms":["mrd","pfs","del17p-tp53"],"trials":["amplify","cll13-gaia","glow"],"people":[],"bottlenecks":["b-combination-space","b-drug-pricing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"authors":"Brown JR, Seymour JF, Jurczak W, et al.","paperType":"rct","findings":["867 fit patients without TP53 aberration; 14 cycles of AV or AVO vs 6 cycles of FCR or BR.","36-month PFS: 76.5% (AV), 83.1% (AVO), 66.5% (chemo-immunotherapy); HR 0.65 for AV and 0.42 for AVO vs chemo-immunotherapy.","Overall survival better with AV than chemo-immunotherapy, but many chemo-immunotherapy deaths were from COVID-19.","Undetectable MRD rates were highest with AVO; AV produced a lower MRD-negativity rate than AVO or venetoclax-obinutuzumab in other trials.","Grade 3 or higher neutropenia and infections were more frequent with AVO than AV."],"whatItMeans":"AMPLIFY delivered the first all-oral, fixed-duration doublet for front-line CLL and supported its approval, giving fit patients a way to avoid both chemotherapy and years of continuous BTK inhibitor. It does not settle whether a doublet or triplet is best, or how AV compares with venetoclax-obinutuzumab. Patients with TP53 aberration were excluded and still need different strategies.","caveats":["Chemo-immunotherapy is no longer the preferred comparator in many countries; the relevant question is AV versus venetoclax-obinutuzumab or continuous BTKi.","The OS signal is confounded by pandemic-era deaths.","Excluded del(17p)/TP53-mutated patients.","AV MRD-negativity was lower than with AVO; long-term durability is still maturing."],"changedPractice":true,"participants":867},{"id":"paper-anbl00p2-expectant-observation-nuchtern-ann-surg-2012","kind":"paper","name":"ANBL00P2: expectant observation as primary therapy for neuroblastoma in young infants","aka":[],"tldr":"Small adrenal masses found in infants under six months could safely be watched rather than operated on: nearly half shrank or disappeared and the rest were removed later without any child dying of neuroblastoma.","summary":"Children's Oncology Group prospective study of 87 infants under six months with small (under 3.1 cm solid or 5 cm cystic) adrenal masses managed by observation with serial ultrasound and urinary catecholamines, with surgery for growth or progression.\n\nEighty-one percent avoided surgery; among those observed, 45 percent had complete or partial spontaneous resolution, and three-year event-free and overall survival were 97.7 and 100 percent.","asOf":"2026-09-17","links":[{"label":"Ann Surg 2012","url":"https://doi.org/10.1097/SLA.0b013e31826cbbbd"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22964741/"}],"tags":[],"related":[],"cancers":["neuroblastoma-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Annals of Surgery","year":2012,"doi":"10.1097/SLA.0b013e31826cbbbd","pmid":"22964741","authors":"Nuchtern JG, London WB, Barnewolt CE, et al.","paperType":"observational","findings":["Surgery avoided in 81 percent of infants.","Three-year overall survival 100 percent."],"whatItMeans":"Observation without biopsy is standard for small adrenal masses in young infants, sparing them surgery for tumours that often regress.","caveats":["Applies only to small localised masses in infants under six months with defined imaging criteria."],"changedPractice":true,"participants":87},{"id":"paper-anbl0531-twist-jco-2019","kind":"paper","name":"ANBL0531: response- and biology-based therapy for intermediate-risk neuroblastoma","aka":[],"tldr":"Further reducing chemotherapy according to biology and response, including observation alone for some infants, maintained a three-year survival of 96 percent in intermediate-risk neuroblastoma.","summary":"Children's Oncology Group phase 3 study of 404 children with intermediate-risk neuroblastoma treated with two, four or eight cycles of chemotherapy depending on stage, age, biology and response, with some subgroups receiving surgery alone.\n\nThree-year event-free survival was 83.2 percent and overall survival 94.9 percent; 12q loss and 1p loss identified patients with more events, and reduced therapy was successful in most subgroups.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.19.00919"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31386611/"}],"tags":[],"related":[],"cancers":["neuroblastoma-intermediate-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.19.00919","pmid":"31386611","authors":"Twist CJ, Schmidt ML, Naranjo A, et al.","paperType":"observational","findings":["Three-year overall survival 94.9 percent; event-free survival 83.2 percent.","Reduced therapy safe in favourable biology subgroups."],"whatItMeans":"Current intermediate-risk neuroblastoma protocols minimise chemotherapy to two to eight cycles by response and biology, following this study.","caveats":["Some subgroups with unfavourable biology had lower event-free survival, prompting refinements."],"changedPractice":true,"participants":404},{"id":"paper-anbl0532-tandem-transplant-park-jama-2019","kind":"paper","name":"ANBL0532: tandem versus single autologous stem cell transplant for high-risk neuroblastoma","aka":[],"tldr":"Two consecutive high-dose chemotherapy courses with stem cell rescue improved three-year event-free survival compared with a single transplant in high-risk neuroblastoma, and the gain was largest in children who went on to receive anti-GD2 immunotherapy.","summary":"Children's Oncology Group phase 3 trial of 652 children with high-risk neuroblastoma, of whom 355 were randomised after induction to single transplant (carboplatin-etoposide-melphalan) or tandem transplant (thiotepa-cyclophosphamide followed by carboplatin-etoposide-melphalan).\n\nThree-year event-free survival was 61.6 versus 48.4 percent; overall survival did not differ significantly (74.1 versus 69.6 percent); among patients receiving immunotherapy, event-free survival was 73.7 versus 56.0 percent.","asOf":"2026-09-17","links":[{"label":"JAMA 2019","url":"https://doi.org/10.1001/jama.2019.11642"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31454045/"}],"tags":[],"related":[],"cancers":["neuroblastoma-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["anbl0532"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2019,"doi":"10.1001/jama.2019.11642","pmid":"31454045","authors":"Park JR, Kreissman SG, London WB, et al.","paperType":"rct","findings":["Three-year event-free survival 61.6 percent vs 48.4 percent.","With post-consolidation immunotherapy: 73.7 percent vs 56.0 percent."],"whatItMeans":"Tandem transplant is the standard consolidation in North American protocols for high-risk neuroblastoma; Europe uses single busulfan-melphalan.","caveats":["Only about half of enrolled patients reached randomisation.","No significant overall survival benefit."],"changedPractice":true,"participants":355},{"id":"paper-young-angiosarcoma-review-lancet-oncol-2010","kind":"paper","name":"Angiosarcoma (review)","aka":[],"tldr":"This review summarises the epidemiology, subtypes (including radiation- and lymphoedema-associated forms), surgery, radiotherapy and chemotherapy of angiosarcoma, and why outcomes remain poor.","summary":"Review covering the presentation and risk factors of angiosarcoma at different sites, pathology, staging, wide surgical excision with radiotherapy, systemic therapy with anthracyclines and taxanes, anti-angiogenic agents, and prognostic factors.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2010","url":"https://doi.org/10.1016/S1470-2045(10)70023-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20537949/"}],"tags":[],"related":[],"cancers":["angiosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2010,"doi":"10.1016/S1470-2045(10)70023-1","pmid":"20537949","authors":"Young RJ, Brown NJ, Reed MW, et al.","paperType":"review","findings":[],"whatItMeans":"The angiosarcoma page's structure by site and by aetiology (cutaneous, radiation-associated breast, visceral) follows this review.","caveats":["Predates immunotherapy data in cutaneous angiosarcoma."],"changedPractice":false},{"id":"paper-angiotax-paclitaxel-angiosarcoma-penel-jco-2008","kind":"paper","name":"ANGIOTAX: phase 2 trial of weekly paclitaxel for unresectable angiosarcoma","aka":[],"tldr":"Weekly paclitaxel controlled angiosarcoma in three quarters of patients at two months and produced responses in about one in five, establishing it as a standard first-line chemotherapy for this vascular sarcoma, especially of the scalp and face.","summary":"Phase 2 study of 30 patients with unresectable angiosarcoma treated with weekly paclitaxel 80 mg per square metre.\n\nNon-progression at two months was 74 percent, objective response 19 percent, median progression-free survival 4 months and median overall survival 8 months; responses were more frequent in scalp and face angiosarcomas.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2008","url":"https://doi.org/10.1200/JCO.2008.17.3146"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/18809609/"}],"tags":[],"related":[],"cancers":["angiosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["angiotax"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2008,"doi":"10.1200/JCO.2008.17.3146","pmid":"18809609","authors":"Penel N, Bui BN, Bay JO, et al.","paperType":"observational","findings":["Non-progression rate at two months 74 percent; objective response 19 percent.","Median overall survival 8 months."],"whatItMeans":"Weekly paclitaxel is a standard first-line option for angiosarcoma alongside doxorubicin, and it is also used with radiotherapy for unresectable scalp disease.","caveats":["Small single-arm study; survival remains poor.","The randomised ANNOUNCE and other trials have since compared taxanes with anthracyclines."],"changedPractice":true,"participants":30},{"id":"paper-yu-anti-gd2-neuroblastoma-nejm-2010","kind":"paper","name":"Anti-GD2 antibody with GM-CSF, interleukin-2 and isotretinoin for high-risk neuroblastoma (COG ANBL0032)","aka":[],"tldr":"Adding the anti-GD2 antibody ch14.18 with cytokines to isotretinoin after transplant improved two-year event-free survival in high-risk neuroblastoma from 46 to 66 percent, making immunotherapy a standard part of treatment.","summary":"Phase 3 trial of 226 children with high-risk neuroblastoma who had responded to induction and autologous transplant, randomised to isotretinoin alone or with five cycles of ch14.18 (dinutuximab) plus GM-CSF and interleukin-2.\n\nTwo-year event-free survival was 66 versus 46 percent and overall survival 86 versus 75 percent; pain, capillary leak and hypersensitivity were the main toxicities. Later follow-up confirmed the benefit.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2010","url":"https://doi.org/10.1056/NEJMoa0911123"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20879881/"}],"tags":[],"related":[],"cancers":["neuroblastoma-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa0911123","pmid":"20879881","authors":"Yu AL, Gilman AL, Ozkaynak MF, et al.","paperType":"rct","findings":["Two-year event-free survival 66 percent vs 46 percent.","Two-year overall survival 86 percent vs 75 percent."],"whatItMeans":"Anti-GD2 immunotherapy after consolidation is standard for high-risk neuroblastoma worldwide; interleukin-2 was later dropped after the SIOPEN trial showed no added benefit.","caveats":["Trial stopped early at interim analysis.","Neuropathic pain and capillary leak syndrome are substantial toxicities."],"changedPractice":true,"participants":226},{"id":"paper-nakamura-anti-pd1-acral-melanoma-ann-oncol-2020","kind":"paper","name":"Anti-PD-1 checkpoint inhibitor therapy in acral melanoma: a multicentre study of 193 Japanese patients","aka":[],"tldr":"In the largest series of acral melanoma treated with anti-PD-1 antibodies, only about 17 percent responded, and melanomas of the nail apparatus responded least, showing that acral disease benefits less from immunotherapy than ordinary skin melanoma.","summary":"Retrospective multicentre study of 193 Japanese patients with advanced acral melanoma treated with nivolumab or pembrolizumab monotherapy.\n\nObjective response was 16.6 percent overall (21.3 percent for palm and sole melanoma, 8.3 percent for nail apparatus melanoma), with median progression-free survival of 3.5 months and overall survival of 18.1 months; a higher tumour burden and nail apparatus origin predicted poor outcome.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2020","url":"https://doi.org/10.1016/j.annonc.2020.05.031"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32522691/"}],"tags":[],"related":[],"cancers":["acral-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2020,"doi":"10.1016/j.annonc.2020.05.031","pmid":"32522691","authors":"Nakamura Y, Namikawa K, Yoshino K, et al.","paperType":"real-world","findings":["Objective response 16.6 percent overall; 8.3 percent in nail apparatus melanoma.","Median overall survival 18.1 months."],"whatItMeans":"Acral melanoma needs its own treatment evidence: anti-PD-1 monotherapy has limited activity, so combination immunotherapy, KIT-directed therapy and trials of CDK4/6 inhibitors are important options.","caveats":["Retrospective Japanese cohort; many patients had prior chemotherapy."],"changedPractice":false,"participants":193},{"id":"paper-aphinity-nejm-2017","kind":"paper","name":"APHINITY: adjuvant pertuzumab added to trastuzumab and chemotherapy in early HER2-positive breast cancer","aka":[],"tldr":"Adding a second HER2 antibody, pertuzumab, to a year of trastuzumab after surgery reduced recurrences modestly in early HER2-positive breast cancer, with the gain concentrated in women with lymph node involvement.","summary":"Phase 3 placebo-controlled trial of 4,805 patients with operable HER2-positive breast cancer randomised to chemotherapy plus trastuzumab with pertuzumab or placebo for one year.\n\nThree-year invasive disease-free survival was 94.1 percent with pertuzumab against 93.2 percent with placebo (hazard ratio 0.81); in node-positive disease the absolute gain grew to 4.5 percent at six years, with no benefit seen in node-negative disease. Diarrhoea was the main added toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1703643"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28581356/"}],"tags":[],"related":[],"cancers":["her2-positive-early-breast-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["pertuzumab","trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["aphinity"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1703643","pmid":"28581356","authors":"von Minckwitz G, Procter M, de Azambuja E, et al.","paperType":"rct","findings":["Three-year invasive disease-free survival 94.1 percent vs 93.2 percent; hazard ratio 0.81.","Node-positive subgroup: six-year invasive disease-free survival 87.9 percent vs 83.4 percent."],"whatItMeans":"Dual HER2 blockade after surgery is reserved for node-positive or otherwise higher-risk disease, where the benefit is real but small; node-negative patients can be spared the extra drug.","caveats":["Absolute benefit is small and no overall survival difference has emerged.","Trial predates neoadjuvant therapy as the usual route for stage II to III disease."],"changedPractice":true,"participants":4805},{"id":"paper-apl0406-lo-coco-nejm-2013","kind":"paper","name":"APL0406: retinoic acid plus arsenic trioxide without chemotherapy for low- and intermediate-risk acute promyelocytic leukaemia","aka":[],"tldr":"Combining all-trans retinoic acid with arsenic trioxide cured almost every patient with lower-risk acute promyelocytic leukaemia without any conventional chemotherapy, and did so with fewer complications than the chemotherapy-based standard.","summary":"Phase 3 non-inferiority trial of 162 patients with non-high-risk APL randomised to all-trans retinoic acid plus arsenic trioxide or to retinoic acid plus idarubicin chemotherapy (AIDA).\n\nTwo-year event-free survival was 97 percent with the chemotherapy-free regimen against 86 percent with AIDA, and overall survival 99 versus 91 percent; the arsenic arm had less haematological toxicity and fewer infections but more liver enzyme rises and QT prolongation.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2013","url":"https://doi.org/10.1056/NEJMoa1300874"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23841729/"}],"tags":[],"related":[],"cancers":["apl"],"sections":[],"technologies":[],"targets":[],"drugs":["arsenic-trioxide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["apl0406"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2013,"doi":"10.1056/NEJMoa1300874","pmid":"23841729","authors":"Lo-Coco F, Avvisati G, Vignetti M, et al.","paperType":"rct","findings":["Two-year event-free survival 97 percent vs 86 percent.","Two-year overall survival 99 percent vs 91 percent."],"whatItMeans":"Low- and intermediate-risk APL is now treated without cytotoxic chemotherapy. The regimen has become the standard worldwide and made APL the most curable adult acute leukaemia.","caveats":["High-risk patients (white count over 10,000) were excluded and still receive added chemotherapy or gemtuzumab.","Differentiation syndrome remains a risk with either regimen."],"changedPractice":true,"participants":162},{"id":"paper-apt-tolaney-nejm-2015","kind":"paper","name":"APT: adjuvant paclitaxel and trastuzumab for small, node-negative HER2-positive breast cancer","aka":[],"tldr":"Twelve weeks of paclitaxel with a year of trastuzumab, and no anthracycline, was enough to keep more than 98 percent of women with small node-negative HER2-positive breast cancers free of recurrence at three years.","summary":"Single-arm phase 2 study of 406 patients with node-negative HER2-positive breast cancer up to 3 cm treated with weekly paclitaxel for 12 weeks plus trastuzumab for one year.\n\nThree-year invasive disease-free survival was 98.7 percent, with only two distant recurrences, and seven-year follow-up confirmed durable results with minimal cardiac toxicity. It established a de-escalated regimen for stage I disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2015","url":"https://doi.org/10.1056/NEJMoa1406281"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25564897/"}],"tags":[],"related":[],"cancers":["her2-positive-early-breast-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1406281","pmid":"25564897","authors":"Tolaney SM, Barry WT, Dang CT, et al.","paperType":"observational","findings":["Three-year invasive disease-free survival 98.7 percent.","Seven-year disease-free survival 93 percent with 97.5 percent recurrence-free interval."],"whatItMeans":"Women with small HER2-positive tumours can avoid anthracyclines and multi-agent chemotherapy; the APT regimen is a guideline standard for stage I HER2-positive disease.","caveats":["Non-randomised; the excellent outcomes may partly reflect a favourable population.","Most tumours were under 2 cm and hormone receptor-positive."],"changedPractice":true,"participants":406},{"id":"paper-aquila-daratumumab-smouldering-nejm-2025","kind":"paper","name":"AQUILA: daratumumab versus active monitoring in high-risk smouldering multiple myeloma","aka":[],"tldr":"Giving daratumumab for up to three years to people with high-risk smouldering myeloma roughly halved the risk of progressing to active myeloma or death compared with watching and waiting.","summary":"Phase 3 trial of 390 patients with high-risk smouldering multiple myeloma randomised to subcutaneous daratumumab monotherapy for up to 36 months or active monitoring.\n\nFive-year progression-free survival was 63.1 percent with daratumumab against 40.8 percent with monitoring (hazard ratio 0.49), with a favourable trend in overall survival and a manageable toxicity profile.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2025","url":"https://doi.org/10.1056/NEJMoa2409029"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39652675/"}],"tags":[],"related":[],"cancers":["smouldering-myeloma"],"sections":[],"technologies":[],"targets":[],"drugs":["daratumumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["aquila"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2409029","pmid":"39652675","authors":"Dimopoulos MA, Voorhees PM, Schjesvold F, et al.","paperType":"rct","findings":["Five-year progression-free survival 63.1 percent vs 40.8 percent; hazard ratio 0.49.","Five-year overall survival 93.0 percent vs 86.9 percent."],"whatItMeans":"Early single-agent treatment of high-risk smouldering myeloma is now an option with regulatory approval, though monitoring remains acceptable and the definition of high risk matters.","caveats":["Risk definitions at enrolment predate the 20/2/20 model, so some patients were lower risk than intended.","Whether early treatment improves survival compared with treating at progression remains unproven."],"changedPractice":true,"participants":390},{"id":"paper-aramis-nejm-2019","kind":"paper","name":"ARAMIS: darolutamide in non-metastatic castration-resistant prostate cancer","aka":[],"tldr":"Darolutamide, an androgen receptor inhibitor that barely enters the brain, delayed metastases by nearly two years in men with non-metastatic castration-resistant prostate cancer with side effects close to placebo, and later showed a survival benefit.","summary":"Phase 3 placebo-controlled trial of 1,509 men with non-metastatic castration-resistant prostate cancer and PSA doubling time of ten months or less randomised 2:1 to darolutamide or placebo with continued androgen deprivation.\n\nMedian metastasis-free survival was 40.4 versus 18.4 months (hazard ratio 0.41), three-year overall survival 83 versus 77 percent (hazard ratio 0.69 at final analysis), and adverse events including falls, fractures, seizures and cognitive impairment were similar to placebo.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2019","url":"https://doi.org/10.1056/NEJMoa1815671"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30763142/"}],"tags":[],"related":[],"cancers":["prostate-nmcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["darolutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["aramis"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1815671","pmid":"30763142","authors":"Fizazi K, Shore N, Tammela TL, et al.","paperType":"rct","findings":["Median metastasis-free survival 40.4 vs 18.4 months; hazard ratio 0.41.","Overall survival hazard ratio 0.69; adverse event rates close to placebo."],"whatItMeans":"Darolutamide is often preferred in older men or those with fall or cognitive concerns because of its favourable tolerability among the three approved agents.","caveats":["No head-to-head comparison with enzalutamide or apalutamide.","Non-metastatic by conventional imaging."],"changedPractice":true,"participants":1509},{"id":"paper-arasens-nejm-2022","kind":"paper","name":"ARASENS: darolutamide added to androgen deprivation and docetaxel in metastatic hormone-sensitive prostate cancer","aka":[],"tldr":"Adding the androgen receptor inhibitor darolutamide to hormone therapy and docetaxel chemotherapy cut deaths by a third in metastatic hormone-sensitive prostate cancer, establishing triplet therapy for men fit for chemotherapy.","summary":"Phase 3 placebo-controlled trial of 1,306 men with metastatic hormone-sensitive prostate cancer randomised to androgen deprivation plus docetaxel with darolutamide or placebo.\n\nFour-year overall survival was 62.7 versus 50.4 percent (hazard ratio 0.68), with delayed castration resistance, pain progression and skeletal events, and no meaningful increase in toxicity beyond docetaxel; benefit was seen in both high- and low-volume disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2119115"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35179323/"}],"tags":[],"related":[],"cancers":["prostate-mhspc"],"sections":[],"technologies":[],"targets":[],"drugs":["darolutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["arasens"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2119115","pmid":"35179323","authors":"Smith MR, Hussain M, Saad F, et al.","paperType":"rct","findings":["Four-year overall survival 62.7 percent vs 50.4 percent; hazard ratio 0.68.","Time to castration-resistant disease hazard ratio 0.36."],"whatItMeans":"Triplet therapy with darolutamide is a standard for fit men with metastatic hormone-sensitive prostate cancer, particularly high-volume disease; PEACE-1 showed the same with abiraterone.","caveats":["No arm of androgen deprivation plus darolutamide without docetaxel, so the contribution of docetaxel is unproven.","Most patients had high-volume disease."],"changedPractice":true,"participants":1306},{"id":"paper-wiegand-arid1a-clear-cell-nejm-2010","kind":"paper","name":"ARID1A mutations in endometriosis-associated ovarian carcinomas","aka":[],"tldr":"This study found that about half of ovarian clear cell carcinomas and a third of endometrioid carcinomas carry inactivating mutations in ARID1A, a chromatin remodelling gene, linking these endometriosis-associated cancers to a common driver.","summary":"Sequencing study identifying truncating ARID1A mutations in 46 percent of ovarian clear cell carcinomas and 30 percent of endometrioid carcinomas but not in high-grade serous carcinoma, with loss of the BAF250a protein in mutated tumours and evidence of the mutation in adjacent endometriosis.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2010","url":"https://doi.org/10.1056/NEJMoa1008433"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20942669/"}],"tags":[],"related":[],"cancers":["clear-cell-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa1008433","pmid":"20942669","authors":"Wiegand KC, Shah SP, Al-Agha OM, et al.","paperType":"translational","findings":["ARID1A mutations in 46 percent of clear cell and 30 percent of endometrioid ovarian carcinomas.","No ARID1A mutations in high-grade serous carcinoma."],"whatItMeans":"ARID1A loss defines the biology of clear cell ovarian cancer and is the target of current trials of synthetic-lethal drugs such as ATR and EZH2 inhibitors.","caveats":["No ARID1A-directed therapy has yet been approved."],"changedPractice":true},{"id":"paper-arrow-pralsetinib-gainor-lancet-oncol-2021","kind":"paper","name":"ARROW: pralsetinib for RET fusion-positive non-small-cell lung cancer","aka":[],"tldr":"Pralsetinib, a second selective RET inhibitor, shrank tumours in 61 percent of previously treated and 70 percent of untreated patients with RET fusion-positive lung cancer, giving an alternative to selpercatinib.","summary":"Phase 1/2 study including 233 patients with RET fusion-positive non-small-cell lung cancer treated with pralsetinib 400 mg daily.\n\nObjective response was 61 percent in patients previously treated with platinum chemotherapy and 70 percent in treatment-naive patients, with median duration of response not reached in the latter; neutropenia, hypertension and liver enzyme rise were common.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(21)00247-3"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34118197/"}],"tags":[],"related":[],"cancers":["ret-fusion-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["pralsetinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00247-3","pmid":"34118197","authors":"Gainor JF, Curigliano G, Kim DW, et al.","paperType":"observational","findings":["Objective response 61 percent (previously treated) and 70 percent (treatment-naive).","Grade 3 or worse neutropenia in about 18 percent."],"whatItMeans":"Pralsetinib is approved for RET fusion-positive lung cancer and is used where selpercatinib is unavailable or not tolerated.","caveats":["Single-arm; pneumonitis and haematological toxicity more frequent than with selpercatinib in cross-trial comparison."],"changedPractice":true,"participants":233},{"id":"paper-llovet-tace-lancet-2002","kind":"paper","name":"Arterial embolisation or chemoembolisation versus symptomatic treatment in unresectable hepatocellular carcinoma","aka":[],"tldr":"This Barcelona trial was the first to show that transarterial chemoembolisation lengthens survival in intermediate-stage liver cancer, with two-year survival of 63 percent against 27 percent with supportive care, making it the standard for this stage.","summary":"Randomised trial of 112 patients with unresectable hepatocellular carcinoma, Child-Pugh A or B cirrhosis and no vascular invasion or extrahepatic spread, randomised to arterial embolisation, chemoembolisation with doxorubicin, or conservative treatment; stopped early when chemoembolisation showed a survival benefit.\n\nSurvival at one and two years was 82 and 63 percent with chemoembolisation, 75 and 50 percent with embolisation, and 63 and 27 percent with conservative treatment (hazard ratio for chemoembolisation 0.47).","asOf":"2026-09-17","links":[{"label":"Lancet 2002","url":"https://doi.org/10.1016/S0140-6736(02)08649-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12049862/"}],"tags":[],"related":[],"cancers":["hcc-intermediate"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2002,"doi":"10.1016/S0140-6736(02)08649-X","pmid":"12049862","authors":"Llovet JM, Real MI, Montaña X, et al.","paperType":"rct","findings":["Two-year survival 63 percent (chemoembolisation) vs 27 percent (conservative).","Hazard ratio for death 0.47 with chemoembolisation."],"whatItMeans":"Transarterial chemoembolisation is the standard treatment for BCLC stage B hepatocellular carcinoma, now being combined with systemic therapy.","caveats":["Small trial stopped early; embolisation alone was not significantly better than control."],"changedPractice":true,"participants":112},{"id":"paper-ascent-nejm-2021","kind":"paper","name":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer","aka":[],"tldr":"In triple-negative breast cancer that had already been through at least two treatments, the TROP2 antibody-drug conjugate sacituzumab govitecan roughly doubled the time patients lived compared with standard chemotherapy.","summary":"Open-label phase 3 trial of 529 patients with relapsed or refractory metastatic triple-negative breast cancer after two or more prior chemotherapy regimens, randomised to sacituzumab govitecan or single-agent chemotherapy (eribulin, vinorelbine, capecitabine or gemcitabine). The primary endpoint was PFS in the 468 patients without brain metastases.\n\nMedian PFS was 5.6 vs 1.7 months (HR 0.41) and median overall survival 12.1 vs 6.7 months (HR 0.48). It converted the 2020 accelerated approval into a full approval and was the first ADC to show a survival benefit in TNBC.","asOf":"2026-09-08","links":[{"label":"NEJM 2021","url":"https://doi.org/10.1056/NEJMoa2028485"},{"label":"ClinicalTrials.gov NCT02574455","url":"https://clinicaltrials.gov/study/NCT02574455"}],"tags":[],"related":["idea-post-neoadjuvant-adc","idea-trop2-pet-selection"],"cancers":["tnbc"],"sections":[],"technologies":["adc","topoisomerase-inhibitors"],"targets":["trop2"],"drugs":["sacituzumab-govitecan"],"companies":["gilead"],"institutions":[],"pathways":[],"terms":["linker","payload","orr","pfs","os","accelerated-approval"],"trials":["ascent","ascent-03","ascent-04"],"people":["sara-hurvitz","sara-tolaney","javier-cortes","martine-piccart","sibylle-loibl","hope-rugo"],"bottlenecks":["b-resistance","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2028485","authors":"Bardia A, Hurvitz SA, Tolaney SM, et al.","paperType":"rct","findings":["Median PFS 5.6 vs 1.7 months; HR 0.41 (95% CI 0.32-0.52).","Median overall survival 12.1 vs 6.7 months; HR 0.48 (95% CI 0.38-0.59).","Objective response rate 35% vs 5%.","Grade 3 or higher neutropenia 51% vs 33% and diarrhoea 10% vs under 1%; UGT1A1 *28 homozygotes had more neutropenia.","Benefit was seen regardless of TROP2 expression level and in patients with germline BRCA mutations."],"whatItMeans":"Sacituzumab govitecan is a standard second-line or later treatment for metastatic triple-negative breast cancer, roughly doubling survival compared with the chemotherapies it was tested against. Patients should expect neutropenia and diarrhoea, which are manageable with growth factor support and loperamide. Trials are now testing it earlier, in first-line combinations with pembrolizumab and after surgery for residual disease.","caveats":["Open-label; PFS assessed by blinded review.","The control chemotherapies were of modest efficacy in this setting (ORR 5%).","Patients with brain metastases were excluded from the primary analysis and remain under-studied.","The relatively unstable linker releases SN-38 systemically, which contributes to neutropenia and diarrhoea."],"changedPractice":true,"participants":529},{"id":"paper-asco-irae-guideline-jco-2021","kind":"paper","name":"ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors","aka":[],"tldr":"The ASCO 2021 guideline is the consensus rulebook for checkpoint-inhibitor toxicity: grade the problem, hold or stop the drug, give steroids early, escalate to other immunosuppressants if they fail, and involve specialists.","summary":"This update of the 2018 ASCO guideline, developed with the National Comprehensive Cancer Network, provides organ-by-organ recommendations for immune-related adverse events (irAEs) of PD-1, PD-L1 and CTLA-4 inhibitors, based on systematic review and expert consensus. The general framework is graded: grade 1 events are usually managed with monitoring while continuing therapy (except some neurological, haematological and cardiac events); grade 2 events lead to holding the inhibitor and considering corticosteroids (prednisone 0.5-1 mg/kg/day); grade 3 events require holding therapy and high-dose corticosteroids (1-2 mg/kg/day) tapered over at least four to six weeks, with infliximab or other agents if no improvement in 48-72 hours; grade 4 events generally mandate permanent discontinuation, except endocrinopathies controlled by hormone replacement. Specific sections cover skin, gastrointestinal, hepatic, endocrine, pulmonary, rheumatological, renal, neurological, haematological, cardiovascular and ocular toxicities, and a companion ASCO guideline addresses CAR-T toxicities. The Society for Immunotherapy of Cancer published a parallel consensus in 2021.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=Management%20of%20Immune-Related%20Adverse%20Events%20ASCO%20Guideline%20Update%20Schneider%20JCO%202021"},{"label":"ASCO guidelines","url":"https://www.asco.org/guidelines"}],"tags":[],"related":["paper-checkmate-067-ten-year-nejm-2025","paper-hodi-ipilimumab-melanoma-nejm-2010","cardio-oncology"],"cancers":["melanoma","nsclc"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","ctla4"],"drugs":["nivolumab","ipilimumab","pembrolizumab","atezolizumab"],"companies":[],"institutions":["asco"],"pathways":[],"terms":["irae","crs","icans"],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-knowledge-diffusion","b-care-fragmentation"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2021,"authors":"Schneider BJ, Naidoo J, Santomasso BD, et al.","paperType":"guideline","findings":["Grade-based algorithm: grade 1 monitor and continue (with exceptions); grade 2 hold and consider steroids; grade 3 hold and give 1-2 mg/kg prednisone-equivalent; grade 4 permanently discontinue except endocrinopathies.","Steroid tapers should last at least 4-6 weeks; failure to improve within 48-72 hours should prompt infliximab (colitis, arthritis), mycophenolate (hepatitis) or other second-line immunosuppression.","Myocarditis is rare but has high mortality and warrants high-dose steroids and early cardiology involvement; troponin monitoring is discussed.","Hormone replacement, not steroids, is the treatment for most endocrinopathies, which are often permanent.","Rechallenge after grade 2-3 irAEs can be considered case by case once resolved to grade 1 or less; short steroid courses do not clearly reduce efficacy."],"whatItMeans":"Checkpoint inhibitors are now given to hundreds of thousands of patients a year, many in community clinics and emergency departments, so a common, explicit playbook for their autoimmune side effects saves lives. The guideline standardised when to stop, when to give steroids and when to escalate, and made multidisciplinary toxicity teams routine. It does not remove the judgement needed for rare events or for patients whose cancer is responding.","caveats":["Most recommendations rest on expert consensus and case series rather than randomised trials.","Steroid-sparing strategies and biomarkers for irAEs remain largely unstudied.","Guidance on rechallenge and on combination or adjuvant settings is limited.","Rapidly evolving; later ASCO and SITC updates modify specific sections (for example, myocarditis and CAR-T toxicity)."],"changedPractice":true},{"id":"paper-aspen-armstrong-lancet-oncol-2016","kind":"paper","name":"ASPEN: everolimus versus sunitinib in metastatic non-clear cell renal cell carcinoma","aka":[],"tldr":"In the first randomised trial dedicated to non-clear cell kidney cancers, sunitinib delayed progression more than everolimus overall, though chromophobe tumours appeared to fare better on everolimus.","summary":"Randomised phase 2 trial of 108 patients with metastatic papillary, chromophobe or unclassified renal cell carcinoma randomised to sunitinib or everolimus.\n\nMedian progression-free survival was 8.3 months with sunitinib against 5.6 months with everolimus (hazard ratio 1.41 for everolimus); in the small chromophobe subgroup everolimus gave longer progression-free survival (11.4 versus 5.5 months), while papillary tumours did better with sunitinib.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2016","url":"https://doi.org/10.1016/S1470-2045(15)00515-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26794930/"}],"tags":[],"related":[],"cancers":["chromophobe-rcc","papillary-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["everolimus","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2016,"doi":"10.1016/S1470-2045(15)00515-X","pmid":"26794930","authors":"Armstrong AJ, Halabi S, Eisen T, et al.","paperType":"rct","findings":["Median progression-free survival 8.3 months (sunitinib) vs 5.6 months (everolimus).","Chromophobe subgroup: 11.4 months with everolimus vs 5.5 months with sunitinib."],"whatItMeans":"VEGF-directed therapy is the default for non-clear cell disease, with everolimus considered in chromophobe tumours; cabozantinib later became preferred for papillary disease.","caveats":["Small heterogeneous trial; subgroup findings are hypothesis-generating."],"changedPractice":true,"participants":108},{"id":"paper-atezolizumab-alveolar-soft-part-sarcoma-chen-nejm-2023","kind":"paper","name":"Atezolizumab for advanced alveolar soft part sarcoma","aka":[],"tldr":"The PD-L1 antibody atezolizumab shrank tumours in about a quarter of patients with advanced alveolar soft part sarcoma, with responses lasting years in a disease resistant to chemotherapy, and became the first approved treatment for this sarcoma.","summary":"Phase 2 study of 52 patients aged 2 and older with advanced alveolar soft part sarcoma treated with atezolizumab every three weeks.\n\nObjective response was 24 percent (37 percent in an updated analysis with longer follow-up), with a median duration of response of over 16 months and stable disease in most others; toxicity was typical of PD-L1 blockade and low grade.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2303383"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37672694/"}],"tags":[],"related":[],"cancers":["alveolar-soft-part-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2303383","pmid":"37672694","authors":"Chen AP, Sharon E, O'Sullivan-Coyne G, et al.","paperType":"observational","findings":["Objective response 24 percent (37 percent with longer follow-up).","Median duration of response 16.5 months; many responses ongoing."],"whatItMeans":"Atezolizumab is the first-line systemic treatment for advanced alveolar soft part sarcoma, a rare, slow-growing but ultimately metastatic sarcoma of young adults for which chemotherapy never worked.","caveats":["Single-arm study in a rare disease; responses can take many months to appear."],"changedPractice":true,"participants":52},{"id":"paper-raghav-atezolizumab-bevacizumab-peritoneal-mesothelioma-cancer-discov-2021","kind":"paper","name":"Atezolizumab plus bevacizumab in advanced malignant peritoneal mesothelioma","aka":[],"tldr":"In a small trial combining PD-L1 and VEGF blockade, four in ten patients with previously treated peritoneal mesothelioma responded, with responses lasting well over a year, the first dedicated prospective evidence for immunotherapy in this rare disease.","summary":"Single-centre phase 2 study of 20 patients with advanced unresectable peritoneal mesothelioma progressing after platinum-pemetrexed, treated with atezolizumab and bevacizumab.\n\nObjective response was 40 percent with a median duration of response of 12.8 months, one-year progression-free survival 61 percent and one-year overall survival 85 percent; biomarker analyses linked response to epithelial-mesenchymal transition and immune features.","asOf":"2026-09-17","links":[{"label":"Cancer Discov 2021","url":"https://doi.org/10.1158/2159-8290.CD-21-0331"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34261675/"}],"tags":[],"related":[],"cancers":["peritoneal-mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2021,"doi":"10.1158/2159-8290.CD-21-0331","pmid":"34261675","authors":"Raghav K, Liu S, Overman MJ, et al.","paperType":"observational","findings":["Objective response 40 percent; median duration of response 12.8 months.","One-year overall survival 85 percent."],"whatItMeans":"Immunotherapy combinations, largely extrapolated from pleural trials, now have direct supporting data in peritoneal mesothelioma and are used after or instead of chemotherapy in unresectable disease.","caveats":["Twenty patients at a single centre; no comparator."],"changedPractice":false,"participants":20},{"id":"paper-augment-101-revumenib-menin-nature-2023","kind":"paper","name":"AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation","aka":[],"tldr":"Blocking menin, a scaffold protein the leukaemia depends on, produced remissions in heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukaemia.","summary":"The phase 1 portion of AUGMENT-101 treated 68 adults and children with relapsed or refractory acute leukaemia carrying a KMT2A rearrangement or NPM1 mutation with oral revumenib (SNDX-5613), a small molecule that disrupts the menin-KMT2A interaction. Among 60 efficacy-evaluable patients the overall response rate was 53% and the rate of complete remission or remission with partial haematological recovery 30%, with most responders MRD-negative. QT prolongation was dose limiting and differentiation syndrome occurred in 16%. Resistance through MEN1 mutations was subsequently described. The phase 2 KMT2A-rearranged cohort met its primary endpoint and revumenib was approved in 2024 for KMT2A-rearranged acute leukaemia and in 2025 for NPM1-mutated AML, the first drugs in a new class.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=AUGMENT-101%20revumenib%20menin%20inhibitor%20KMT2A%20NPM1%20Issa%20Nature%202023"},{"label":"ClinicalTrials.gov NCT04065399","url":"https://clinicaltrials.gov/study/NCT04065399"}],"tags":[],"related":["menin-plus-venetoclax-hma"],"cancers":["aml","all-leukemia"],"sections":[],"technologies":[],"targets":["menin","kmt2a","npm1"],"drugs":["revumenib","ziftomenib"],"companies":["syndax","kura-oncology"],"institutions":["md-anderson"],"pathways":[],"terms":["mrd-negative-cr","orr"],"trials":["augment-101"],"people":[],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2023,"authors":"Issa GC, Aldoss I, DiPersio J, et al.","paperType":"translational","findings":["68 patients treated (60 efficacy-evaluable) with relapsed/refractory KMT2A-rearranged or NPM1-mutated acute leukaemia.","Overall response 53%; CR/CRh 30%; most remissions MRD-negative.","Dose-limiting toxicity was QT prolongation; differentiation syndrome in 16%.","Responses in both KMT2A-rearranged and NPM1-mutated disease and in children and adults.","Phase 2 KMT2A-rearranged cohort: CR/CRh in roughly a fifth of patients, sufficient for regulatory approval; acquired MEN1 mutations identified as a resistance mechanism."],"whatItMeans":"Revumenib proved that a transcriptional dependency, rather than a kinase, can be drugged in leukaemia, opening treatment for two genetic subgroups that together cover roughly a third of AML plus most infant ALL. It is now approved and is being combined with venetoclax-azacitidine and intensive chemotherapy in front-line trials. Single-agent remissions are often short without transplant.","caveats":["Single-arm phase 1/2 in end-stage patients; no randomised data yet.","Modest CR/CRh rates as monotherapy; benefit likely to come from combinations and as a bridge to transplant.","QT prolongation and drug interactions with azoles require dose adjustment.","Resistance via MEN1 mutations emerges within months in some patients."],"changedPractice":true,"participants":68},{"id":"paper-augment-lenalidomide-rituximab-leonard-jco-2019","kind":"paper","name":"AUGMENT: lenalidomide plus rituximab versus rituximab alone in relapsed indolent lymphoma","aka":[],"tldr":"Adding lenalidomide to rituximab more than doubled the time to progression in relapsed follicular and marginal zone lymphoma compared with rituximab alone, establishing a chemotherapy-free option for relapsed indolent lymphoma.","summary":"Phase 3 trial of 358 patients with relapsed or refractory follicular (grade 1 to 3a) or marginal zone lymphoma randomised to lenalidomide plus rituximab (R2) or placebo plus rituximab for 12 cycles.\n\nMedian progression-free survival was 39.4 versus 14.1 months (hazard ratio 0.46) and response 78 versus 53 percent; the benefit was clear in follicular lymphoma while the marginal zone subgroup was small and inconclusive. Neutropenia was more frequent with lenalidomide.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.19.00010"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30897038/"}],"tags":[],"related":[],"cancers":["marginal-zone-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["lenalidomide","rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["augment"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.19.00010","pmid":"30897038","authors":"Leonard JP, Trneny M, Izutsu K, et al.","paperType":"rct","findings":["Median progression-free survival 39.4 vs 14.1 months; hazard ratio 0.46.","Objective response 78 percent vs 53 percent."],"whatItMeans":"Lenalidomide-rituximab is approved for relapsed follicular and marginal zone lymphoma and is a standard chemotherapy-free choice, though marginal zone-specific evidence is thinner.","caveats":["Only 63 patients had marginal zone lymphoma, with no clear progression-free survival benefit in that subgroup."],"changedPractice":true,"participants":358},{"id":"paper-aurelia-jco-2014","kind":"paper","name":"AURELIA: bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer","aka":[],"tldr":"Adding bevacizumab to single-agent chemotherapy doubled the time to progression and the response rate in platinum-resistant ovarian cancer, becoming the first regimen to improve outcomes in this hard-to-treat setting.","summary":"Phase 3 trial of 361 patients with platinum-resistant ovarian cancer (progression within six months of platinum) and up to two prior regimens randomised to weekly paclitaxel, pegylated liposomal doxorubicin or topotecan with or without bevacizumab.\n\nMedian progression-free survival was 6.7 versus 3.4 months (hazard ratio 0.48) and objective response 27.3 versus 11.8 percent; overall survival was not significantly improved (16.6 versus 13.3 months), partly because of crossover.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2014","url":"https://doi.org/10.1200/JCO.2013.51.4489"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24637997/"}],"tags":[],"related":[],"cancers":["platinum-resistant-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2014,"doi":"10.1200/JCO.2013.51.4489","pmid":"24637997","authors":"Pujade-Lauraine E, Hilpert F, Weber B, et al.","paperType":"rct","findings":["Median progression-free survival 6.7 vs 3.4 months; hazard ratio 0.48.","Objective response 27.3 percent vs 11.8 percent."],"whatItMeans":"Bevacizumab with weekly paclitaxel or other single agents is a standard for platinum-resistant ovarian cancer in bevacizumab-naive patients, and the control regimen for later trials such as MIRASOL and ROSELLA.","caveats":["No significant overall survival benefit.","Patients with bowel involvement were excluded because of perforation risk."],"changedPractice":true,"participants":361},{"id":"paper-aza-001-fenaux-lancet-oncol-2009","kind":"paper","name":"AZA-001: azacitidine versus conventional care in higher-risk myelodysplastic syndromes","aka":[],"tldr":"Azacitidine was the first drug shown to lengthen survival in higher-risk myelodysplastic syndromes, adding about nine months of median survival compared with the usual supportive care or chemotherapy.","summary":"Phase 3 trial of 358 patients with higher-risk MDS randomised to azacitidine or a pre-selected conventional care regimen (best supportive care, low-dose cytarabine or intensive chemotherapy).\n\nMedian overall survival was 24.5 months with azacitidine against 15.0 months with conventional care (hazard ratio 0.58), with two-year survival roughly doubled and fewer transfusions and infections.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2009","url":"https://doi.org/10.1016/S1470-2045(09)70003-8"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19230772/"}],"tags":[],"related":[],"cancers":["mds-higher-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["azacitidine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["aza-001"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2009,"doi":"10.1016/S1470-2045(09)70003-8","pmid":"19230772","authors":"Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.","paperType":"rct","findings":["Median overall survival 24.5 vs 15.0 months; hazard ratio 0.58.","Two-year survival 50.8 percent vs 26.2 percent."],"whatItMeans":"Azacitidine (and decitabine) became the standard for higher-risk MDS in patients not going straight to transplant, and the backbone for combination trials that have so far failed to beat it.","caveats":["Median time to response is several cycles, so treatment must continue for at least four to six cycles before judging failure.","Responses are not durable; outcomes after hypomethylating failure are poor."],"changedPractice":true,"participants":358},{"id":"paper-aza-aml-001-dombret-blood-2015","kind":"paper","name":"AZA-AML-001: azacitidine versus conventional care in older patients with acute myeloid leukaemia and more than 30 percent blasts","aka":[],"tldr":"In older people with acute myeloid leukaemia who were not good candidates for intensive chemotherapy, azacitidine lengthened median survival by about four months compared with the usual options and became the backbone that venetoclax was later added to.","summary":"Phase 3 trial of 488 patients aged 65 or over with newly diagnosed AML and over 30 percent marrow blasts, randomised to azacitidine or a pre-selected conventional care regimen (intensive chemotherapy, low-dose cytarabine or supportive care).\n\nMedian overall survival was 10.4 months with azacitidine against 6.5 months with conventional care, a difference that was clinically meaningful but not statistically significant in the primary analysis. One-year survival was 46.5 versus 34.2 percent.","asOf":"2026-09-17","links":[{"label":"Blood 2015","url":"https://doi.org/10.1182/blood-2015-01-621664"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25987659/"}],"tags":[],"related":[],"cancers":["aml-older-unfit"],"sections":[],"technologies":[],"targets":[],"drugs":["azacitidine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2015,"doi":"10.1182/blood-2015-01-621664","pmid":"25987659","authors":"Dombret H, Seymour JF, Butrym A, et al.","paperType":"rct","findings":["Median overall survival 10.4 vs 6.5 months (hazard ratio 0.85, not significant in the primary analysis).","One-year survival 46.5 percent vs 34.2 percent."],"whatItMeans":"Azacitidine became the standard low-intensity treatment for older or unfit patients with AML and the control arm for later trials; venetoclax plus azacitidine (VIALE-A) now supersedes azacitidine alone where available.","caveats":["The primary endpoint was not formally met.","The comparator was heterogeneous and chosen by the investigator before randomisation."],"changedPractice":true,"participants":488},{"id":"paper-balkwill-mantovani-inflammation-virchow-lancet-2001","kind":"paper","name":"Balkwill and Mantovani 2001: inflammation and cancer, back to Virchow?","aka":[],"tldr":"A short, widely cited essay reviving Virchow's 1863 observation that tumours are full of white blood cells, arguing that the inflammatory cells and cytokines in tumours help them grow rather than fight them.","summary":"Balkwill and Mantovani revisited Rudolf Virchow's observation of leukocytes in tumours and assembled the modern evidence: that chronic inflammatory conditions predispose to cancer, that tumours recruit macrophages and other inflammatory cells whose cytokines and chemokines promote growth, angiogenesis and invasion, and that inflammatory mediators such as TNF, IL-1 and IL-6 have tumour-promoting roles. They noted the reduced colorectal cancer risk in long-term users of non-steroidal anti-inflammatory drugs as clinical support and proposed anti-inflammatory strategies for prevention and treatment.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/S0140-6736(00)04046-0"}],"tags":[],"related":["paper-coussens-werb-inflammation-cancer-nature-2002","paper-grivennikov-immunity-inflammation-cancer-cell-2010"],"cancers":[],"sections":[],"technologies":["aspirin-cancer-prevention"],"targets":[],"drugs":[],"companies":[],"institutions":["humanitas"],"pathways":["inflammation-nfkb"],"terms":["inflammation","tumor-associated-macrophages","macrophage"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2001,"doi":"10.1016/S0140-6736(00)04046-0","authors":"Balkwill F, Mantovani A.","paperType":"review","findings":["Chronic inflammation predisposes to cancer and tumours themselves recruit inflammatory cells.","Cytokines and chemokines from tumour-associated leukocytes promote proliferation, angiogenesis and invasion.","Long-term NSAID use is associated with lower colorectal cancer risk, supporting the causal link."],"whatItMeans":"Together with the 2002 Nature review this essay put inflammation on the cancer research agenda; the tumour-associated macrophage and IL-6 work that followed, and the aspirin prevention trials, trace back to it.","caveats":["An essay rather than a systematic review.","Distinguishing tumour-promoting from tumour-fighting inflammation remains a central challenge."],"changedPractice":false},{"id":"paper-bao-glioma-stem-cells-radioresistance-nature-2006","kind":"paper","name":"Bao 2006: glioma stem cells resist radiotherapy by activating the DNA damage response","aka":[],"tldr":"The glioblastoma cells with stem-like features survive radiotherapy better than the rest of the tumour because they repair DNA damage more efficiently, which helps explain why the cancer returns after treatment and points to checkpoint inhibitors as a way to sensitise it.","summary":"Bao, Rich and colleagues showed that CD133-positive glioma cells, the fraction with stem cell properties, became enriched after ionising radiation both in mouse xenografts and in patient specimens. These cells activated the DNA damage checkpoint proteins ATM, Rad17, Chk1 and Chk2 more strongly and repaired radiation-induced DNA damage more effectively than CD133-negative cells. Blocking Chk1 and Chk2 with a small molecule reversed the radioresistance, suggesting a way to target the cells that survive standard treatment.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature05236"}],"tags":[],"related":["paper-reya-cancer-stem-cells-nature-2001"],"cancers":["glioblastoma"],"sections":[],"technologies":[],"targets":["atr"],"drugs":[],"companies":[],"institutions":["duke-cancer-institute"],"pathways":[],"terms":["stem-cell","radiotherapy","relapse-recurrence"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2006,"doi":"10.1038/nature05236","authors":"Bao S, Wu Q, McLendon RE, et al.","paperType":"basic","findings":["CD133-positive glioma cells were enriched after radiation in xenografts and in patient tumours.","These cells showed preferential activation of the DNA damage checkpoint (ATM, Rad17, Chk1, Chk2) and more effective DNA repair.","A Chk1 and Chk2 inhibitor reversed the radioresistance of the CD133-positive cells."],"whatItMeans":"This paper connected the cancer stem cell idea to a clinical problem, the near-universal recurrence of glioblastoma after radiotherapy, and gave a mechanism and a drug target. It is part of the rationale for combining radiotherapy with DNA damage response inhibitors now in trials.","caveats":["CD133 is an imperfect marker of glioma stem cells and CD133-negative cells can also initiate tumours.","Mouse xenograft and cell line work; the clinical benefit of checkpoint inhibition with radiotherapy is not yet proven."],"changedPractice":false},{"id":"paper-basch-epro-survival-jama-2017","kind":"paper","name":"Basch: asking patients to report symptoms online during chemotherapy improved survival","aka":[],"tldr":"Patients on chemotherapy for advanced cancer who reported 12 symptoms weekly through a web tool, with nurse alerts for severe symptoms, lived a median 5 months longer than those receiving usual care.","summary":"This single-centre trial at Memorial Sloan Kettering randomised 766 patients starting chemotherapy for metastatic solid tumours to weekly electronic self-reporting of 12 common symptoms (with email alerts to nurses when symptoms worsened or were severe) or to usual care, in which symptoms were discussed at visits.\n\nThe 2016 JCO report showed better health-related quality of life at 6 months (improved in 34% vs 18%), fewer emergency department visits (34% vs 41%), fewer hospitalisations and longer time on chemotherapy (8.2 vs 6.3 months). This 2017 research letter reported the overall survival analysis: median 31.2 months with self-reporting versus 26.0 months with usual care.\n\nThe survival result, replicated in a French lung cancer trial (Denis, JAMA 2019), turned symptom monitoring into a standard of care and drove the design of the multi-site PRO-TECT trial.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1001/jama.2017.7156"},{"label":"Primary report (JCO 2016)","url":"https://doi.org/10.1200/JCO.2015.63.0830"},{"label":"ClinicalTrials.gov NCT00578006","url":"https://clinicaltrials.gov/study/NCT00578006"}],"tags":[],"related":["idea-moon-pro-monitoring-standard","idea-acc-electronic-pro-monitoring-standard","idea-data-pro-as-structured-standard","idea-moon-pro-ctcae-in-every-pivotal-trial"],"cancers":[],"sections":["supportive-care"],"technologies":["epro-symptom-monitoring","remote-patient-monitoring"],"targets":[],"drugs":[],"companies":[],"institutions":["mskcc"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-patient-voice","b-toxicity-qol","b-care-fragmentation"],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2017,"doi":"10.1001/jama.2017.7156","pmid":"28586821","authors":"Basch E, Deal AM, Dueck AC, et al.","paperType":"rct","findings":["Median overall survival 31.2 vs 26.0 months (HR 0.83, 95% CI 0.70-0.99; p = 0.03)","Health-related quality of life improved in 34% vs 18% at 6 months (JCO 2016)","Emergency department visits 34% vs 41%; hospitalisations 45% vs 49%","Patients stayed on chemotherapy longer: median 8.2 vs 6.3 months"],"whatItMeans":"Routinely asking patients how they feel between visits, and acting on the answers, is a treatment in itself. It catches problems early, keeps people on effective therapy longer and appears to extend life. Cancer centres now build symptom monitoring into electronic records, though implementation is uneven.","caveats":["Single centre; survival was a secondary endpoint and the effect size is modest","The larger multi-site PRO-TECT trial (2022) improved physical function and symptom control but did not show a survival benefit","Requires nursing capacity to respond to alerts; the mechanism may be earlier intervention rather than the reporting itself","Patients unfamiliar with computers were given a bespoke system, a subgroup that showed the largest benefit"],"changedPractice":true,"participants":766},{"id":"paper-bclc-2022-reig-j-hepatol-2022","kind":"paper","name":"BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update","aka":[],"tldr":"The 2022 Barcelona Clinic Liver Cancer update refines the staging system that links liver cancer stage to treatment, incorporating immunotherapy as first-line systemic therapy, treatment stage migration and a more nuanced view of intermediate-stage disease.","summary":"Update of the BCLC staging and treatment algorithm for hepatocellular carcinoma covering very early, early, intermediate, advanced and terminal stages, with revised recommendations for resection, ablation, transplantation, transarterial therapies, and systemic therapy led by atezolizumab-bevacizumab and durvalumab-tremelimumab, plus the concepts of treatment stage migration and untreatable progression.","asOf":"2026-09-17","links":[{"label":"J Hepatol 2022","url":"https://doi.org/10.1016/j.jhep.2021.11.018"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34801630/"}],"tags":[],"related":[],"cancers":["hcc-early","hcc-intermediate","hcc-advanced"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Hepatology","year":2022,"doi":"10.1016/j.jhep.2021.11.018","pmid":"34801630","authors":"Reig M, Forner A, Rimola J, et al.","paperType":"guideline","findings":[],"whatItMeans":"The BCLC stages used on this site's hepatocellular carcinoma pages and their default treatments follow this update.","caveats":["Combination of locoregional and systemic therapy for intermediate disease (EMERALD-1, LEAP-012) postdates the update."],"changedPractice":true},{"id":"paper-beacon-crc-kopetz-nejm-2019","kind":"paper","name":"BEACON CRC: encorafenib and cetuximab with or without binimetinib in BRAF V600E-mutated colorectal cancer","aka":[],"tldr":"Blocking BRAF with encorafenib and EGFR with cetuximab lengthened survival compared with standard chemotherapy in previously treated BRAF V600E-mutant colorectal cancer, the first targeted regimen to work in this poor-prognosis group.","summary":"Phase 3 trial of 665 patients with BRAF V600E-mutated metastatic colorectal cancer after one or two prior regimens randomised to encorafenib, binimetinib and cetuximab (triplet), encorafenib and cetuximab (doublet), or investigator's choice of irinotecan-based chemotherapy with cetuximab.\n\nMedian overall survival was 9.0 months with the triplet and 8.4 months with the doublet against 5.4 months with control; response rates were 26 and 20 percent against 2 percent. The MEK inhibitor added little, so the doublet was approved.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2019","url":"https://doi.org/10.1056/NEJMoa1908075"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31566309/"}],"tags":[],"related":[],"cancers":["braf-v600e-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["binimetinib","cetuximab","encorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["beacon-crc"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1908075","pmid":"31566309","authors":"Kopetz S, Grothey A, Yaeger R, et al.","paperType":"rct","findings":["Median overall survival 9.0 (triplet) and 8.4 (doublet) vs 5.4 months (control).","Objective response 26 percent, 20 percent and 2 percent."],"whatItMeans":"Encorafenib-cetuximab became the standard second-line treatment for BRAF V600E colorectal cancer, and BREAKWATER has since moved the combination, with chemotherapy, into first line.","caveats":["Responses are short-lived compared with BRAF-targeted therapy in melanoma.","Control arm chemotherapy performed poorly."],"changedPractice":true,"participants":665},{"id":"paper-beamion-lung-1-zongertinib-nejm-2025","kind":"paper","name":"Beamion LUNG-1: zongertinib in previously treated HER2-mutant non-small-cell lung cancer","aka":[],"tldr":"The oral HER2-selective kinase inhibitor zongertinib shrank tumours in about seven in ten patients with previously treated HER2-mutant lung cancer with little of the diarrhoea and rash that plagued earlier HER2 pills, becoming the first oral drug approved for this driver.","summary":"Phase 1a/1b study; the primary cohort treated 75 patients with previously treated HER2 tyrosine kinase domain-mutant advanced non-small-cell lung cancer with zongertinib 120 mg daily.\n\nObjective response was 71 percent with a median progression-free survival of 12.4 months, intracranial activity in patients with brain metastases, and mainly low-grade diarrhoea and rash; a separate cohort showed activity after prior trastuzumab deruxtecan.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2025","url":"https://doi.org/10.1056/NEJMoa2503704"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/40293180/"}],"tags":[],"related":[],"cancers":["her2-mutant-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["zongertinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["beamion-lung-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2503704","pmid":"40293180","authors":"Heymach JV, Ruiter G, Ahn MJ, et al.","paperType":"observational","findings":["Objective response 71 percent.","Median progression-free survival 12.4 months."],"whatItMeans":"Zongertinib gives HER2-mutant lung cancer an oral targeted option with brain activity, used after platinum chemotherapy and increasingly before or after trastuzumab deruxtecan.","caveats":["Single-arm phase 1 data; first-line trials against chemo-immunotherapy are ongoing."],"changedPractice":true,"participants":75},{"id":"paper-belzutifan-vhl-jonasch-nejm-2021","kind":"paper","name":"Belzutifan for renal cell carcinoma and other tumours in von Hippel-Lindau disease","aka":[],"tldr":"The oral HIF-2 alpha inhibitor belzutifan shrank kidney cancers in about half of people with von Hippel-Lindau disease and also shrank their brain and spinal haemangioblastomas and pancreatic tumours, letting many avoid repeated operations.","summary":"Phase 2 study of 61 patients with von Hippel-Lindau disease and at least one measurable renal cell carcinoma not needing immediate surgery, treated with belzutifan 120 mg daily.\n\nObjective response in renal tumours was 49 percent, with responses in 30 percent of central nervous system haemangioblastomas and 77 percent of pancreatic neuroendocrine tumours; anaemia and hypoxia were the main side effects.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2021","url":"https://doi.org/10.1056/NEJMoa2103425"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34818478/"}],"tags":[],"related":[],"cancers":["spinal-cord-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":["belzutifan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2103425","pmid":"34818478","authors":"Jonasch E, Donskov F, Iliopoulos O, et al.","paperType":"observational","findings":["Renal cell carcinoma objective response 49 percent.","Central nervous system haemangioblastoma response 30 percent; pancreatic neuroendocrine tumour response 77 percent."],"whatItMeans":"Belzutifan is the first systemic therapy for von Hippel-Lindau disease, approved for renal, central nervous system and pancreatic tumours not needing immediate surgery, changing a lifetime of surveillance and surgery for many patients.","caveats":["Single-arm study; long-term durability and the effect on survival are unknown.","Anaemia in most patients, hypoxia in a minority; teratogenic."],"changedPractice":true,"participants":61},{"id":"paper-bilcap-lancet-oncol-2019","kind":"paper","name":"BILCAP: capecitabine compared with observation in resected biliary tract cancer","aka":[],"tldr":"Six months of capecitabine tablets after surgery for bile duct or gallbladder cancer lengthened survival by about a year in the per-protocol analysis, and became the standard adjuvant treatment despite narrowly missing its primary endpoint.","summary":"Phase 3 trial of 447 patients with completely resected cholangiocarcinoma (intrahepatic, perihilar or distal) or gallbladder cancer randomised to eight cycles of capecitabine or observation.\n\nIn the intention-to-treat analysis median overall survival was 51.1 versus 36.4 months (hazard ratio 0.81, not significant); in the prespecified per-protocol analysis it was 53 versus 36 months (hazard ratio 0.75, significant), and the adjusted analysis and long-term follow-up supported benefit.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2019","url":"https://doi.org/10.1016/S1470-2045(18)30915-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30922733/"}],"tags":[],"related":[],"cancers":["extrahepatic-cholangiocarcinoma","intrahepatic-cholangiocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["capecitabine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["bilcap"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2019,"doi":"10.1016/S1470-2045(18)30915-X","pmid":"30922733","authors":"Primrose JN, Fox RP, Palmer DH, et al.","paperType":"rct","findings":["Intention to treat: median overall survival 51.1 vs 36.4 months; hazard ratio 0.81 (not significant).","Per protocol: 53 vs 36 months; hazard ratio 0.75."],"whatItMeans":"Adjuvant capecitabine is the standard after resection of intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, endorsed by ASCO and ESMO guidelines.","caveats":["Primary endpoint not met in the intention-to-treat population.","Whether gemcitabine-cisplatin or chemo-immunotherapy adjuvant regimens are better is under study."],"changedPractice":true,"participants":447},{"id":"paper-binnewies-tumor-immune-microenvironment-natmed-2018","kind":"paper","name":"Binnewies 2018: understanding the tumour immune microenvironment for effective therapy","aka":[],"tldr":"A review that sorted tumours by where their immune cells sit, inflamed and infiltrated, infiltrated but excluded, or immune-poor, and argued that this classification should guide which immunotherapy a patient receives.","summary":"Binnewies, Krummel and colleagues proposed classifying the tumour immune microenvironment (TIME) by the density and position of immune cells: infiltrated-excluded tumours with T cells confined to the margins and stroma, infiltrated-inflamed tumours with T cells among the cancer cells and high PD-L1, and a subclass with tertiary lymphoid structures. They reviewed how these states arise from tumour genetics, the microbiome and host factors, how they predict response to checkpoint blockade, and how therapies including chemotherapy, radiotherapy and myeloid-targeting agents might convert excluded or cold tumours into inflamed ones.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/s41591-018-0014-x"}],"tags":[],"related":["paper-thorsson-immune-landscape-of-cancer-immunity-2018","paper-tumeh-pd1-adaptive-immune-resistance-nature-2014"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pdl1"],"drugs":[],"companies":[],"institutions":["ucsf"],"pathways":[],"terms":["cold-vs-hot","tils","immune-system"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2018,"doi":"10.1038/s41591-018-0014-x","authors":"Binnewies M, Roberts EW, Kersten K, et al.","paperType":"review","findings":["Tumour immune microenvironments fall into infiltrated-excluded, infiltrated-inflamed and tertiary lymphoid structure classes.","Inflamed tumours with intratumoural T cells and PD-L1 are the most likely to respond to checkpoint blockade.","Proposed therapeutic strategies to convert excluded or immune-poor tumours into inflamed ones."],"whatItMeans":"This framework is behind the everyday language of hot and cold tumours and the design of combination trials that pair checkpoint inhibitors with treatments meant to draw T cells into the tumour.","caveats":["Classes are descriptive and the boundaries between them are not sharp.","A review; prospective use of TIME classification to choose therapy is still being tested."],"changedPractice":false},{"id":"paper-rossi-richter-syndrome-blood-2018","kind":"paper","name":"Biology and treatment of Richter syndrome","aka":[],"tldr":"This review lays out how chronic lymphocytic leukaemia transforms into aggressive lymphoma, which genetic changes drive it, and how the diffuse large B-cell type should be treated, including the role of transplant and new agents.","summary":"Comprehensive review of Richter syndrome covering incidence, clonal relationship to the underlying CLL, the roles of TP53, NOTCH1, MYC and CDKN2A lesions, the effect of BTK inhibitor exposure, diagnostic work-up with PET-directed biopsy, prognostic scores, chemoimmunotherapy outcomes, consolidation with stem cell transplantation, and emerging targeted and immune therapies.","asOf":"2026-09-17","links":[{"label":"Blood 2018","url":"https://doi.org/10.1182/blood-2018-01-791376"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29692342/"}],"tags":[],"related":[],"cancers":["richter-transformation-cll"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2018,"doi":"10.1182/blood-2018-01-791376","pmid":"29692342","authors":"Rossi D, Spina V, Gaidano G.","paperType":"review","findings":[],"whatItMeans":"The page's approach to Richter transformation (biopsy the hottest node, R-CHOP-type therapy, consolidate with transplant if fit, trial enrolment otherwise) follows the framework in this review.","caveats":["Predates the bispecific antibody and pirtobrutinib data that now shape trials."],"changedPractice":false},{"id":"paper-blinatumomab-infant-all-van-der-sluis-nejm-2023","kind":"paper","name":"Blinatumomab added to chemotherapy in infant KMT2A-rearranged acute lymphoblastic leukaemia","aka":[],"tldr":"Adding a single course of the bispecific antibody blinatumomab after induction chemotherapy in infants with KMT2A-rearranged leukaemia raised two-year disease-free survival from a historical 49 percent to 82 percent, the first major advance in infant leukaemia in decades.","summary":"Single-arm phase 2 study of 30 infants with newly diagnosed KMT2A-rearranged ALL treated on the Interfant-06 backbone with one 28-day course of blinatumomab after induction, compared with historical Interfant-06 controls.\n\nTwo-year disease-free survival was 81.6 percent against 49.4 percent historically, overall survival 93.3 versus 65.8 percent, and blinatumomab was well tolerated with no treatment discontinuations for toxicity; measurable residual disease became negative or low in almost all infants.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2214171"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37099340/"}],"tags":[],"related":[],"cancers":["all-infant"],"sections":[],"technologies":[],"targets":[],"drugs":["blinatumomab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2214171","pmid":"37099340","authors":"van der Sluis IM, de Lorenzo P, Kotecha RS, et al.","paperType":"observational","findings":["Two-year disease-free survival 81.6 percent vs 49.4 percent in historical controls.","Two-year overall survival 93.3 percent vs 65.8 percent."],"whatItMeans":"Blinatumomab after induction is now standard for KMT2A-rearranged infant ALL through the Interfant-21 protocol.","caveats":["Thirty patients with historical comparison; longer follow-up needed."],"changedPractice":true,"participants":30},{"id":"paper-bolt-sonidegib-migden-lancet-oncol-2015","kind":"paper","name":"BOLT: two doses of sonidegib in locally advanced or metastatic basal cell carcinoma","aka":[],"tldr":"Sonidegib, a second hedgehog inhibitor, shrank tumours in about 40 percent of patients with locally advanced basal cell carcinoma at the lower 200 mg dose with fewer side effects than the higher dose, and was approved as an alternative to vismodegib.","summary":"Randomised phase 2 trial of 230 patients with locally advanced or metastatic basal cell carcinoma randomised to sonidegib 200 mg or 800 mg daily.\n\nObjective response by central review was 36 percent (200 mg) and 34 percent (800 mg) in locally advanced disease, with lower toxicity and discontinuation at 200 mg; the metastatic cohort response was lower, and later analyses reported higher responses with longer follow-up.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2015","url":"https://doi.org/10.1016/S1470-2045(15)70100-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25981810/"}],"tags":[],"related":[],"cancers":["locally-advanced-bcc"],"sections":[],"technologies":[],"targets":[],"drugs":["sonidegib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["bolt"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2015,"doi":"10.1016/S1470-2045(15)70100-2","pmid":"25981810","authors":"Migden MR, Guminski A, Gutzmer R, et al.","paperType":"rct","findings":["Objective response 36 percent (200 mg) vs 34 percent (800 mg) in locally advanced disease.","Fewer grade 3 to 4 adverse events at 200 mg."],"whatItMeans":"Sonidegib 200 mg is an approved option for locally advanced basal cell carcinoma with a side-effect profile similar to vismodegib.","caveats":["Randomised between doses only; no comparison with vismodegib or placebo."],"changedPractice":true,"participants":230},{"id":"paper-esmo-bone-sarcoma-guideline-strauss-ann-oncol-2021","kind":"paper","name":"Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan clinical practice guideline","aka":[],"tldr":"The European guideline for bone sarcomas covers referral to specialist centres, biopsy, surgery, chemotherapy for osteosarcoma and Ewing sarcoma, and the surgery-based management of chondrosarcoma and chordoma including proton and carbon-ion radiotherapy.","summary":"Joint European guideline on the diagnosis, treatment and follow-up of bone sarcomas in adults and children, with sections on osteosarcoma, Ewing sarcoma, chondrosarcoma (including atypical cartilaginous tumour, dedifferentiated and mesenchymal subtypes), chordoma and giant cell tumour of bone.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2021","url":"https://doi.org/10.1016/j.annonc.2021.08.1995"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34500044/"}],"tags":[],"related":[],"cancers":["chondrosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2021,"doi":"10.1016/j.annonc.2021.08.1995","pmid":"34500044","authors":"Strauss SJ, Frezza AM, Abecassis N, et al.","paperType":"guideline","findings":[],"whatItMeans":"The chondrosarcoma page's recommendations for curettage of low-grade limb lesions, wide resection for higher grades and particle therapy for skull base tumours follow this guideline.","caveats":["Evidence for chemotherapy in dedifferentiated and mesenchymal chondrosarcoma remains weak."],"changedPractice":true},{"id":"paper-bray-globocan-2018-cacancer-2018","kind":"paper","name":"Bray 2018: GLOBOCAN 2018, worldwide incidence and mortality for 36 cancers","aka":[],"tldr":"The IARC count for 2018: about 18.1 million new cancer cases worldwide, with lung cancer the most commonly diagnosed and most lethal, and about one in five men and one in six women developing cancer during their lifetime.","summary":"GLOBOCAN 2018 estimated cancer incidence and mortality for 36 cancers in 185 countries from national and regional registries and modelling. It counted 18.1 million new cases in 2018. Lung cancer was the most commonly diagnosed cancer and the leading cause of cancer death, followed for incidence by female breast, colorectal and prostate cancers. The report described how cancer patterns differ with a country's level of development, with infection-related cancers of the cervix, liver and stomach concentrated in transitioning economies.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21492"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-sung-globocan-2020-cacancer-2021","paper-bray-globocan-2022-cacancer-2024"],"cancers":["nsclc","breast-hr-positive","colorectal","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":["bray-freddie"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2018,"doi":"10.3322/caac.21492","authors":"Bray F, Ferlay J, Soerjomataram I, et al.","paperType":"observational","findings":["About 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018.","Lung cancer the most commonly diagnosed (11.6% of cases) and the leading cause of cancer death (18.4% of deaths); female breast cancer also 11.6% of cases; colorectal 10.2%; prostate 7.1%.","About one in five men and one in six women develop cancer during their lifetime; one in eight men and one in eleven women die from it."],"whatItMeans":"This was the most cited description of the global cancer burden until the 2020 release and is the reference behind many national cancer plans of the late 2010s. Its country-level comparisons showed where prevention, such as HPV and hepatitis B vaccination and tobacco control, would have the largest effect.","caveats":["Registry coverage is incomplete in much of Africa and Asia, so those estimates depend on modelling.","Superseded by the 2020 and 2022 releases."],"changedPractice":false},{"id":"paper-bray-globocan-2022-cacancer-2024","kind":"paper","name":"Bray 2024: GLOBOCAN 2022, the world's cancer count for 36 cancers in 185 countries","aka":[],"tldr":"The IARC estimate that about 20 million people were diagnosed with cancer in 2022 and 9.7 million died of it, with lung cancer the most common and most lethal, breast cancer second, and the total expected to rise by about three quarters by 2050 as populations grow and age.","summary":"GLOBOCAN 2022, produced by the International Agency for Research on Cancer, estimates new cases and deaths for 36 cancer types in 185 countries from national registries and modelling. It counted close to 20 million new cases (including non-melanoma skin cancer) and 9.7 million deaths in 2022. Lung cancer was the most frequently diagnosed cancer and the leading cause of cancer death, followed by female breast cancer for incidence and colorectal cancer for both. About one in five people develop cancer in their lifetime. The report projects around 35 million new cases a year by 2050, an increase of roughly 77% driven mostly by demographic change, and it is the reference that country pages, prevalence charts and policy papers cite.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21834"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":[],"cancers":["nsclc","breast-hr-positive","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":[],"trials":[],"people":["bray-freddie"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2024,"doi":"10.3322/caac.21834","authors":"Bray F, Laversanne M, Sung H, et al.","paperType":"observational","findings":["Close to 20 million new cancer cases and 9.7 million cancer deaths worldwide in 2022.","Lung cancer: about 2.5 million cases (12.4% of the total) and 1.8 million deaths (18.7%), the leading cause of cancer death.","Female breast cancer second most common (about 2.3 million cases); colorectal cancer third for incidence and second for deaths.","Roughly one in five people develop cancer in their lifetime; about one in nine men and one in twelve women die from it.","Projection of about 35 million new cases in 2050, a 77% increase over 2022."],"whatItMeans":"This is the number behind almost every statement about how much cancer there is. It shows the burden shifting towards low- and middle-income countries and towards older populations, which is why prevention, screening and affordable treatment in those settings decide the global trend. OnCo's country and prevalence pages draw on the same GLOBOCAN release.","caveats":["Many countries lack population-based registries, so estimates there rest on modelling from neighbours and mortality data.","Non-melanoma skin cancer is counted inconsistently across registries and is often excluded from headline totals.","Estimates are for 2022 and are revised as registries report."],"changedPractice":false},{"id":"paper-breakwater-nejm-2025","kind":"paper","name":"BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer","aka":[],"tldr":"Adding a BRAF inhibitor and an EGFR antibody to first-line chemotherapy roughly doubled survival in BRAF V600E-mutated metastatic bowel cancer, one of the worst-prognosis subtypes.","summary":"Open-label phase 3 trial of patients with untreated BRAF V600E-mutated metastatic colorectal cancer randomised to encorafenib plus cetuximab plus mFOLFOX6, encorafenib plus cetuximab alone (arm later closed), or standard chemotherapy with or without bevacizumab. Primary endpoints were PFS and objective response rate.\n\nThe first report (Nature Medicine 2025) showed a response rate of about 61% vs 40%, supporting accelerated FDA approval in December 2024. The 2025 NEJM report showed median PFS 12.8 vs 7.1 months (HR 0.53) and median OS 30.3 vs 15.1 months (HR 0.49). It moved BRAF-targeted therapy from second line (BEACON) to first line and is the largest survival gain ever seen in this subgroup.","asOf":"2026-09-08","links":[{"label":"PubMed search: BREAKWATER encorafenib NEJM 2025","url":"https://pubmed.ncbi.nlm.nih.gov/?term=BREAKWATER+encorafenib+cetuximab+mFOLFOX6+colorectal"},{"label":"ClinicalTrials.gov NCT04607421","url":"https://clinicaltrials.gov/study/NCT04607421"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["kinase-inhibitors","monoclonal-antibody","cytotoxic-chemotherapy","cgp"],"targets":["braf","egfr"],"drugs":["encorafenib"],"companies":["pfizer"],"institutions":["vall-dhebron","md-anderson"],"pathways":[],"terms":["orr","pfs","os","first-line","accelerated-approval"],"trials":[],"people":["elena-elez","yoshino-takayuki","shen-lin","kim-tae-won","josep-tabernero"],"bottlenecks":["b-resistance","b-combination-space","b-drug-pricing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"authors":"Elez E, Yoshino T, Shen L, et al.","paperType":"rct","findings":["Objective response about 61% vs 40% in the first analysis (Nature Medicine 2025), with longer duration of response.","Median PFS 12.8 vs 7.1 months; HR 0.53.","Median overall survival 30.3 vs 15.1 months; HR 0.49.","Grade 3 or higher adverse events were more frequent with the triplet plus chemotherapy, driven by skin toxicity, gastrointestinal events and neutropenia.","The chemotherapy-free encorafenib plus cetuximab arm was stopped early after emerging data from other studies."],"whatItMeans":"Patients with newly diagnosed metastatic colorectal cancer whose tumour carries a BRAF V600E mutation, which is about 8-12% of cases, should now be offered encorafenib and cetuximab together with FOLFOX from the start rather than after chemotherapy fails; median survival has roughly doubled to about two and a half years. BRAF testing at diagnosis is therefore essential, alongside RAS and mismatch repair testing. The regimen is more toxic than chemotherapy alone.","caveats":["Open-label; some figures come from conference presentations and interim analyses, and long-term follow-up is short.","Most patients had microsatellite-stable tumours; dMMR BRAF-mutated tumours should still receive immunotherapy first.","Combination toxicity and cost are considerable; treatment requires three targeted or antibody agents plus chemotherapy.","Resistance to BRAF/EGFR blockade remains universal; the trial does not address what follows."],"changedPractice":true},{"id":"paper-chapman-vemurafenib-nejm-2011","kind":"paper","name":"BRIM-3: improved survival with vemurafenib in melanoma with BRAF V600E mutation","aka":[],"tldr":"Vemurafenib, the first drug targeting the BRAF V600E mutation, reduced deaths by 63 percent compared with dacarbazine chemotherapy in metastatic melanoma, launching targeted therapy in the disease.","summary":"Phase 3 trial of 675 patients with previously untreated BRAF V600E-mutant metastatic melanoma randomised to vemurafenib or dacarbazine.\n\nAt interim analysis, the hazard ratio for death was 0.37 and for progression 0.26, with response of 48 versus 5 percent; cutaneous squamous cell carcinomas, arthralgia and photosensitivity were the characteristic toxicities, and the data monitoring board recommended crossover.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2011","url":"https://doi.org/10.1056/NEJMoa1103782"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21639808/"}],"tags":[],"related":[],"cancers":["braf-v600-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["vemurafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1103782","pmid":"21639808","authors":"Chapman PB, Hauschild A, Robert C, et al.","paperType":"rct","findings":["Hazard ratio for death 0.37; for progression 0.26 at interim analysis.","Objective response 48 percent vs 5 percent."],"whatItMeans":"BRAF testing became mandatory in advanced melanoma and vemurafenib the first approved BRAF inhibitor; combination with MEK inhibitors soon replaced monotherapy.","caveats":["Early analysis; responses were often short because of acquired resistance.","Keratoacanthomas and squamous cell carcinomas in about 18 percent."],"changedPractice":true,"participants":675},{"id":"paper-burris-gemcitabine-pancreatic-jco-1997","kind":"paper","name":"Burris 1997: gemcitabine becomes the first standard treatment for advanced pancreatic cancer","aka":[],"tldr":"A small trial that made gemcitabine the standard chemotherapy for pancreatic cancer for the next fifteen years, on the strength of more patients feeling better on treatment and a modest gain in survival over fluorouracil.","summary":"Burris and colleagues randomised 126 patients with advanced, symptomatic pancreatic cancer to weekly gemcitabine or weekly bolus fluorouracil. The primary endpoint was clinical benefit response, a composite of pain, performance status and weight, which gemcitabine improved in about a quarter of patients compared with a few percent on fluorouracil. Median survival was modestly longer and more patients were alive at one year. The trial led to gemcitabine's approval and defined the comparator arm for every pancreatic cancer trial until FOLFIRINOX and nab-paclitaxel.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1200/JCO.1997.15.6.2403"}],"tags":[],"related":["paper-conroy-folfirinox-pancreatic-nejm-2011","paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013"],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":[],"drugs":["gemcitabine","fluorouracil"],"companies":[],"institutions":[],"pathways":[],"terms":["os","quality-of-life"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":1997,"doi":"10.1200/JCO.1997.15.6.2403","authors":"Burris HA 3rd, Moore MJ, Andersen J, et al.","paperType":"rct","findings":["126 patients with advanced pancreatic cancer; gemcitabine vs fluorouracil.","Clinical benefit response 23.8% vs 4.8%.","Median survival 5.65 vs 4.41 months; survival at 12 months 18% vs 2%."],"whatItMeans":"This trial introduced a patient-centred composite endpoint and a drug that remained the backbone of pancreatic cancer treatment for a generation. Its small survival gain also shows how low the bar was, which is the context for the FOLFIRINOX and MPACT trials that followed.","caveats":["Small trial with a novel primary endpoint that regulators accepted once and rarely since.","The survival advantage was modest and the comparator, bolus fluorouracil, is no longer used this way."],"changedPractice":true,"participants":126},{"id":"paper-c-144-01-lifileucel-melanoma-jco-2021","kind":"paper","name":"C-144-01: lifileucel, tumour-infiltrating lymphocytes grown from a patient's own tumour, in melanoma after checkpoint inhibitors have failed","aka":[],"tldr":"Immune cells harvested from a patient's tumour, expanded in the lab and reinfused shrank melanoma in 36% of patients whose disease had progressed on PD-1 blockade, with responses that mostly lasted.","summary":"Cohort 2 of the C-144-01 phase 2 trial treated 66 patients with advanced melanoma that had progressed after anti-PD-1 therapy (and BRAF/MEK inhibitors where indicated; median 3.3 prior lines) with a single infusion of lifileucel, autologous tumour-infiltrating lymphocytes expanded centrally over about 22 days, after non-myeloablative lymphodepletion and followed by up to six doses of high-dose interleukin-2. The objective response rate was 36% (2 complete, 22 partial) with disease control in 80%; median duration of response was not reached at 18.7 months of follow-up. Adverse events were largely attributable to lymphodepletion and IL-2 and resolved within two weeks, with two treatment-related deaths. Pooled analysis of 153 patients from cohorts 2 and 4 showed a 31% response rate and supported FDA accelerated approval in February 2024, the first TIL therapy and first cell therapy for a solid tumour.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=C-144-01%20lifileucel%20tumor-infiltrating%20lymphocyte%20melanoma%20Sarnaik%20JCO%202021"},{"label":"ClinicalTrials.gov NCT02360579","url":"https://clinicaltrials.gov/study/NCT02360579"}],"tags":[],"related":["paper-rohaas-til-vs-ipilimumab-nejm-2022"],"cancers":["melanoma"],"sections":[],"technologies":["til-therapy"],"targets":[],"drugs":["lifileucel","aldesleukin","cyclophosphamide"],"companies":["iovance"],"institutions":["moffitt","nci"],"pathways":[],"terms":["tils","orr"],"trials":["c-144-01"],"people":["amod-sarnaik","steven-rosenberg"],"bottlenecks":["b-manufacturing-cell-therapy","b-immunotherapy-response"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2021,"authors":"Sarnaik AA, Hamid O, Khushalani NI, et al.","paperType":"translational","findings":["66 patients with anti-PD-1-refractory advanced melanoma; median 3.3 prior therapies; single lifileucel infusion after cyclophosphamide-fludarabine lymphodepletion, then up to 6 doses of high-dose IL-2.","Objective response 36% (3% complete); disease control 80%.","Median duration of response not reached at 18.7 months; responses deepened over time in some patients.","Grade 3-4 adverse events mostly cytopenias, febrile neutropenia and IL-2-related hypotension, resolving within 2 weeks; 2 treatment-related deaths.","Pooled cohorts 2 and 4 (153 patients): objective response 31.4%, supporting accelerated approval in 2024."],"whatItMeans":"Lifileucel proved that Steven Rosenberg's decades-old TIL concept could be industrialised into a licensed product and gave patients with checkpoint-refractory melanoma, who otherwise have few options, a chance of durable remission. It is the first cell therapy approved for any solid tumour. The treatment requires surgery to harvest tumour, hospitalisation for lymphodepletion and IL-2, and specialised centres, so its reach is limited.","caveats":["Single-arm trial; approval rested on response rate rather than survival.","Toxic conditioning and high-dose IL-2 make the regimen unsuitable for frail patients.","Manufacturing takes about three weeks and needs a resectable lesion; not all patients yield a product.","Cost (list price above 500,000 US dollars) and centre requirements restrict access."],"changedPractice":true,"participants":66},{"id":"paper-c-post-adjuvant-cemiplimab-nejm-2025","kind":"paper","name":"C-POST: adjuvant cemiplimab versus placebo in high-risk cutaneous squamous cell carcinoma","aka":[],"tldr":"A year of cemiplimab after surgery and radiotherapy for high-risk cutaneous squamous cell carcinoma cut the risk of recurrence or death by more than two thirds, the first adjuvant therapy to work in this skin cancer.","summary":"Phase 3 placebo-controlled trial of 415 patients with cutaneous squamous cell carcinoma at high risk of recurrence after surgery and postoperative radiotherapy (nodal disease with extracapsular extension, in-transit metastases, perineural invasion or recurrent tumours) randomised to cemiplimab or placebo for up to 48 weeks.\n\nDisease-free survival at 24 months was 87.1 versus 64.1 percent (hazard ratio 0.32), with reductions in both locoregional and distant recurrence; grade 3 or higher adverse events were 23.9 versus 14.2 percent.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2025","url":"https://doi.org/10.1056/NEJMoa2502449"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/40454639/"}],"tags":[],"related":[],"cancers":["advanced-cutaneous-scc"],"sections":[],"technologies":[],"targets":[],"drugs":["cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2502449","pmid":"40454639","authors":"Rischin D, Porceddu S, Day F, et al.","paperType":"rct","findings":["24-month disease-free survival 87.1 percent vs 64.1 percent; hazard ratio 0.32.","Freedom from locoregional recurrence hazard ratio 0.20; from distant recurrence 0.35."],"whatItMeans":"Adjuvant cemiplimab is a new standard for high-risk cutaneous squamous cell carcinoma after surgery and radiotherapy, particularly in patients with extracapsular nodal extension.","caveats":["Overall survival data immature.","Immunosuppressed and transplant patients, who bear much of the disease burden, were excluded."],"changedPractice":true,"participants":415},{"id":"paper-cabinet-cabozantinib-nejm-2024","kind":"paper","name":"CABINET (Alliance A021602): cabozantinib for advanced neuroendocrine tumours","aka":[],"tldr":"Cabozantinib delayed progression in previously treated advanced neuroendocrine tumours of both pancreatic and extra-pancreatic origin compared with placebo, adding a new option after somatostatin analogues, everolimus or radioligand therapy.","summary":"Two parallel phase 3 placebo-controlled trials of cabozantinib in 298 patients with progressive advanced neuroendocrine tumours: 203 with extra-pancreatic (including lung and small bowel) and 95 with pancreatic tumours, all previously treated.\n\nMedian progression-free survival was 8.4 versus 3.9 months in extra-pancreatic tumours (hazard ratio 0.38) and 13.8 versus 4.4 months in pancreatic tumours (hazard ratio 0.23); hypertension, fatigue and diarrhoea were common.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2025","url":"https://doi.org/10.1056/NEJMoa2403991"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39282913/"}],"tags":[],"related":[],"cancers":["lung-net","pancreatic-net","small-intestinal-net"],"sections":[],"technologies":[],"targets":[],"drugs":["cabozantinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["cabinet"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2403991","pmid":"39282913","authors":"Chan JA, Geyer S, Zemla T, et al.","paperType":"rct","findings":["Extra-pancreatic: median progression-free survival 8.4 vs 3.9 months; hazard ratio 0.38.","Pancreatic: 13.8 vs 4.4 months; hazard ratio 0.23."],"whatItMeans":"Cabozantinib is approved for previously treated neuroendocrine tumours of any origin and is a standard later-line choice, including for lung carcinoids.","caveats":["Trials stopped early at interim analysis; overall survival not powered.","Dose reductions needed in most patients."],"changedPractice":true,"participants":298},{"id":"paper-calle-obesity-cancer-mortality-nejm-2003","kind":"paper","name":"Calle 2003: overweight, obesity and death from cancer in 900,000 US adults","aka":[],"tldr":"Following more than 900,000 American adults for 16 years, this study linked higher body weight to death from a wide range of cancers and estimated that excess weight could account for roughly one in seven cancer deaths in men and one in five in women in the United States.","summary":"Using the American Cancer Society's Cancer Prevention Study II, Calle and colleagues followed more than 900,000 adults who were cancer-free at enrolment in 1982 through 1998 and recorded 57,145 cancer deaths. Death rates from cancer rose with body mass index across most cancer sites, including cancers of the oesophagus, colon and rectum, liver, gallbladder, pancreas, kidney, stomach and prostate in men and breast, uterus, cervix and ovary in women. The heaviest participants had cancer death rates about half again higher than people of normal weight, and the authors estimated the share of US cancer deaths attributable to overweight and obesity.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa021423"}],"tags":[],"related":[],"cancers":["colorectal","hcc","pancreatic","endometrial","rcc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["obesity-related-cancers","risk-factor","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2003,"doi":"10.1056/NEJMoa021423","authors":"Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ.","paperType":"observational","findings":["Prospective cohort of more than 900,000 US adults followed for 16 years, with 57,145 cancer deaths.","Body mass index of 40 or more was associated with cancer death rates 52% higher in men and 62% higher in women than normal weight.","Overweight and obesity were estimated to account for about 14% of cancer deaths in men and 20% in women in the United States."],"whatItMeans":"This is the study most often cited for the size of the obesity and cancer link, and it broadened the list of weight-related cancers well beyond the few known before. It underlies weight management advice in cancer prevention guidance and the current interest in whether GLP-1 drugs change cancer risk.","caveats":["Observational, so confounding by diet, activity and other factors cannot be excluded.","Body weight was self-reported at enrolment only.","A US cohort in the 1980s and 1990s; patterns may differ elsewhere."],"changedPractice":false},{"id":"paper-vogelstein-cancer-genome-landscapes-science-2013","kind":"paper","name":"Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful","aka":[],"tldr":"Synthesising the first generation of cancer genome sequencing, Vogelstein and colleagues concluded that about 140 genes can drive cancer when mutated, that a typical solid tumour has 2 to 8 driver mutations among tens of passengers, and that all drivers act through a dozen signalling pathways.","summary":"By 2013 hundreds of tumours had been exome- or genome-sequenced. This review organised the results. Common adult solid tumours carry an average of 33 to 66 non-synonymous somatic mutations, most of them passengers; paediatric tumours and leukaemias carry far fewer, and tumours caused by mutagens (lung, melanoma) or with mismatch-repair defects carry many more.\n\nThe authors listed about 138 driver genes (71 tumour suppressors, 54 oncogenes), described the mutational landscape as a few mountains (frequently mutated genes) and many hills, and grouped all drivers into 12 pathways governing cell fate, cell survival and genome maintenance. They emphasised that intratumoural heterogeneity, the relative paucity of new driver genes and the small number of drugs against tumour suppressor pathways set limits on precision oncology, and argued that early detection and prevention would be at least as important as new drugs.\n\nThe framework shaped how targeted-therapy panels, driver calling and basket trials were designed.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1126/science.1235122"}],"tags":[],"related":["paper-tcga-pancancer-atlas-cell-2018","paper-detect-a-science-2020"],"cancers":[],"sections":["drug-discovery","diagnostics"],"technologies":["wes-wgs","cgp"],"targets":["tp53","kras","pik3ca","braf"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":[],"terms":["oncogene-addiction","tmb","mutational-signature"],"trials":[],"people":["bert-vogelstein","kenneth-kinzler"],"bottlenecks":["b-undruggable-targets","b-tumor-heterogeneity","b-early-detection"],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2013,"doi":"10.1126/science.1235122","pmid":"23539594","authors":"Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW","paperType":"review","findings":["About 140 driver genes identified; a typical common solid tumour has 2-8 driver mutations","Average 33-66 non-synonymous mutations per common adult solid tumour, with mutagen-exposed tumours carrying 200 or more","Drivers converge on 12 pathways in three core processes: cell fate, cell survival, genome maintenance","Most drivers are tumour suppressors, which cannot be directly targeted by conventional drugs","Argued that early detection would deliver more than new drugs for most cancers, foreshadowing the authors' later ctDNA work"],"whatItMeans":"There are not thousands of cancer genes, and any one patient's tumour is driven by only a few of them. That makes targeted sequencing panels sensible, but because most drivers are lost tumour suppressors, drugs exist for only a minority, which is why the same group turned to early detection.","caveats":["Counts of driver genes depend on statistical thresholds and have since grown with larger cohorts (about 300 in TCGA 2018)","Focus on point mutations and small indels; structural variants, epigenetic drivers and non-coding drivers were under-counted","Based on primary tumours; metastatic and treated tumours have additional drivers","Pathway assignments are a simplification of overlapping networks"],"changedPractice":false},{"id":"paper-mathur-ncrp-cancer-statistics-2020","kind":"paper","name":"Cancer Statistics, 2020: Report from National Cancer Registry Programme, India","aka":[],"tldr":"India's official cancer count: about 1.39 million new cancers in 2020, led by breast, lung, mouth, cervix and tongue, with most breast, cervical and head and neck cancers found only once locally advanced.","summary":"Analysis of 28 population-based and 58 hospital-based registries of the ICMR National Cancer Registry Programme (667,666 cases, 2012-2016). The projected number of cancer patients in India for 2020 was 1,392,179. The five leading sites were breast, lung, mouth, cervix uteri and tongue. Most patients presented at a locally advanced stage (breast 57.0%, cervix 60.0%, head and neck 66.6%, stomach 50.8%), while lung cancer presented mainly with distant metastasis (44.0% of men, 47.6% of women). Incidence rose over time at all registries, fastest in Kamrup urban (3.8% annual change); the highest age-adjusted rates were in Aizawl (men, 269.4 per 100,000) and Papumpare (women, 219.8). A 2022 update estimated 1,461,427 cases and a 12.8% rise by 2025.","asOf":"2026-09-10","links":[{"label":"JCO Global Oncology 2020","url":"https://doi.org/10.1200/GO.20.00122"},{"label":"2022 estimates and 2025 projection (IJMR)","url":"https://doi.org/10.4103/ijmr.ijmr_1821_22"}],"tags":[],"related":[],"cancers":["head-and-neck","cervical","breast-hr-positive","nsclc","gastric"],"sections":[],"technologies":["cancer-registries-surveillance"],"targets":[],"drugs":[],"companies":[],"institutions":["icmr-ncrp","icmr","nha-pmjay"],"pathways":[],"terms":[],"trials":[],"people":["mathur-prashant"],"bottlenecks":["b-early-detection","b-data-silos"],"keyPapers":[],"journals":["jco-global-oncology"],"dependsOn":[],"notes":[],"journal":"JCO Global Oncology","year":2020,"doi":"10.1200/GO.20.00122","authors":"Mathur P, Sathishkumar K, Chaturvedi M, et al.","paperType":"observational","findings":["1,392,179 projected new cancers in India in 2020 (1,461,427 estimated for 2022; +12.8% by 2025).","Leading sites: breast, lung, mouth, cervix uteri, tongue; tobacco-related cancers dominate in men.","Locally advanced at diagnosis: breast 57.0%, cervix 60.0%, head and neck 66.6%, stomach 50.8%.","Highest incidence in the north-east (Aizawl and Papumpare districts)."],"whatItMeans":"India's cancer problem is a late-diagnosis problem as much as a treatment problem: the same cancers that dominate (oral, cervical, breast) are the ones screening and vaccination can prevent or catch early. The numbers set the priorities of the National Cancer Grid, PM-JAY oncology packages and the national screening programme.","caveats":["Registries cover about a tenth of the population and are urban-weighted; national figures are projections.","GLOBOCAN 2022 estimates for India (1,413,316 cases) use different methods and are not identical.","Stage data come from hospital registries and may not represent patients never reaching hospital."],"changedPractice":false,"participants":667666},{"id":"paper-capitello-291-nejm-2023","kind":"paper","name":"CAPItello-291: capivasertib plus fulvestrant in hormone receptor-positive advanced breast cancer","aka":[],"tldr":"Adding the AKT inhibitor capivasertib to fulvestrant doubled the time to progression in advanced hormone receptor-positive breast cancer after aromatase inhibitor failure, with the largest gain in tumours with PIK3CA, AKT1 or PTEN alterations.","summary":"Phase 3 placebo-controlled trial of 708 patients with hormone receptor-positive, HER2-negative advanced breast cancer that had relapsed or progressed on an aromatase inhibitor, about 70 percent after a CDK4/6 inhibitor, randomised to capivasertib or placebo with fulvestrant.\n\nMedian progression-free survival was 7.2 versus 3.6 months overall (hazard ratio 0.60) and 7.3 versus 3.1 months in the AKT pathway-altered population (hazard ratio 0.50). Diarrhoea, rash and hyperglycaemia were the main toxicities.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2214131"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37256976/"}],"tags":[],"related":[],"cancers":["hr-positive-metastatic-post-cdk46"],"sections":[],"technologies":[],"targets":[],"drugs":["capivasertib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["capitello-291"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2214131","pmid":"37256976","authors":"Turner NC, Oliveira M, Howell SJ, et al.","paperType":"rct","findings":["Median progression-free survival 7.2 vs 3.6 months overall; hazard ratio 0.60.","AKT pathway-altered: 7.3 vs 3.1 months; hazard ratio 0.50."],"whatItMeans":"Capivasertib-fulvestrant is a standard option for tumours with PIK3CA, AKT1 or PTEN alterations after a CDK4/6 inhibitor, adding a second targeted pathway to endocrine therapy.","caveats":["Approval was limited to pathway-altered tumours because benefit in non-altered disease was uncertain.","Overall survival data were immature."],"changedPractice":true,"participants":708},{"id":"paper-capp2-aspirin-lynch-lancet-2020","kind":"paper","name":"CAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years","aka":[],"tldr":"In carriers of Lynch syndrome, 600 mg of aspirin a day for about two years reduced colorectal cancer over the following decade (HR 0.65 by intention to treat; 0.56 in those who took it for at least two years).","summary":"CAPP2 randomised 861 carriers of a mismatch-repair gene mutation (Lynch syndrome) to aspirin 600 mg daily or placebo for a mean of 25 months, in a factorial design with resistant starch. The pre-specified 10-year follow-up reported here used national registries and questionnaires.\n\nBy intention to treat, 40 aspirin-arm and 58 placebo-arm participants developed colorectal cancer (HR 0.65). Among those who completed at least two years of treatment, the hazard ratio was 0.56. The protective effect emerged only after about five years and persisted for at least a decade after stopping. Adverse events did not differ during the treatment period.\n\nThe result led NICE and other guidelines to recommend daily aspirin for people with Lynch syndrome; the CAPP3 dose-finding trial (100 vs 300 vs 600 mg) followed.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S0140-6736(20)30366-4"},{"label":"CAPP3 ISRCTN16261285","url":"https://www.isrctn.com/ISRCTN16261285"}],"tags":[],"related":["idea-prev-lynch-aspirin-implementation","idea-reg-aspirin-pik3ca-implementation"],"cancers":["colorectal","endometrial"],"sections":["prevention"],"technologies":["chemoprevention","germline-testing"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lynch-syndrome","msi","germline-vs-somatic"],"trials":[],"people":[],"bottlenecks":["b-hereditary-risk","b-prevention-adoption","b-generic-repurposing"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2020,"doi":"10.1016/S0140-6736(20)30366-4","pmid":"32534647","authors":"Burn J, Sheth H, Elliott F, et al.","paperType":"rct","findings":["Colorectal cancer: 40 of 427 on aspirin vs 58 of 434 on placebo, HR 0.65 (95% CI 0.43-0.97) by intention to treat","Per-protocol (at least 2 years of treatment): HR 0.56 (95% CI 0.34-0.91)","Protection was delayed, appearing about 5 years after randomisation, and persisted after aspirin was stopped","No significant difference in serious adverse events during the intervention period"],"whatItMeans":"People with Lynch syndrome should be offered daily aspirin, which roughly halves bowel cancer risk with a delayed and durable effect. Whether a lower dose (as tested in CAPP3) is as effective, and whether the finding extends to the general population, are separate questions.","caveats":["Original primary endpoint at the 2008 analysis was null; the effect emerged only with long follow-up, which invites scepticism about post-hoc timing","600 mg is a high dose with bleeding risk in older people; CAPP3 addresses dose","Most participants were under 60 and from specialist registries","Resistant starch, the other factorial arm, showed a reduction in non-colorectal Lynch cancers, complicating interpretation"],"changedPractice":true,"participants":861},{"id":"paper-fader-trastuzumab-uterine-serous-jco-2018","kind":"paper","name":"Carboplatin-paclitaxel with or without trastuzumab in HER2-positive advanced or recurrent uterine serous carcinoma","aka":[],"tldr":"Adding trastuzumab to chemotherapy for HER2-positive uterine serous carcinoma, an aggressive endometrial cancer, lengthened progression-free survival by about four months and later showed a survival benefit, making HER2 testing routine in this subtype.","summary":"Randomised phase 2 trial of 61 women with HER2-positive (immunohistochemistry 3+ or amplified) advanced or recurrent uterine serous carcinoma treated with carboplatin-paclitaxel with or without trastuzumab continued as maintenance.\n\nMedian progression-free survival was 12.6 versus 8.0 months (hazard ratio 0.44), with the largest gain in newly diagnosed stage III to IV disease (17.9 versus 9.3 months); an update showed improved overall survival in that group.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2018","url":"https://doi.org/10.1200/JCO.2017.76.5966"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29584549/"}],"tags":[],"related":[],"cancers":["endometrial-p53-abnormal"],"sections":[],"technologies":[],"targets":[],"drugs":["carboplatin","trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2018,"doi":"10.1200/JCO.2017.76.5966","pmid":"29584549","authors":"Fader AN, Roque DM, Siegel E, et al.","paperType":"rct","findings":["Median progression-free survival 12.6 vs 8.0 months; hazard ratio 0.44.","Stage III to IV newly diagnosed: 17.9 vs 9.3 months, with an overall survival benefit on update."],"whatItMeans":"HER2 testing of every serous endometrial cancer and trastuzumab with first-line chemotherapy for HER2-positive advanced disease are now guideline recommendations; trastuzumab deruxtecan extends the option.","caveats":["Small phase 2 trial.","About 30 percent of uterine serous carcinomas are HER2-positive; benefit in lower expression is unknown."],"changedPractice":true,"participants":61},{"id":"paper-cartitude-1-cilta-cel-lancet-2021","kind":"paper","name":"CARTITUDE-1: cilta-cel, a BCMA CAR-T, in heavily pretreated myeloma","aka":[],"tldr":"A single infusion of BCMA-directed CAR-T cells produced responses in 97% of patients whose myeloma had failed a median of six prior lines, with two-thirds reaching stringent complete response.","summary":"CARTITUDE-1 was a phase 1b/2 single-arm study of ciltacabtagene autoleucel (cilta-cel), a CAR-T with two BCMA-binding domains, in 97 patients with relapsed or refractory multiple myeloma exposed to a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody (median six prior lines, 88% triple-class refractory). The overall response rate was 97%, with stringent complete response in 67%; 12-month PFS was 77% and OS 89%. Cytokine release syndrome occurred in 95% (grade 3-4 in about 4%) and neurotoxicity in about 21%, including a small number of delayed movement and neurocognitive events. Long-term follow-up showed roughly a third of patients progression-free at five years without further therapy, unprecedented in this population.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CARTITUDE-1%20ciltacabtagene%20autoleucel%20Berdeja%20Lancet%202021"},{"label":"ClinicalTrials.gov NCT03548207","url":"https://clinicaltrials.gov/study/NCT03548207"}],"tags":[],"related":["paper-cartitude-4-cilta-cel-nejm-2023"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["car-t"],"targets":["bcma"],"drugs":["ciltacabtagene-autoleucel"],"companies":["legend-biotech","johnson-johnson"],"institutions":[],"pathways":[],"terms":["crs","icans","orr"],"trials":["cartitude-1"],"people":["saad-usmani"],"bottlenecks":["b-manufacturing-cell-therapy","b-toxicity-qol"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"authors":"Berdeja JG, Madduri D, Usmani SZ, et al.","paperType":"translational","findings":["97 patients infused; median 6 prior lines; 88% triple-class refractory.","Overall response 97%; stringent complete response 67%; MRD-negativity in most evaluable responders.","12-month PFS 77%, OS 89%; median PFS about 35 months in later follow-up; about a third progression-free at 5 years.","CRS in 95% (grade 3-4 about 4%); ICANS 17%; delayed movement/neurocognitive syndrome in a minority.","Median time to CRS onset was 7 days, later than with CD19 CAR-Ts, enabling outpatient monitoring strategies."],"whatItMeans":"CARTITUDE-1 showed that a single CAR-T infusion can put late-stage myeloma into deep, multi-year remission, leading to FDA approval of cilta-cel in 2022 for heavily pretreated disease. It set the efficacy bar for BCMA-directed therapy and motivated moving CAR-T earlier (CARTITUDE-4). Late neurological toxicity and secondary malignancies remain the safety questions.","caveats":["Single-arm trial in fit, selected patients; no randomised comparator.","Manufacturing failures and bridging deaths are not captured in infused-patient analyses.","Delayed parkinsonism-like neurotoxicity and rare second primary malignancies (including T-cell lymphoma) emerged with follow-up.","Access limited by manufacturing slots and cost."],"changedPractice":true,"participants":97},{"id":"paper-cartitude-4-cilta-cel-nejm-2023","kind":"paper","name":"CARTITUDE-4: cilta-cel CAR-T versus standard combinations after one to three prior lines of myeloma therapy","aka":[],"tldr":"Moving BCMA CAR-T to the second line cut the risk of progression or death by 74% compared with standard triplets, and later improved overall survival.","summary":"CARTITUDE-4 randomised 419 patients with lenalidomide-refractory multiple myeloma after one to three prior lines to a single infusion of ciltacabtagene autoleucel (after bridging therapy) or standard of care (pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone). The primary endpoint was PFS by intention to treat. At 12 months PFS was 75.9% versus 48.6% (hazard ratio 0.26); overall response was 84.6% versus 67.3%, complete response or better 73.1% versus 21.8%, and MRD-negativity 60.6% versus 15.6%. In later follow-up overall survival was significantly better with cilta-cel (hazard ratio about 0.55). Toxicity was manageable, with lower CRS and neurotoxicity rates than in CARTITUDE-1.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2303379"},{"label":"ClinicalTrials.gov NCT04181827","url":"https://clinicaltrials.gov/study/NCT04181827"}],"tags":[],"related":["paper-karmma-3-ide-cel-nejm-2023"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["car-t"],"targets":["bcma"],"drugs":["ciltacabtagene-autoleucel","daratumumab","pomalidomide","bortezomib"],"companies":["legend-biotech","johnson-johnson"],"institutions":[],"pathways":[],"terms":["pfs","os","mrd-negativity-myeloma","crs"],"trials":["cartitude-4","cartitude-5"],"people":[],"bottlenecks":["b-manufacturing-cell-therapy","b-global-access"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2303379","authors":"San-Miguel J, Dhakal B, Yong K, et al.","paperType":"rct","findings":["419 lenalidomide-refractory patients after 1-3 prior lines; cilta-cel vs PVd or DPd.","12-month PFS 75.9% vs 48.6%; hazard ratio 0.26 (intention-to-treat).","Complete response or better 73.1% vs 21.8%; MRD-negativity 60.6% vs 15.6%.","Overall survival significantly improved at second analysis (HR about 0.55).","CRS in 76% of infused patients (grade 3-4 about 1%); ICANS about 5%; cranial nerve palsy and movement disorders in a small minority."],"whatItMeans":"CARTITUDE-4 is the first randomised trial to show that a CAR-T improves survival in myeloma, and it moved cilta-cel into second-line use (FDA approval 2024). For patients whose disease returns after first-line lenalidomide, a one-off cell therapy now competes with continuous drug combinations. Capacity, cost and the need for bridging therapy still limit who actually receives it.","caveats":["Open-label; standard-of-care arm was a mix of two regimens, neither of which is the strongest available.","Intention-to-treat analysis includes patients who progressed during bridging; per-protocol PFS is even more favourable.","Only about 15% of standard-arm patients later received CAR-T, so the comparison is partly CAR-T now versus never.","Secondary haematological malignancies and late neurotoxicity remain concerns."],"changedPractice":true,"participants":419},{"id":"paper-cassiopeia-lancet-2019","kind":"paper","name":"CASSIOPEIA: daratumumab added to bortezomib, thalidomide and dexamethasone before and after transplant in newly diagnosed myeloma","aka":[],"tldr":"Adding the antibody daratumumab to a standard three-drug induction and consolidation around autologous transplant deepened responses and delayed progression in newly diagnosed myeloma, establishing four-drug induction.","summary":"Phase 3 trial of 1,085 transplant-eligible patients with newly diagnosed multiple myeloma randomised to bortezomib, thalidomide and dexamethasone with or without daratumumab for induction and consolidation around autologous stem cell transplant.\n\nStringent complete response after consolidation was 29 percent with daratumumab against 20 percent without, measurable residual disease negativity 64 versus 44 percent, and progression-free survival was improved (hazard ratio 0.47 at the first analysis).","asOf":"2026-09-17","links":[{"label":"Lancet 2019","url":"https://doi.org/10.1016/S0140-6736(19)31240-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31171419/"}],"tags":[],"related":[],"cancers":["myeloma-transplant-eligible"],"sections":[],"technologies":[],"targets":[],"drugs":["bortezomib","daratumumab","dexamethasone","thalidomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["cassiopeia"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2019,"doi":"10.1016/S0140-6736(19)31240-1","pmid":"31171419","authors":"Moreau P, Attal M, Hulin C, et al.","paperType":"rct","findings":["Stringent complete response 29 percent vs 20 percent after consolidation.","Measurable residual disease negativity 64 percent vs 44 percent; 18-month progression-free survival 93 percent vs 85 percent."],"whatItMeans":"Quadruplet induction with a CD38 antibody became the standard for transplant-eligible patients in Europe. PERSEUS later did the same with the lenalidomide-based backbone used elsewhere.","caveats":["Thalidomide-based backbone is used less in the United States.","The second randomisation to daratumumab maintenance showed benefit mainly in those who had not received daratumumab induction."],"changedPractice":true,"participants":1085},{"id":"paper-catnon-lancet-2017","kind":"paper","name":"CATNON: concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion","aka":[],"tldr":"Twelve cycles of temozolomide after radiotherapy lengthened survival in grade 3 glioma without 1p/19q codeletion, while giving temozolomide during radiotherapy added nothing in these tumours.","summary":"Phase 3 factorial trial of 745 adults with newly diagnosed anaplastic glioma without 1p/19q codeletion randomised to radiotherapy alone, with concurrent temozolomide, with 12 cycles of adjuvant temozolomide, or with both.\n\nAdjuvant temozolomide improved overall survival (hazard ratio 0.65; five-year survival 55.9 versus 44.1 percent); concurrent temozolomide did not, and later analysis showed benefit was confined to IDH-mutant tumours.","asOf":"2026-09-17","links":[{"label":"Lancet 2017","url":"https://doi.org/10.1016/S0140-6736(17)31442-3"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28801186/"}],"tags":[],"related":[],"cancers":["idh-mutant-astrocytoma"],"sections":[],"technologies":[],"targets":[],"drugs":["temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["catnon"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2017,"doi":"10.1016/S0140-6736(17)31442-3","pmid":"28801186","authors":"van den Bent MJ, Baumert B, Erridge SC, et al.","paperType":"rct","findings":["Adjuvant temozolomide: five-year overall survival 55.9 percent vs 44.1 percent; hazard ratio 0.65.","Concurrent temozolomide: no significant benefit."],"whatItMeans":"Radiotherapy followed by a year of temozolomide is the standard for grade 3 IDH-mutant astrocytoma; concurrent temozolomide is not needed, and IDH-wild-type tumours behave and are treated like glioblastoma.","caveats":["Interim analysis; final results confirmed the pattern.","Applies to the pre-2021 category of anaplastic astrocytoma, now IDH-mutant astrocytoma grade 3."],"changedPractice":true,"participants":745},{"id":"paper-cella-fact-g-jco-1993","kind":"paper","name":"Cella 1993: the Functional Assessment of Cancer Therapy (FACT-G) quality of life scale","aka":[],"tldr":"The other widely used cancer quality of life questionnaire, developed in the United States alongside the EORTC QLQ-C30, covering physical, social and family, emotional and functional wellbeing and extended by cancer-specific modules.","summary":"Cella and colleagues developed and validated the Functional Assessment of Cancer Therapy general scale (FACT-G), a self-administered questionnaire for patients receiving cancer treatment, through item generation with patients and clinicians, item reduction and testing in patients with a range of cancers. The scale covers physical wellbeing, social and family wellbeing, emotional wellbeing and functional wellbeing, showed good reliability and validity, distinguished patients by performance status and stage, and was sensitive to change over time. Disease-, treatment- and symptom-specific subscales were built on top of the core.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1200/JCO.1993.11.3.570"},{"label":"FACIT measurement system","url":"https://www.facit.org/"}],"tags":[],"related":["paper-aaronson-eortc-qlq-c30-jnci-1993"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["northwestern-lurie"],"pathways":[],"terms":["quality-of-life","qol-pro"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":1993,"doi":"10.1200/JCO.1993.11.3.570","authors":"Cella DF, Tulsky DS, Gray G, et al.","paperType":"methods","findings":["A brief, self-administered general quality of life measure for patients on cancer treatment, with physical, social and family, emotional and functional wellbeing domains.","Demonstrated internal consistency, test-retest reliability and validity against performance status and stage.","Designed as a core to which cancer-specific subscales are added, now the FACIT measurement system."],"whatItMeans":"FACT-G and the EORTC QLQ-C30 are the two instruments behind most patient-reported quality of life results in cancer trials and regulatory submissions. Knowing which was used matters when comparing quality of life claims between trials.","caveats":["Developed and validated mainly in US patients.","Quality of life data in trials are often incomplete because the sickest patients stop completing questionnaires."],"changedPractice":true},{"id":"paper-cemiplimab-bcc-stratigos-lancet-oncol-2021","kind":"paper","name":"Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy","aka":[],"tldr":"In patients whose locally advanced basal cell carcinoma had progressed on or could not tolerate a hedgehog inhibitor, cemiplimab shrank tumours in about three in ten, giving a second-line option where none existed.","summary":"Phase 2 study of 84 patients with locally advanced basal cell carcinoma after progression on or intolerance of hedgehog pathway inhibitors treated with cemiplimab.\n\nObjective response was 31 percent (6 percent complete), with an estimated 85 percent of responses lasting at least a year and toxicity typical of PD-1 blockade; the metastatic cohort responded in about a fifth.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(21)00126-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34000246/"}],"tags":[],"related":[],"cancers":["locally-advanced-bcc"],"sections":[],"technologies":[],"targets":[],"drugs":["cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00126-1","pmid":"34000246","authors":"Stratigos AJ, Sekulic A, Peris K, et al.","paperType":"observational","findings":["Objective response 31 percent; complete response 6 percent.","Estimated duration of response of at least 12 months in 85 percent of responders."],"whatItMeans":"Cemiplimab is approved for advanced basal cell carcinoma after hedgehog inhibitor therapy, adding immunotherapy to the pathway for this common but rarely advanced skin cancer.","caveats":["Single-arm; responses can take many months to become apparent."],"changedPractice":true,"participants":84},{"id":"paper-cepheus-dara-vrd-natmed-2025","kind":"paper","name":"CEPHEUS: daratumumab quadruplet for newly diagnosed myeloma patients not having a transplant, with MRD-negativity as the main endpoint","aka":[],"tldr":"In patients who were transplant-ineligible or deferred transplant, the daratumumab quadruplet raised deep-remission rates from about 39% to 61% and cut progression risk by 43%.","summary":"CEPHEUS randomised 395 patients with newly diagnosed multiple myeloma who were transplant-ineligible or for whom transplant was deferred to daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRd) or VRd. Unusually, the primary endpoint was the overall MRD-negativity rate at 10^-5 sensitivity, reflecting the FDA advisory committee's 2024 acceptance of MRD as an endpoint supporting accelerated approval. MRD-negativity was 60.9% versus 39.4%, complete response or better 81.2% versus 61.6%, and PFS favoured D-VRd (hazard ratio 0.57). Toxicity was in line with other daratumumab quadruplets.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CEPHEUS%20daratumumab%20bortezomib%20lenalidomide%20transplant-ineligible%20Usmani%20Nature%20Medicine%202025"},{"label":"ClinicalTrials.gov NCT03652064","url":"https://clinicaltrials.gov/study/NCT03652064"}],"tags":[],"related":["paper-maia-daratumumab-rd-nejm-2019"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["mrd-testing"],"targets":["cd38"],"drugs":["daratumumab","bortezomib","lenalidomide"],"companies":["johnson-johnson"],"institutions":[],"pathways":[],"terms":["mrd-negativity-myeloma","pfs"],"trials":["cepheus","imroz"],"people":["saad-usmani"],"bottlenecks":["b-trial-design","b-dormancy-mrd"],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2025,"authors":"Usmani SZ, Facon T, Hungria V, et al.","paperType":"rct","findings":["395 transplant-ineligible or transplant-deferred patients; D-VRd vs VRd.","Primary endpoint, overall MRD-negativity at 10^-5: 60.9% vs 39.4%.","Complete response or better 81.2% vs 61.6%.","PFS hazard ratio 0.57 in favour of D-VRd.","Infection and cytopenia rates were higher with the quadruplet, consistent with PERSEUS."],"whatItMeans":"CEPHEUS extends the quadruplet standard to patients who are not going to transplant, closing the gap between transplant-eligible and ineligible populations. It is also one of the first phase 3 trials to be designed around MRD-negativity as the primary endpoint, which could shorten future myeloma trials by years. Frailer patients still need dose-adapted approaches.","caveats":["MRD-negativity is a surrogate; PFS and OS benefits need longer follow-up to confirm.","Included relatively fit transplant-deferred patients as well as truly ineligible ones.","Bortezomib-based induction is not ideal for very frail patients; the parallel IMROZ trial used a different quadruplet.","Cross-trial comparison with MAIA is indirect."],"changedPractice":true,"participants":395},{"id":"paper-cercek-dostarlimab-rectal-nejm-2022","kind":"paper","name":"Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency","aka":[],"tldr":"All 12 patients with locally advanced dMMR rectal cancer had a complete clinical response to a PD-1 antibody alone, avoiding chemotherapy, radiotherapy and surgery.","summary":"This single-centre phase 2 study at Memorial Sloan Kettering treated patients with stage II or III mismatch-repair-deficient rectal adenocarcinoma with dostarlimab 500 mg every three weeks for six months, with the plan to proceed to chemoradiotherapy and surgery only if disease persisted. In the first 12 patients who completed treatment and had at least six months of follow-up, all had a clinical complete response on MRI, endoscopy, digital examination and biopsy, and none required chemoradiotherapy or surgery; no grade 3 or higher adverse events occurred. The follow-up report (NEJM 2025) extended the approach to more than 100 patients with dMMR cancers of several organs, with rectal cancer patients continuing to show near-universal complete responses and most avoiding surgery at two years.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2201445"},{"label":"ClinicalTrials.gov NCT04165772","url":"https://clinicaltrials.gov/study/NCT04165772"}],"tags":[],"related":["paper-niche-2-neoadjuvant-colon-nejm-2024","paper-le-mmr-deficiency-pd1-nejm-2015"],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["dostarlimab","pembrolizumab"],"companies":["gsk"],"institutions":["mskcc"],"pathways":[],"terms":["msi","pcr"],"trials":[],"people":["andrea-cercek","luis-diaz"],"bottlenecks":["b-surgery-radiation-innovation","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2201445","authors":"Cercek A, Lumish M, Sinopoli J, et al.","paperType":"translational","findings":["12 patients with stage II-III dMMR rectal adenocarcinoma; dostarlimab 500 mg every 3 weeks for 6 months.","Clinical complete response in 12 of 12 (100%) at 6 months or more of follow-up.","No patient needed chemoradiotherapy or surgery; no recurrence at 6-25 months follow-up in the initial report.","No grade 3 or higher adverse events.","Larger follow-up (2025): sustained complete responses in the great majority of dMMR rectal cancer patients, and high rates of organ preservation across other dMMR tumour types."],"whatItMeans":"Cercek's dostarlimab study is the clearest demonstration that immunotherapy can replace surgery in a solid tumour: patients with dMMR rectal cancer can keep their rectum and avoid the permanent effects of pelvic radiotherapy and surgery. Non-operative management after PD-1 blockade is now in guidelines for this group, and MMR testing before treatment of rectal cancer is essential. The approach applies only to the 5-10% of rectal cancers that are dMMR.","caveats":["Small, single-centre, single-arm study; the 2022 report had only 12 patients and short follow-up.","Clinical complete response requires expert surveillance with MRI and endoscopy; salvage surgery must remain available.","Applies only to dMMR disease, a minority of rectal cancers.","Long-term durability beyond five years and late relapse risk are not yet known."],"changedPractice":true,"participants":12},{"id":"paper-chaarted-nejm-2015","kind":"paper","name":"CHAARTED: chemohormonal therapy in metastatic hormone-sensitive prostate cancer","aka":[],"tldr":"Giving six cycles of docetaxel at the start of hormone therapy for metastatic prostate cancer lengthened survival by over a year in men with high-volume disease, the first trial to show that early chemotherapy helps.","summary":"Phase 3 trial of 790 men with metastatic hormone-sensitive prostate cancer randomised to androgen deprivation alone or with six cycles of docetaxel.\n\nMedian overall survival was 57.6 versus 44.0 months (hazard ratio 0.61) overall, and 49.2 versus 32.2 months in high-volume disease; long-term follow-up showed no benefit in low-volume disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2015","url":"https://doi.org/10.1056/NEJMoa1503747"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26244877/"}],"tags":[],"related":[],"cancers":["prostate-mhspc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["chaarted"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1503747","pmid":"26244877","authors":"Sweeney CJ, Chen YH, Carducci M, et al.","paperType":"rct","findings":["Median overall survival 57.6 vs 44.0 months; hazard ratio 0.61.","High-volume disease: 49.2 vs 32.2 months; no benefit in low-volume disease on follow-up."],"whatItMeans":"Docetaxel with androgen deprivation is a standard for high-volume metastatic hormone-sensitive prostate cancer, now usually combined with an androgen receptor pathway inhibitor as triplet therapy.","caveats":["Open-label; defined the high-volume criteria (visceral metastases or four or more bone lesions with one beyond the pelvis and spine) used since."],"changedPractice":true,"participants":790},{"id":"paper-challenge-exercise-nejm-2025","kind":"paper","name":"CHALLENGE: a structured exercise programme after chemotherapy improves survival in colon cancer","aka":[],"tldr":"In CHALLENGE, three years of supervised, goal-based exercise after adjuvant chemotherapy for colon cancer reduced recurrence or death by 28% and deaths by 37%, the first randomised proof that exercise itself improves cancer survival.","summary":"CHALLENGE (CCTG CO.21) randomised 889 patients with resected stage III or high-risk stage II colon cancer who had completed adjuvant chemotherapy to a 3-year structured exercise programme (behavioural support and supervised sessions, targeting an increase of at least 10 MET-hours per week) or to health-education materials alone. The primary endpoint was disease-free survival.\n\nAfter a median follow-up of nearly 8 years, 5-year DFS was 80.3% with exercise versus 73.9% with education (HR 0.72). Eight-year overall survival was 90.3% versus 83.2% (HR 0.63). Physical functioning improved and musculoskeletal adverse events were more common in the exercise arm.\n\nThis is the first phase 3 trial to show that an exercise intervention, rather than exercise as a correlate, lengthens survival in cancer.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa2502760"},{"label":"ClinicalTrials.gov NCT00819208","url":"https://clinicaltrials.gov/study/NCT00819208"}],"tags":[],"related":["idea-exercise-as-adjuvant","idea-bio2-exercise-reimbursement","idea-bio2-gdf15-plus-exercise"],"cancers":["colorectal"],"sections":["nutrition-lifestyle","supportive-care"],"technologies":["exercise-oncology"],"targets":[],"drugs":[],"companies":[],"institutions":["cctg"],"pathways":[],"terms":[],"trials":[],"people":["dancey-janet"],"bottlenecks":["b-survivorship","b-prevention-adoption","b-generic-repurposing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2502760","authors":"Courneya KS, Vardy JL, O'Callaghan CJ, et al. (Canadian Cancer Trials Group CO.21)","paperType":"rct","findings":["Five-year disease-free survival 80.3% vs 73.9% (HR 0.72, 95% CI 0.55-0.94)","Eight-year overall survival 90.3% vs 83.2% (HR 0.63, 95% CI 0.43-0.94)","Median follow-up 7.9 years across 55 centres in Canada, Australia, the UK, France, Israel and the US","Musculoskeletal adverse events 18.5% vs 11.5%; the programme was delivered by physical activity consultants over 3 years"],"whatItMeans":"For colon cancer survivors, a prescribed, supported exercise programme is now an evidence-based treatment with a survival benefit comparable to many drugs. Health systems will need to fund exercise consultants as they fund chemotherapy. The trial does not tell us whether unsupervised advice achieves the same.","caveats":["The intervention was intensive (behavioural support for 3 years); uptake and cost in routine care are untested","Participants were fit enough to enrol and motivated; benefit in frail or sedentary populations is unproven","Open-label; DFS assessment could be influenced by differential surveillance","Recruitment took 15 years, so adjuvant regimens evolved during the trial"],"changedPractice":true,"participants":889},{"id":"paper-heetfeld-grade-3-net-erc-2015","kind":"paper","name":"Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms","aka":[],"tldr":"Studying 204 grade 3 neuroendocrine neoplasms showed that well-differentiated tumours with a Ki-67 in the 20 to 55 percent range respond poorly to platinum chemotherapy but survive far longer than poorly differentiated carcinomas, establishing grade 3 neuroendocrine tumour as a separate disease.","summary":"Retrospective multicentre study of 204 patients with gastroenteropancreatic neuroendocrine neoplasms with Ki-67 over 20 percent, divided into well-differentiated neuroendocrine tumours and poorly differentiated carcinomas.\n\nWell-differentiated grade 3 tumours had a median survival of 99 months against 17 months for carcinomas, lower response to platinum-etoposide, and better response to alkylating agents and other tumour-type treatments; Ki-67 of 55 percent separated the groups.","asOf":"2026-09-17","links":[{"label":"Endocr Relat Cancer 2015","url":"https://doi.org/10.1530/ERC-15-0119"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26113608/"}],"tags":[],"related":[],"cancers":["grade-3-net"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["endocrine-related-cancer"],"dependsOn":[],"notes":[],"journal":"Endocrine-related cancer","year":2015,"doi":"10.1530/ERC-15-0119","pmid":"26113608","authors":"Heetfeld M, Chougnet CN, Olsen IH, et al.","paperType":"observational","findings":["Median overall survival 99 months for grade 3 neuroendocrine tumour vs 17 months for neuroendocrine carcinoma.","Platinum response 33 percent in tumours vs higher in carcinomas."],"whatItMeans":"Grade 3 neuroendocrine tumours are treated like aggressive grade 2 tumours (somatostatin analogues, capecitabine-temozolomide, radioligand therapy) rather than with small-cell regimens.","caveats":["Retrospective and treatment was heterogeneous."],"changedPractice":true,"participants":204},{"id":"paper-checkmate-017-nejm-2015","kind":"paper","name":"CheckMate 017: nivolumab beats docetaxel in squamous lung cancer after chemotherapy","aka":[],"tldr":"In squamous non-small-cell lung cancer that had progressed after platinum chemotherapy, the PD-1 antibody nivolumab prolonged life compared with docetaxel with far fewer severe side effects, regardless of PD-L1 status.","summary":"CheckMate 017 randomised 272 patients with advanced squamous non-small-cell lung cancer that had progressed during or after first-line platinum chemotherapy to nivolumab or docetaxel. Nivolumab improved overall survival, the primary endpoint, as well as response rate and progression-free survival, with a fraction of the grade 3 or 4 toxicity of docetaxel. Unlike its non-squamous companion trial CheckMate 057, the benefit did not depend on PD-L1 expression, which led to nivolumab's approval in squamous disease without a biomarker requirement.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1504627"},{"label":"ClinicalTrials.gov NCT01642004","url":"https://clinicaltrials.gov/study/NCT01642004"}],"tags":[],"related":["paper-checkmate-057-nejm-2015"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["nivolumab","docetaxel"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["os","orr"],"trials":[],"people":["julie-brahmer"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1504627","authors":"Brahmer J, Reckamp KL, Baas P, et al.","paperType":"rct","findings":["272 patients with previously treated squamous NSCLC; nivolumab vs docetaxel.","Median overall survival 9.2 vs 6.0 months, hazard ratio 0.59; one-year survival 42% vs 24%.","Response rate 20% vs 9%; median progression-free survival 3.5 vs 2.8 months, hazard ratio 0.62.","Grade 3 or 4 treatment-related adverse events 7% vs 55%; benefit was independent of PD-L1 expression."],"whatItMeans":"With CheckMate 057 this trial ended docetaxel's role as the default second-line treatment in lung cancer and gave the first phase 3 proof that PD-1 blockade extends life in a common carcinoma. Its PD-L1-independent benefit in squamous disease still shapes how the biomarker is used.","caveats":["Open-label design.","Second-line setting; first-line immunotherapy has since changed who reaches this point.","Squamous histology only."],"changedPractice":true,"participants":272},{"id":"paper-checkmate-057-nejm-2015","kind":"paper","name":"CheckMate 057: nivolumab beats docetaxel after chemotherapy in non-squamous lung cancer","aka":[],"tldr":"After platinum chemotherapy had failed, the PD-1 antibody nivolumab prolonged life compared with docetaxel in non-squamous lung cancer with far fewer severe side effects, and the benefit was largest in tumours expressing PD-L1.","summary":"CheckMate 057 randomised 582 patients with non-squamous non-small-cell lung cancer that had progressed during or after platinum-based chemotherapy to nivolumab or docetaxel. Nivolumab improved overall survival, the primary endpoint, with a higher response rate, longer duration of response and a fraction of the severe toxicity of docetaxel. Unlike its squamous counterpart CheckMate 017, the benefit depended on PD-L1 expression, with little difference in PD-L1-negative tumours, which fuelled the debate about PD-L1 as a biomarker.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1507643"},{"label":"ClinicalTrials.gov NCT01673867","url":"https://clinicaltrials.gov/study/NCT01673867"}],"tags":[],"related":["paper-keynote-024-nejm-2016"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["nivolumab","docetaxel"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["os","orr"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1507643","authors":"Borghaei H, Paz-Ares L, Horn L, et al.","paperType":"rct","findings":["582 patients with previously treated non-squamous NSCLC; nivolumab vs docetaxel.","Median overall survival 12.2 vs 9.4 months, hazard ratio 0.73.","Response rate 19% vs 12%; median duration of response 17.2 vs 5.6 months.","Grade 3 or 4 treatment-related adverse events 10% vs 54%.","Survival benefit increased with PD-L1 expression and was not evident in PD-L1-negative tumours."],"whatItMeans":"With CheckMate 017 in squamous disease, this trial ended docetaxel's reign as the default second-line treatment for lung cancer and established PD-1 blockade as standard after chemotherapy. Its PD-L1 finding shaped how later first-line trials were designed and how the biomarker is used in the clinic.","caveats":["Open-label design.","Early crossing of the survival curves suggested some patients fared worse on nivolumab in the first months.","PD-L1 was assessed retrospectively on archival tissue."],"changedPractice":true,"participants":582},{"id":"paper-checkmate-067-ten-year-nejm-2025","kind":"paper","name":"CheckMate 067 at ten years: half of melanoma patients treated with nivolumab plus ipilimumab were alive a decade later","aka":[],"tldr":"Ten-year follow-up of the trial that established combination checkpoint blockade shows median survival over six years with nivolumab plus ipilimumab and a plateau in the survival curve consistent with cure.","summary":"CheckMate 067 randomised 945 patients with previously untreated advanced melanoma to nivolumab plus ipilimumab, nivolumab alone, or ipilimumab alone (Larkin et al., NEJM 2015). The final 10-year report (minimum follow-up 10 years) showed median overall survival of 71.9 months with the combination, 36.9 months with nivolumab and 19.9 months with ipilimumab; 10-year OS was about 43%, 37% and 19%, and melanoma-specific survival 52%, 44% and 23%. Survival curves plateaued after about three years, and most patients alive at 10 years had been off treatment for years without further therapy. Grade 3-4 treatment-related adverse events occurred in nearly 60% with the combination versus roughly a quarter with either monotherapy, but no new late safety signals emerged. Ipilimumab plus nivolumab produced its largest relative benefit in BRAF-mutant and PD-L1-negative subgroups, though the trial was not powered to compare the combination with nivolumab alone.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CheckMate%20067%2010-year%20nivolumab%20ipilimumab%20melanoma%20Wolchok%20NEJM%202025"},{"label":"Original report (Larkin 2015)","url":"https://doi.org/10.1056/NEJMoa1504030"},{"label":"ClinicalTrials.gov NCT01844505","url":"https://clinicaltrials.gov/study/NCT01844505"}],"tags":[],"related":["paper-hodi-ipilimumab-melanoma-nejm-2010","paper-asco-irae-guideline-jco-2021"],"cancers":["melanoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","ctla4","lag3"],"drugs":["nivolumab","ipilimumab","relatlimab-nivolumab"],"companies":["bms"],"institutions":["mskcc"],"pathways":[],"terms":["os","irae"],"trials":["checkmate-067","relativity-047"],"people":["james-larkin","f-stephen-hodi"],"bottlenecks":["b-toxicity-qol","b-survivorship"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"authors":"Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al.","paperType":"rct","findings":["945 previously untreated advanced melanoma patients; nivolumab + ipilimumab vs nivolumab vs ipilimumab (1:1:1).","Median OS 71.9 vs 36.9 vs 19.9 months; 10-year OS about 43% vs 37% vs 19%.","10-year melanoma-specific survival 52% vs 44% vs 23%; median not reached for the combination.","Survival curves plateau from around year 3; most long-term survivors are off therapy.","Grade 3-4 treatment-related adverse events nearly 60% with the combination vs about a quarter with monotherapy; no new late toxicities."],"whatItMeans":"Before 2011 median survival in metastatic melanoma was under a year; this trial shows that roughly half of patients treated with combination checkpoint blockade are now long-term survivors, effectively cured. It anchors first-line treatment of advanced melanoma and sets the benchmark for every new regimen, including nivolumab-relatlimab. The combination's toxicity means nivolumab alone or newer doublets remain reasonable for some patients.","caveats":["The trial was not designed or powered for a formal comparison of the combination against nivolumab alone; that difference is descriptive.","Toxicity of the combination is high and around 40% stopped treatment early for adverse events, though many still benefited.","Subsequent therapies (including crossover-like use of the other agents) influence long-term survival.","Results are in melanoma; long-term cure fractions in other cancers are lower."],"changedPractice":true,"participants":945},{"id":"paper-checkmate-067-10-year-nejm-2025","kind":"paper","name":"CheckMate 067 at ten years: nivolumab plus ipilimumab produces long-term survival in half of patients with advanced melanoma","aka":[],"tldr":"Ten years after starting treatment, about half of patients with advanced melanoma treated with nivolumab plus ipilimumab were still alive, most without any further treatment, showing that immunotherapy can cure a disease that once killed most patients within a year.","summary":"Final ten-year analysis of the double-blind phase 3 trial of 945 patients with untreated advanced melanoma randomised to nivolumab plus ipilimumab, nivolumab alone, or ipilimumab alone.\n\nMedian overall survival was 71.9 months with the combination, 36.9 months with nivolumab and 19.9 months with ipilimumab; 10-year OS was 43%, 37% and 19%. Median melanoma-specific survival was not reached for the combination, with 10-year melanoma-specific survival of 52%. The survival curves plateaued after about three years, and most surviving patients had been off treatment for years. It is the longest follow-up of any checkpoint inhibitor trial and the definitive evidence that immunotherapy can be curative.","asOf":"2026-09-08","links":[{"label":"NEJM 2025","url":"https://doi.org/10.1056/NEJMoa2407417"},{"label":"ClinicalTrials.gov NCT01844505","url":"https://clinicaltrials.gov/study/NCT01844505"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","ctla4"],"drugs":["nivolumab","ipilimumab","relatlimab-nivolumab"],"companies":["bms"],"institutions":["mskcc"],"pathways":[],"terms":["os","irae","hazard-ratio"],"trials":["checkmate-067"],"people":["john-haanen","mcarthur-grant","f-stephen-hodi","james-larkin"],"bottlenecks":["b-immunotherapy-response","b-toxicity-qol","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2407417","authors":"Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al.","paperType":"rct","findings":["Median overall survival 71.9 months (nivolumab plus ipilimumab) vs 36.9 months (nivolumab) vs 19.9 months (ipilimumab).","10-year overall survival 43% vs 37% vs 19%; 10-year melanoma-specific survival 52% vs 44% vs 23%.","Median melanoma-specific survival not reached for the combination (over 120 months) vs 49.4 months for nivolumab.","Among patients alive at three years, subsequent melanoma deaths were rare, and most survivors had received no further systemic therapy.","The combination versus nivolumab alone was not formally powered for comparison; grade 3-4 treatment-related adverse events were 59% vs 24% vs 28% in the original report."],"whatItMeans":"For patients with advanced melanoma, immunotherapy offers a realistic chance of long-term survival and probably cure, and the ten-year data show that patients who are alive and progression-free at three years rarely die of melanoma afterwards. Nivolumab plus ipilimumab gives the best long-term results but at a high price in serious side effects; nivolumab alone or nivolumab plus relatlimab are alternatives for patients at lower risk or with autoimmune concerns. The trial is also a caution about surrogate endpoints: the survival plateau took years to become visible.","caveats":["The trial was not designed to compare the combination with nivolumab alone, and that difference is not statistically established.","Toxicity of the combination is substantial, with roughly one in three patients stopping for adverse events.","Patients were treated before BRAF/MEK inhibitors and relatlimab were standard, so sequencing questions are not answered.","Predicting who is cured versus who relapses late is still not possible from baseline biomarkers."],"changedPractice":true,"participants":945},{"id":"paper-checkmate-141-ferris-nejm-2016","kind":"paper","name":"CheckMate 141: nivolumab for recurrent head and neck squamous cell carcinoma after platinum","aka":[],"tldr":"Nivolumab lengthened survival compared with standard single-agent chemotherapy in head and neck cancer that had progressed within six months of platinum treatment, the first immunotherapy to improve survival in the disease.","summary":"Phase 3 trial of 361 patients with recurrent or metastatic head and neck squamous cell carcinoma progressing within six months of platinum-based therapy, randomised 2:1 to nivolumab or investigator's choice of methotrexate, docetaxel or cetuximab.\n\nMedian overall survival was 7.5 versus 5.1 months (hazard ratio 0.70) and one-year survival 36.0 versus 16.6 percent, with fewer grade 3 to 4 adverse events (13.1 versus 35.1 percent) and better quality of life.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2016","url":"https://doi.org/10.1056/NEJMoa1602252"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27718784/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-hnscc","oropharyngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-141"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1602252","pmid":"27718784","authors":"Ferris RL, Blumenschein G, Fayette J, et al.","paperType":"rct","findings":["Median overall survival 7.5 vs 5.1 months; hazard ratio 0.70.","One-year overall survival 36.0 percent vs 16.6 percent."],"whatItMeans":"PD-1 blockade after platinum became standard, and the trial opened the way for first-line pembrolizumab in KEYNOTE-048.","caveats":["Response rate was low (13.3 percent); benefit accrues to a minority of durable responders."],"changedPractice":true,"participants":361},{"id":"paper-checkmate-214-nejm-2018","kind":"paper","name":"CheckMate 214: nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma","aka":[],"tldr":"Dual immunotherapy with nivolumab and ipilimumab lengthened survival compared with sunitinib in intermediate- and poor-risk advanced kidney cancer, with about one in ten patients achieving a complete response that has proved durable over years.","summary":"Phase 3 trial of 1,096 patients with untreated advanced clear cell renal cell carcinoma randomised to nivolumab plus ipilimumab (four doses) followed by nivolumab, or sunitinib, with co-primary endpoints in intermediate- and poor-risk patients.\n\nIn intermediate and poor risk, 18-month overall survival was 75 versus 60 percent (hazard ratio 0.63), response 42 versus 27 percent and complete response 9 versus 1 percent; favourable-risk patients had higher response to sunitinib at first analysis. Long-term follow-up shows sustained survival benefit.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1712126"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29562145/"}],"tags":[],"related":[],"cancers":["clear-cell-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["ipilimumab","nivolumab","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-214"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1712126","pmid":"29562145","authors":"Motzer RJ, Tannir NM, McDermott DF, et al.","paperType":"rct","findings":["Intermediate and poor risk: 18-month overall survival 75 percent vs 60 percent; hazard ratio 0.63.","Complete response 9 percent vs 1 percent."],"whatItMeans":"Nivolumab-ipilimumab is a first-line standard for intermediate- and poor-risk clear cell kidney cancer, notable for durable complete responses and treatment-free intervals.","caveats":["Favourable-risk patients showed no clear benefit.","Immune-related adverse events requiring high-dose steroids in about a third."],"changedPractice":true,"participants":1096},{"id":"paper-checkmate-238-nejm-2017","kind":"paper","name":"CheckMate 238: adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma","aka":[],"tldr":"A year of adjuvant nivolumab after surgery for high-risk melanoma reduced recurrences more than the previous standard, high-dose ipilimumab, with a quarter of the severe toxicity, making PD-1 blockade the adjuvant standard.","summary":"Phase 3 trial of 906 patients with resected stage IIIB, IIIC or IV melanoma randomised to nivolumab or ipilimumab 10 mg/kg for one year.\n\nTwelve-month recurrence-free survival was 70.5 versus 60.8 percent (hazard ratio 0.65), with grade 3 to 4 treatment-related adverse events in 14.4 versus 45.9 percent; four-year recurrence-free survival was 51.7 versus 41.2 percent, with no overall survival difference.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1709030"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28891423/"}],"tags":[],"related":[],"cancers":["stage-iii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["ipilimumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-238"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1709030","pmid":"28891423","authors":"Weber J, Mandala M, Del Vecchio M, et al.","paperType":"rct","findings":["Twelve-month recurrence-free survival 70.5 percent vs 60.8 percent; hazard ratio 0.65.","Grade 3 to 4 adverse events 14.4 percent vs 45.9 percent."],"whatItMeans":"Adjuvant nivolumab (or pembrolizumab) is standard for resected stage III and IV melanoma; ipilimumab is no longer used in the adjuvant setting.","caveats":["No placebo arm; the comparison is against an active but toxic agent.","Overall survival did not differ, probably because of effective therapy at relapse."],"changedPractice":true,"participants":906},{"id":"paper-checkmate-577-nejm-2021","kind":"paper","name":"CheckMate 577: adjuvant nivolumab in resected oesophageal or gastro-oesophageal junction cancer","aka":[],"tldr":"A year of nivolumab after chemoradiotherapy and surgery doubled disease-free survival in patients with oesophageal or junctional cancer who still had residual tumour at surgery, the first adjuvant therapy to work in this setting.","summary":"Phase 3 placebo-controlled trial of 794 patients with resected stage II to III oesophageal or gastro-oesophageal junction cancer (both histologies) and residual pathological disease after neoadjuvant chemoradiotherapy, randomised 2:1 to nivolumab or placebo for up to one year.\n\nMedian disease-free survival was 22.4 versus 11.0 months (hazard ratio 0.69), with benefit in both squamous and adenocarcinoma and regardless of PD-L1 expression; grade 3 to 4 treatment-related adverse events were 13 versus 6 percent.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2021","url":"https://doi.org/10.1056/NEJMoa2032125"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33789008/"}],"tags":[],"related":[],"cancers":["oesophageal-squamous-cell-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-577"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2032125","pmid":"33789008","authors":"Kelly RJ, Ajani JA, Kuzdzal J, et al.","paperType":"rct","findings":["Median disease-free survival 22.4 vs 11.0 months; hazard ratio 0.69.","Benefit in squamous (hazard ratio 0.61) and adenocarcinoma (0.75)."],"whatItMeans":"Adjuvant nivolumab is standard for patients with residual disease after trimodality therapy for oesophageal cancer.","caveats":["Overall survival data pending.","Applies only after neoadjuvant chemoradiotherapy, not after perioperative chemotherapy."],"changedPractice":true,"participants":794},{"id":"paper-checkmate-648-nejm-2022","kind":"paper","name":"CheckMate 648: nivolumab combination therapy in advanced oesophageal squamous cell carcinoma","aka":[],"tldr":"Adding nivolumab to chemotherapy, or combining nivolumab with ipilimumab without chemotherapy, lengthened survival compared with chemotherapy alone in advanced oesophageal squamous cell carcinoma, with the largest gains in PD-L1-positive tumours.","summary":"Phase 3 trial of 970 patients with previously untreated advanced oesophageal squamous cell carcinoma randomised to nivolumab plus fluorouracil-cisplatin, nivolumab plus ipilimumab, or chemotherapy alone.\n\nIn tumours with PD-L1 expression of 1 percent or more, median overall survival was 15.4 months with nivolumab-chemotherapy and 13.7 months with nivolumab-ipilimumab against 9.1 months with chemotherapy (hazard ratios 0.54 and 0.64); benefit was also seen in the overall population.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2111380"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35108470/"}],"tags":[],"related":[],"cancers":["oesophageal-squamous-cell-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-648"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2111380","pmid":"35108470","authors":"Doki Y, Ajani JA, Kato K, et al.","paperType":"rct","findings":["PD-L1 1 percent or more: median overall survival 15.4 (nivolumab-chemotherapy) and 13.7 (nivolumab-ipilimumab) vs 9.1 months (chemotherapy).","All randomised: 13.2 and 12.7 vs 10.7 months."],"whatItMeans":"Nivolumab plus chemotherapy or nivolumab plus ipilimumab are first-line standards for advanced oesophageal squamous cell carcinoma, joining pembrolizumab-chemotherapy from KEYNOTE-590.","caveats":["Early progression was more frequent with chemotherapy-free nivolumab-ipilimumab.","Benefit in PD-L1-negative tumours was uncertain."],"changedPractice":true,"participants":970},{"id":"paper-checkmate-649-lancet-2021","kind":"paper","name":"CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma","aka":[],"tldr":"Adding the immunotherapy nivolumab to first-line chemotherapy helped patients with advanced stomach and oesophageal adenocarcinoma live longer, especially when the tumour showed PD-L1, making chemo-immunotherapy the new standard.","summary":"Open-label phase 3 trial of 1,581 patients with untreated, HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma randomised to nivolumab plus chemotherapy (XELOX or FOLFOX) or chemotherapy alone (a third arm tested nivolumab plus ipilimumab). Primary endpoints were OS and PFS in patients with PD-L1 combined positive score (CPS) of 5 or more.\n\nIn CPS 5 or more, median OS was 14.4 vs 11.1 months (HR 0.71) and PFS 7.7 vs 6.0 months (HR 0.68); in all randomised patients OS was 13.8 vs 11.6 months (HR 0.80). It was the first immunotherapy to improve first-line survival in gastric cancer and it made PD-L1 CPS testing standard, though regulators disagreed about the CPS threshold for use.","asOf":"2026-09-08","links":[{"label":"PubMed search: CheckMate 649 Lancet 2021","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CheckMate+649+nivolumab+chemotherapy+gastric+Janjigian+Lancet+2021"},{"label":"ClinicalTrials.gov NCT02872116","url":"https://clinicaltrials.gov/study/NCT02872116"}],"tags":[],"related":[],"cancers":["gastric","esophageal"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","platinum"],"targets":["pd1","pdl1"],"drugs":["nivolumab","ipilimumab"],"companies":["bms"],"institutions":["mskcc"],"pathways":[],"terms":["cps","os","pfs","first-line","msi"],"trials":[],"people":["yelena-janjigian","shitara-kohei","shen-lin"],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response","b-regulatory-fragmentation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"authors":"Janjigian YY, Shitara K, Moehler M, et al.","paperType":"rct","findings":["CPS 5 or more: median OS 14.4 vs 11.1 months, HR 0.71 (98.4% CI 0.59-0.86); median PFS 7.7 vs 6.0 months, HR 0.68.","All randomised patients: median OS 13.8 vs 11.6 months, HR 0.80 (99.3% CI 0.68-0.94).","Objective response in CPS 5 or more: 60% vs 45%.","Exploratory analysis showed little benefit in CPS below 5, and the EMA restricted the label to CPS 5 or more while the FDA initially approved it regardless of PD-L1 (later narrowed to CPS 1 or more).","Grade 3-4 treatment-related adverse events 59% vs 44%."],"whatItMeans":"Patients with newly diagnosed advanced stomach or oesophageal adenocarcinoma whose tumour is HER2-negative and PD-L1 positive (CPS 5 or more, or at least 1 in some regions) should receive chemotherapy with nivolumab (or pembrolizumab, from KEYNOTE-859), which adds about three months of median survival and doubles the chance of being alive at three years. The benefit in PD-L1-negative tumours is doubtful, and these patients may be better served by chemotherapy alone or by trials.","caveats":["Benefit is concentrated in PD-L1-positive tumours; the ITT result is driven by the CPS 5 or more subgroup.","Open-label design; CPS scoring reproducibility is imperfect.","Microsatellite-instability-high tumours (about 3%) derived very large benefit and inflate pooled estimates.","The nivolumab plus ipilimumab chemotherapy-free arm failed to improve OS."],"changedPractice":true,"participants":1581},{"id":"paper-checkmate-743-lancet-2021","kind":"paper","name":"CheckMate 743: first-line nivolumab plus ipilimumab in unresectable pleural mesothelioma","aka":[],"tldr":"Dual immunotherapy with nivolumab and ipilimumab lengthened survival compared with platinum-pemetrexed chemotherapy in pleural mesothelioma, the first improvement in first-line treatment in almost twenty years, with the largest gain in non-epithelioid tumours.","summary":"Phase 3 trial of 605 patients with untreated unresectable malignant pleural mesothelioma randomised to nivolumab plus ipilimumab or platinum plus pemetrexed.\n\nMedian overall survival was 18.1 versus 14.1 months (hazard ratio 0.74); in non-epithelioid histology it was 18.1 versus 8.8 months (hazard ratio 0.46), while the difference in epithelioid disease was small. Three-year survival was 23 versus 15 percent.","asOf":"2026-09-17","links":[{"label":"Lancet 2021","url":"https://doi.org/10.1016/S0140-6736(20)32714-8"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33485464/"}],"tags":[],"related":[],"cancers":["pleural-mesothelioma","peritoneal-mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":["ipilimumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-743"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"doi":"10.1016/S0140-6736(20)32714-8","pmid":"33485464","authors":"Baas P, Scherpereel A, Nowak AK, et al.","paperType":"rct","findings":["Median overall survival 18.1 vs 14.1 months; hazard ratio 0.74.","Non-epithelioid: 18.1 vs 8.8 months; hazard ratio 0.46."],"whatItMeans":"Nivolumab-ipilimumab is the preferred first-line treatment for non-epithelioid pleural mesothelioma and an option in epithelioid disease alongside chemo-immunotherapy.","caveats":["Open-label; early crossing of survival curves indicates some patients do worse without chemotherapy.","Epithelioid benefit was modest."],"changedPractice":true,"participants":605},{"id":"paper-checkmate-76k-nat-med-2023","kind":"paper","name":"CheckMate 76K: adjuvant nivolumab in resected stage IIB or IIC melanoma","aka":[],"tldr":"Adjuvant nivolumab for a year after surgery cut the risk of recurrence by more than half in stage IIB and IIC melanoma, confirming the benefit seen with pembrolizumab in the same setting.","summary":"Phase 3 placebo-controlled trial of 790 patients with completely resected stage IIB or IIC melanoma randomised 2:1 to nivolumab or placebo for 12 months.\n\nTwelve-month recurrence-free survival was 89.0 versus 79.4 percent (hazard ratio 0.42), with benefit across subgroups and a distant metastasis-free survival hazard ratio of 0.47; treatment-related grade 3 to 4 adverse events occurred in 10.3 percent.","asOf":"2026-09-17","links":[{"label":"Nat Med 2023","url":"https://doi.org/10.1038/s41591-023-02583-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37845511/"}],"tags":[],"related":[],"cancers":["stage-ii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["nct04099251"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2023,"doi":"10.1038/s41591-023-02583-2","pmid":"37845511","authors":"Kirkwood JM, Del Vecchio M, Weber J, et al.","paperType":"rct","findings":["Twelve-month recurrence-free survival 89.0 percent vs 79.4 percent; hazard ratio 0.42.","Distant metastasis-free survival hazard ratio 0.47."],"whatItMeans":"Nivolumab is a second approved adjuvant option for stage IIB and IIC melanoma with the same trade-offs as pembrolizumab.","caveats":["Short follow-up at primary analysis; no survival data."],"changedPractice":true,"participants":790},{"id":"paper-checkmate-816-nejm-2022","kind":"paper","name":"CheckMate 816: three cycles of nivolumab plus chemotherapy before lung cancer surgery","aka":[],"tldr":"Just three cycles of chemotherapy with the immunotherapy nivolumab before surgery wiped out all viable tumour in a quarter of patients and reduced relapse or death by about a third, without making surgery harder.","summary":"Open-label phase 3 trial of 358 patients with resectable stage IB-IIIA NSCLC randomised to three cycles of neoadjuvant nivolumab plus platinum-doublet chemotherapy or chemotherapy alone, followed by surgery. Primary endpoints were pathological complete response (pCR) and event-free survival (EFS).\n\npCR was 24.0% vs 2.2% and median EFS 31.6 vs 20.8 months (HR 0.63). Surgery rates and complications were not worse with nivolumab. A 2025 report confirmed an overall survival benefit (HR about 0.72). It was the first neoadjuvant immunotherapy approval in lung cancer and, together with the perioperative trials (KEYNOTE-671, AEGEAN, CheckMate 77T), moved immunotherapy before surgery.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2202170"},{"label":"ClinicalTrials.gov NCT02998528","url":"https://clinicaltrials.gov/study/NCT02998528"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy"],"targets":["pd1"],"drugs":["nivolumab","carboplatin","paclitaxel"],"companies":["bms"],"institutions":["johns-hopkins"],"pathways":[],"terms":["pcr","efs","neoadjuvant-adjuvant"],"trials":[],"people":["patrick-forde","lu-shun","enriqueta-felip","julie-brahmer","everett-vokes"],"bottlenecks":["b-immunotherapy-response","b-trial-design","b-dormancy-mrd"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2202170","authors":"Forde PM, Spicer J, Lu S, et al.","paperType":"rct","findings":["Pathological complete response 24.0% vs 2.2% (odds ratio 13.9).","Median event-free survival 31.6 vs 20.8 months; HR 0.63 (97.38% CI 0.43-0.91).","Definitive surgery was performed in 83% vs 75% of patients; grade 3-4 surgery-related adverse events 11% in both arms.","Patients achieving pCR had markedly better EFS (HR about 0.13 within the nivolumab arm).","Overall survival (2025 update): HR about 0.72, with 5-year OS of roughly 65% vs 55%."],"whatItMeans":"Patients with operable stage II-III lung cancer without EGFR or ALK alterations should have chemo-immunotherapy discussed before surgery rather than only afterwards. Three pre-operative cycles do not compromise the operation and improve cure rates. Whether to continue immunotherapy after surgery, as the perioperative trials do, and whether patients with pCR need any further treatment, remain open questions.","caveats":["Open-label; EFS by blinded review.","About one in six patients did not proceed to surgery in either arm, an under-appreciated risk of any neoadjuvant strategy.","Benefit was smaller in stage IB-II and in PD-L1-negative tumours.","No adjuvant immunotherapy was given, so the trial cannot say whether the perioperative approach adds value over neoadjuvant alone."],"changedPractice":true,"participants":358},{"id":"paper-checkmate-8hw-lancet-2025","kind":"paper","name":"CheckMate 8HW: nivolumab plus ipilimumab versus nivolumab alone in MSI-high metastatic colorectal cancer","aka":[],"tldr":"Dual immunotherapy with nivolumab and ipilimumab delayed progression more than nivolumab alone across all lines of treatment in microsatellite-unstable colorectal cancer, with about seven in ten patients progression-free at three years.","summary":"Phase 3 trial of 707 patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer randomised to nivolumab plus ipilimumab, nivolumab alone or chemotherapy; this report compares the two immunotherapy arms across all lines.\n\nProgression-free survival favoured the combination (hazard ratio 0.62; three-year rate about 68 versus 51 percent) with a higher response rate (71 versus 58 percent); grade 3 to 4 treatment-related adverse events were 22 versus 14 percent.","asOf":"2026-09-17","links":[{"label":"Lancet 2025","url":"https://doi.org/10.1016/S0140-6736(24)02848-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39874977/"}],"tags":[],"related":[],"cancers":["msi-high-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["ipilimumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["checkmate-8hw"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2025,"doi":"10.1016/S0140-6736(24)02848-4","pmid":"39874977","authors":"André T, Elez E, Lenz HJ, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.62 for the combination vs nivolumab alone.","Objective response 71 percent vs 58 percent."],"whatItMeans":"Nivolumab-ipilimumab is a first-line standard for microsatellite-unstable metastatic colorectal cancer alongside pembrolizumab, with the trade-off of more immune toxicity for deeper and more durable control.","caveats":["Overall survival data immature at this report.","The earlier comparison with chemotherapy was first line only."],"changedPractice":true,"participants":707},{"id":"paper-chen-cancer-statistics-china-2015-cacancer-2016","kind":"paper","name":"Chen 2016: Cancer statistics in China, 2015","aka":[],"tldr":"The first national cancer estimate for China built from population registries, projecting about 4.3 million new cancer cases in 2015, with lung cancer the most common cancer and leading cause of cancer death, and stomach, oesophageal and liver cancers far more prominent than in Western countries.","summary":"Chen and colleagues at China's National Cancer Center used data from 72 local population-based cancer registries covering 2009 to 2011, about 6.5% of the population, to project cancer incidence and mortality in China for 2015. They estimated about 4.3 million new cases and 2.8 million deaths. Lung cancer was the most common cancer and the leading cause of death, followed by stomach, oesophageal, liver and colorectal cancers, and the report documented rising incidence in cities alongside higher mortality in rural areas, as well as a large burden of infection-related cancers.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21338"}],"tags":[],"related":["paper-bray-globocan-2018-cacancer-2018"],"cancers":["nsclc","gastric","hcc","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["ncc-china"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2016,"doi":"10.3322/caac.21338","authors":"Chen W, Zheng R, Baade PD, et al.","paperType":"observational","findings":["About 4,292,000 new cancer cases and 2,814,000 cancer deaths projected for China in 2015.","Lung cancer the most common cancer and leading cause of cancer death; stomach, oesophageal, liver and colorectal cancers next.","Based on 72 population-based registries covering about 6.5% of the population; rural areas had higher mortality than cities."],"whatItMeans":"China accounts for roughly a quarter of the world's cancer cases, and this paper is the reference that made its burden legible internationally. It explains why Chinese trial programmes and drug pipelines concentrate on lung, stomach, oesophageal and liver cancers.","caveats":["Registries covered a small, mainly urban share of the population, so estimates involve substantial extrapolation.","Later National Cancer Center reports have updated the figures."],"changedPractice":false},{"id":"paper-chen-mellman-cancer-immunity-cycle-immunity-2013","kind":"paper","name":"Chen and Mellman 2013: the cancer-immunity cycle","aka":[],"tldr":"The seven-step diagram of how the immune system should destroy a cancer, from releasing tumour antigens to killing tumour cells, and the idea that each patient's cancer breaks the cycle at a different step, which tells you which immunotherapies to combine.","summary":"Chen and Mellman at Genentech laid out the cancer-immunity cycle: release of cancer cell antigens, antigen presentation by dendritic cells, priming and activation of T cells, trafficking to the tumour, infiltration, recognition of cancer cells and killing, which releases more antigens. They argued that effective immunity requires every step to work, that tumours block different steps in different patients, and that therapies should be matched to the rate-limiting step, with PD-L1 and PD-1 blockade acting at the final killing step. They introduced the term immunostat for the factors that set the balance.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/j.immuni.2013.07.012"}],"tags":[],"related":["paper-pardoll-immune-checkpoint-blockade-nrc-2012","paper-binnewies-tumor-immune-microenvironment-natmed-2018"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","pdl1"],"drugs":[],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["immune-system","neoantigen","cold-vs-hot"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Immunity","year":2013,"doi":"10.1016/j.immuni.2013.07.012","authors":"Chen DS, Mellman I.","paperType":"review","findings":["Anti-cancer immunity proceeds through seven steps from antigen release to tumour cell killing, each of which can fail.","Different tumours and patients are limited at different steps, so no single immunotherapy will work for all.","Checkpoint blockade acts at the recognition and killing step; other therapies target priming, trafficking or infiltration."],"whatItMeans":"The cycle is the most used framework for designing immunotherapy combinations, from vaccines and radiotherapy that release antigens to drugs that recruit T cells into cold tumours. Most trial rationales in immuno-oncology cite it.","caveats":["A conceptual review; the steps are idealised and the rate-limiting step is hard to measure in practice.","Written by authors at a company developing a PD-L1 antibody."],"changedPractice":false},{"id":"paper-chhip-lancet-oncol-2016","kind":"paper","name":"CHHiP: conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer","aka":[],"tldr":"Delivering prostate radiotherapy in 20 larger daily doses over four weeks was as effective as 37 smaller doses over seven and a half weeks, with no more side effects, and became the standard schedule in many countries.","summary":"Phase 3 non-inferiority trial of 3,216 men with localised prostate cancer (mostly intermediate risk) randomised to 74 Gy in 37 fractions, 60 Gy in 20 fractions or 57 Gy in 19 fractions of intensity-modulated radiotherapy with short-course androgen deprivation.\n\nFive-year biochemical or clinical failure-free rates were 88.3 percent (74 Gy), 90.6 percent (60 Gy) and 85.9 percent (57 Gy); 60 Gy in 20 fractions was non-inferior and toxicity was similar.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2016","url":"https://doi.org/10.1016/S1470-2045(16)30102-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27339115/"}],"tags":[],"related":[],"cancers":["prostate-intermediate-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["chhip"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2016,"doi":"10.1016/S1470-2045(16)30102-4","pmid":"27339115","authors":"Dearnaley D, Syndikus I, Mossop H, et al.","paperType":"rct","findings":["Five-year failure-free rate 90.6 percent (60 Gy/20) vs 88.3 percent (74 Gy/37); non-inferior.","57 Gy in 19 fractions did not meet non-inferiority."],"whatItMeans":"Moderate hypofractionation (60 Gy in 20 fractions) is a standard of care for localised prostate cancer, halving the number of hospital visits.","caveats":["Most men received short-course androgen deprivation.","Ultra-hypofractionation (five fractions) was tested separately in PACE-B."],"changedPractice":true,"participants":3216},{"id":"paper-aall1731-blinatumomab-children-nejm-2025","kind":"paper","name":"Children's Oncology Group AALL1731: blinatumomab added to chemotherapy for children with standard-risk B-cell ALL","aka":[],"tldr":"Two courses of blinatumomab added to standard chemotherapy cut relapses in children with average- or higher-risk standard-risk leukaemia, raising three-year disease-free survival from 88% to 96%.","summary":"AALL1731 was a phase 3 Children's Oncology Group trial in children aged 1 to under 10 with newly diagnosed National Cancer Institute standard-risk B-cell ALL. Those with average- or high-risk features after induction (1440 patients) were randomised to standard chemotherapy or the same chemotherapy with two 28-day cycles of blinatumomab. The primary endpoint was disease-free survival. At the first interim analysis three-year DFS was 96.0% with blinatumomab versus 87.9% (hazard ratio 0.39), and randomisation was stopped early for efficacy. Sepsis and catheter-related infections were more frequent with blinatumomab, but there were few grade 3 or higher CRS or neurological events.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=AALL1731%20blinatumomab%20standard-risk%20B-ALL%20children%20Gupta%20NEJM%202025"},{"label":"ClinicalTrials.gov NCT03914625","url":"https://clinicaltrials.gov/study/NCT03914625"}],"tags":[],"related":["blinatumomab-frontline-consolidation","paper-e1910-blinatumomab-mrd-negative-all-nejm-2024"],"cancers":["all-leukemia","all-paediatric-standard-risk"],"sections":[],"technologies":["bispecific-antibody","t-cell-engager"],"targets":["cd19","cd3"],"drugs":["blinatumomab"],"companies":["amgen"],"institutions":["childrens-oncology-group"],"pathways":[],"terms":["efs","mrd"],"trials":["aall1731"],"people":["rachel-rau"],"bottlenecks":["b-trial-design","b-survivorship"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"authors":"Gupta S, Rau RE, Kairalla JA, et al.","paperType":"rct","findings":["1440 children with NCI standard-risk B-ALL (average- or high-risk subgroups) randomised; chemotherapy with or without 2 cycles of blinatumomab.","3-year disease-free survival 96.0% vs 87.9%; hazard ratio 0.39.","Benefit in both the average-risk and high-risk standard-risk subgroups.","Randomisation halted early at interim analysis for efficacy.","Higher rates of sepsis and catheter-related infections with blinatumomab; CRS and neurotoxicity rare and mostly low grade."],"whatItMeans":"AALL1731 brings immunotherapy into the front-line treatment of the commonest childhood cancer, in the group of children where most relapses were occurring despite good initial risk. Blinatumomab was approved for this use in 2024 and paediatric protocols worldwide are being amended. Whether it can allow less chemotherapy, and its effect on very low-risk children, are the next questions.","caveats":["Early stopping at interim analysis may overestimate the effect size.","Follow-up is short for a disease where late relapses occur; overall survival not yet different.","Infection-related toxicity and central-line management are practical concerns in small children.","Very favourable-risk children (not randomised) were not tested."],"changedPractice":true,"participants":1440},{"id":"paper-clarinet-lanreotide-nejm-2014","kind":"paper","name":"CLARINET: lanreotide in metastatic enteropancreatic neuroendocrine tumours","aka":[],"tldr":"The long-acting somatostatin analogue lanreotide roughly halved the risk of progression in non-functioning gut and pancreatic neuroendocrine tumours, extending the use of these drugs from symptom control to slowing tumour growth.","summary":"Phase 3 placebo-controlled trial of 204 patients with advanced, well- or moderately differentiated, non-functioning, somatostatin receptor-positive enteropancreatic neuroendocrine tumours (Ki-67 under 10 percent) randomised to lanreotide autogel 120 mg monthly or placebo.\n\nMedian progression-free survival was not reached with lanreotide against 18.0 months with placebo (hazard ratio 0.47), with benefit in pancreatic and midgut tumours and in patients with high hepatic tumour load.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2014","url":"https://doi.org/10.1056/NEJMoa1316158"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25014687/"}],"tags":[],"related":[],"cancers":["pancreatic-net","small-intestinal-net"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["clarinet"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/NEJMoa1316158","pmid":"25014687","authors":"Caplin ME, Pavel M, Ćwikła JB, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.47.","24-month progression-free survival 65.1 percent vs 33.0 percent."],"whatItMeans":"Somatostatin analogues are the standard first-line antiproliferative treatment for grade 1 to 2 gastroenteropancreatic neuroendocrine tumours whether or not they cause a hormone syndrome.","caveats":["Most patients had stable disease at entry, so the natural history was slow.","No overall survival benefit shown."],"changedPractice":true,"participants":204},{"id":"paper-clear-nejm-2021","kind":"paper","name":"CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer","aka":[],"tldr":"Combining the multi-kinase inhibitor lenvatinib with pembrolizumab more than doubled the time to progression compared with sunitinib in advanced clear-cell kidney cancer and improved survival, with 71% of patients responding.","summary":"Open-label phase 3 trial of 1,069 patients with untreated advanced clear-cell renal cell carcinoma randomised to lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib. Primary endpoint was PFS by independent review.\n\nMedian PFS was 23.9 vs 9.2 months (HR 0.39) for lenvatinib plus pembrolizumab, with OS HR 0.66 and an objective response rate of 71.0% vs 36.1%. Alongside KEYNOTE-426 (axitinib plus pembrolizumab), CheckMate 9ER (cabozantinib plus nivolumab) and CheckMate 214 (nivolumab plus ipilimumab), it established immunotherapy-based combinations as universal first-line therapy for advanced kidney cancer.","asOf":"2026-09-08","links":[{"label":"NEJM 2021","url":"https://doi.org/10.1056/NEJMoa2035716"},{"label":"ClinicalTrials.gov NCT02811861","url":"https://clinicaltrials.gov/study/NCT02811861"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":["checkpoint-inhibitor","kinase-inhibitors","antiangiogenic"],"targets":["pd1","vegf"],"drugs":["pembrolizumab"],"companies":["merck","eli-lilly"],"institutions":[],"pathways":[],"terms":["pfs","os","orr","first-line"],"trials":[],"people":["rha-sun-young","toni-choueiri"],"bottlenecks":["b-combination-space","b-toxicity-qol","b-dose-optimisation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2035716","authors":"Motzer R, Alekseev B, Rha SY, et al.","paperType":"rct","findings":["Median PFS 23.9 vs 9.2 months; HR 0.39 (95% CI 0.32-0.49).","Overall survival HR 0.66 (95% CI 0.49-0.88) at the primary analysis; subsequent follow-up showed median OS about 53.7 vs 54.3 months with HR 0.79, as sunitinib patients received later immunotherapy.","Objective response 71.0% vs 36.1%; complete response 16.1% vs 4.2%.","Benefit across all IMDC risk groups, including favourable risk.","Grade 3 or higher adverse events 82.4% vs 71.8%; hypertension, diarrhoea and proteinuria led to frequent lenvatinib dose reductions."],"whatItMeans":"Patients with newly diagnosed advanced clear-cell kidney cancer should receive an immunotherapy-based combination; lenvatinib plus pembrolizumab gives the highest response rate and longest PFS of the available options, at the cost of more side effects requiring dose adjustment. Sunitinib alone is no longer an appropriate standard. Choosing among the combinations depends on risk group, symptoms, comorbidity and the value placed on treatment-free survival, which favours nivolumab plus ipilimumab in intermediate and poor risk.","caveats":["Open-label; no head-to-head comparison among the immunotherapy combinations.","The OS advantage narrowed with longer follow-up because of subsequent immunotherapy in the sunitinib arm.","High rates of dose reduction and discontinuation of lenvatinib; the 20 mg starting dose is debated.","Non-clear-cell histologies were excluded."],"changedPractice":true,"participants":1069},{"id":"paper-wagner-sirolimus-pecoma-jco-2010","kind":"paper","name":"Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumours","aka":[],"tldr":"This report of three patients with malignant PEComa responding to oral sirolimus was the first evidence that these tumours, which share TSC1/TSC2 loss with tuberous sclerosis, depend on the mTOR pathway.","summary":"Case series of three patients with metastatic malignant PEComa treated with sirolimus, all showing radiological responses, with molecular analysis of tumour tissue demonstrating loss of TSC2 and activation of mTORC1 signalling.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2010","url":"https://doi.org/10.1200/JCO.2009.25.2981"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20048174/"}],"tags":[],"related":[],"cancers":["pecoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2010,"doi":"10.1200/JCO.2009.25.2981","pmid":"20048174","authors":"Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al.","paperType":"observational","findings":["Radiological responses in all three patients treated with sirolimus.","TSC2 loss and mTORC1 activation in tumour tissue."],"whatItMeans":"mTOR inhibition became the therapeutic strategy for PEComa, culminating in the AMPECT trial and approval of nab-sirolimus.","caveats":["Three patients; hypothesis-generating."],"changedPractice":true,"participants":3},{"id":"paper-aggarwal-t-sccpc-jco-2018","kind":"paper","name":"Clinical and genomic characterisation of treatment-emergent small-cell neuroendocrine prostate cancer","aka":[],"tldr":"Biopsying metastases in men progressing on modern hormone therapy found small-cell neuroendocrine prostate cancer in 17 percent, with a median survival under three years, showing how commonly the lineage switch occurs and why biopsy at progression matters.","summary":"Prospective multi-institutional study of 202 men with metastatic castration-resistant prostate cancer who underwent metastatic biopsy, with histological and transcriptomic classification of treatment-emergent small-cell neuroendocrine prostate cancer.\n\nSmall-cell neuroendocrine histology was found in 17 percent, associated with worse overall survival (36.6 versus 44.5 months), a distinct expression signature and low androgen receptor signalling; serum markers such as chromogranin were unreliable.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2018","url":"https://doi.org/10.1200/JCO.2017.77.6880"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29985747/"}],"tags":[],"related":[],"cancers":["prostate-nepc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2018,"doi":"10.1200/JCO.2017.77.6880","pmid":"29985747","authors":"Aggarwal R, Huang J, Alumkal JJ, et al.","paperType":"observational","findings":["Treatment-emergent small-cell neuroendocrine prostate cancer in 17 percent of biopsied patients.","Median overall survival 36.6 vs 44.5 months for adenocarcinoma."],"whatItMeans":"Biopsy of progressing lesions, especially with low PSA or visceral spread, is recommended to detect neuroendocrine transformation and switch to platinum-based therapy or trials.","caveats":["Selected patients undergoing biopsy at academic centres."],"changedPractice":true,"participants":202},{"id":"paper-cll14-venetoclax-obinutuzumab-nejm-2019","kind":"paper","name":"CLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patients","aka":[],"tldr":"A fixed one-year course of two targeted drugs kept CLL under control far longer than chemo-immunotherapy, and most patients had no detectable disease when treatment stopped.","summary":"CLL14 randomised 432 previously untreated patients with CLL and coexisting conditions (CIRS score above 6 or creatinine clearance under 70 mL/min) to 12 cycles of venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab. The primary endpoint was investigator-assessed progression-free survival. At 24 months PFS was 88.2% versus 64.1% (hazard ratio 0.35), and undetectable MRD in peripheral blood three months after treatment ended was 75.5% versus 35.2%. Grade 3-4 neutropenia and infections were similar between arms. With six years of follow-up more than half of venetoclax-obinutuzumab patients remained progression-free against roughly a fifth on chemo-immunotherapy, though overall survival was not significantly different.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1815281"},{"label":"ClinicalTrials.gov NCT02242942","url":"https://clinicaltrials.gov/study/NCT02242942"}],"tags":[],"related":["venetoclax-plus-obinutuzumab"],"cancers":["cll"],"sections":[],"technologies":[],"targets":["bcl2","cd20"],"drugs":["venetoclax","obinutuzumab"],"companies":["abbvie","roche-genentech"],"institutions":[],"pathways":[],"terms":["mrd","pfs","ighv-status","del17p-tp53"],"trials":["cll14","cll13-gaia"],"people":["michael-hallek"],"bottlenecks":["b-dormancy-mrd","b-aging-comorbidity"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1815281","authors":"Fischer K, Al-Sawaf O, Bahlo J, et al.","paperType":"rct","findings":["432 patients with untreated CLL and comorbidities; 12 cycles of venetoclax-obinutuzumab vs chlorambucil-obinutuzumab.","24-month PFS 88.2% vs 64.1%; hazard ratio 0.35.","Undetectable MRD (below 10^-4) in blood 3 months after treatment end: 75.5% vs 35.2%.","Grade 3-4 neutropenia 52.8% vs 48.1%; grade 3-4 infections 17.5% vs 15.0%.","Benefit held across IGHV-unmutated and TP53-aberrant subgroups, though del(17p)/TP53 patients relapsed earlier."],"whatItMeans":"CLL14 established the first chemotherapy-free, fixed-duration regimen for front-line CLL and made MRD-guided thinking mainstream in the disease. Patients get a year of treatment and then a treatment-free period rather than indefinite therapy. The choice today is between fixed-duration venetoclax combinations and continuous BTK inhibitors, with no proven survival difference.","caveats":["Overall survival has not differed significantly, partly because effective salvage therapies exist.","Patients were older and less fit; CLL13/GAIA later confirmed benefit in fit patients.","Venetoclax requires a 5-week ramp-up and tumour-lysis monitoring, which is a practical burden.","Retreatment strategy after relapse was not defined by the trial."],"changedPractice":true,"participants":432},{"id":"paper-codebreak-200-lancet-2023","kind":"paper","name":"CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug","aka":[],"tldr":"The first drug to directly block mutant KRAS beat docetaxel chemotherapy on delaying progression in KRAS G12C lung cancer, but only by about a month, and did not improve survival.","summary":"Open-label phase 3 trial of 345 patients with KRAS G12C-mutated advanced NSCLC previously treated with platinum chemotherapy and a PD-1 inhibitor, randomised to sotorasib 960 mg daily or docetaxel. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 5.6 vs 4.5 months (HR 0.66) with a higher response rate (28.1% vs 13.2%) and less high-grade toxicity, but overall survival was not different (HR about 1.0), partly because a third of docetaxel patients crossed over. It confirmed that KRAS G12C is druggable, and also that first-generation inhibitors give short-lived benefit; the FDA's concerns about the trial's design and a later dose-comparison requirement shaped how KRAS inhibitors were subsequently developed.","asOf":"2026-09-08","links":[{"label":"PubMed search: CodeBreaK 200 Lancet 2023","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CodeBreaK+200+sotorasib+docetaxel+de+Langen+Lancet"},{"label":"ClinicalTrials.gov NCT04303780","url":"https://clinicaltrials.gov/study/NCT04303780"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["kras-inhibitors","kinase-inhibitors"],"targets":["kras"],"drugs":["sotorasib","adagrasib"],"companies":["amgen"],"institutions":["nki"],"pathways":[],"terms":["pfs","os","orr","resistance","accelerated-approval"],"trials":["codebreak-300"],"people":[],"bottlenecks":["b-undruggable-targets","b-resistance","b-trial-design","b-dose-optimisation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"authors":"de Langen AJ, Johnson ML, Mazieres J, et al.","paperType":"rct","findings":["Median PFS 5.6 vs 4.5 months; HR 0.66 (95% CI 0.51-0.86); 12-month PFS 24.8% vs 10.1%.","Objective response 28.1% vs 13.2%; disease control 82.5% vs 60.3%.","Grade 3 or higher treatment-related adverse events 33% vs 40%; diarrhoea and liver enzyme elevation were the main sotorasib toxicities.","Overall survival not significantly different; the trial was not powered for OS and 34% of docetaxel patients crossed over to sotorasib.","The KRYSTAL-12 trial of adagrasib versus docetaxel later reported a similar PFS result (5.5 vs 3.8 months, HR 0.58)."],"whatItMeans":"Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.","caveats":["Open-label with a modest absolute PFS gain of about one month and no OS benefit.","Crossover and the sample size reduction made during the trial (from 650 to 345) drew criticism from regulators.","Resistance develops through multiple mechanisms (secondary KRAS mutations, bypass pathways), limiting durability.","Response rates in KRAS G12C lung cancer (around 30-40%) are far lower than for EGFR or ALK inhibitors, reflecting KRAS biology."],"changedPractice":true,"participants":345},{"id":"paper-codebreak-300-nejm-2023","kind":"paper","name":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer","aka":[],"tldr":"Combining a KRAS G12C inhibitor with an EGFR antibody produced responses in about a quarter of patients with heavily pretreated KRAS G12C bowel cancer, versus none with standard chemotherapy, and more than doubled the time to progression.","summary":"Open-label phase 3 trial of 160 patients with KRAS G12C-mutated metastatic colorectal cancer that had progressed after fluoropyrimidine, oxaliplatin and irinotecan, randomised 1:1:1 to sotorasib 960 mg or 240 mg daily plus panitumumab, or investigator's choice of trifluridine-tipiracil or regorafenib. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 5.6 months with sotorasib 960 mg (HR 0.49) and 3.9 months with 240 mg (HR 0.58) versus 2.2 months with standard care; response rates were 26.4%, 5.7% and 0%. It showed that KRAS G12C inhibition in colorectal cancer needs EGFR co-blockade to overcome adaptive feedback, and led to FDA approval of the combination in 2025.","asOf":"2026-09-08","links":[{"label":"NEJM 2023","url":"https://doi.org/10.1056/NEJMoa2308795"},{"label":"ClinicalTrials.gov NCT05198934","url":"https://clinicaltrials.gov/study/NCT05198934"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["kras-inhibitors","monoclonal-antibody"],"targets":["kras","egfr"],"drugs":["sotorasib"],"companies":["amgen"],"institutions":[],"pathways":[],"terms":["pfs","orr","resistance"],"trials":["codebreak-300"],"people":["kim-tae-won","david-cunningham"],"bottlenecks":["b-undruggable-targets","b-resistance","b-dose-optimisation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2308795","authors":"Fakih MG, Salvatore L, Esaki T, et al.","paperType":"rct","findings":["Median PFS 5.6 months (sotorasib 960 mg plus panitumumab) vs 2.2 months (standard care); HR 0.49 (95% CI 0.30-0.80).","Median PFS 3.9 months with sotorasib 240 mg plus panitumumab; HR 0.58.","Objective response 26.4% (960 mg), 5.7% (240 mg) and 0% (standard care).","Skin toxicity (from panitumumab) and hypomagnesaemia were the main adverse events; grade 3 or higher treatment-related events about 36% (960 mg), 30% (240 mg) and 43% (standard care).","Overall survival showed a trend favouring the 960 mg arm but was not powered to detect a difference."],"whatItMeans":"Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone barely works in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.","caveats":["Small trial with a PFS primary endpoint; OS benefit not established.","The comparator drugs are of very limited efficacy, so the bar was low.","Median PFS of 5.6 months underlines that resistance develops quickly.","Only KRAS G12C is covered; the far more common G12D and G12V mutations await other inhibitors."],"changedPractice":true,"participants":160},{"id":"paper-p9641-low-risk-neuroblastoma-strother-jco-2012","kind":"paper","name":"COG P9641: surgery alone or with restricted chemotherapy for low-risk neuroblastoma","aka":[],"tldr":"In the largest low-risk neuroblastoma trial, surgery alone cured almost all children with stage 1 and most with stage 2 disease, with chemotherapy reserved for symptoms or unfavourable features, confirming that many children need no drug treatment.","summary":"Children's Oncology Group phase 3 study of 915 children with low-risk neuroblastoma (stage 1, asymptomatic stage 2 and 4S with favourable biology) treated with surgery alone, with chemotherapy only for symptomatic, unresectable or progressive disease.\n\nFive-year event-free survival was 89 percent and overall survival 97 percent; outcomes were excellent for stage 1 and for stage 2 with favourable biology, and lower in stage 2 with unfavourable histology or diploidy in children over 18 months.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2012","url":"https://doi.org/10.1200/JCO.2011.37.9990"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22529259/"}],"tags":[],"related":[],"cancers":["neuroblastoma-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2012,"doi":"10.1200/JCO.2011.37.9990","pmid":"22529259","authors":"Strother DR, London WB, Schmidt ML, et al.","paperType":"observational","findings":["Five-year overall survival 97 percent; event-free survival 89 percent.","Stage 1: event-free survival 93 percent with surgery alone."],"whatItMeans":"Surgery alone, or observation, is standard for low-risk neuroblastoma, with chemotherapy limited to those with symptoms or unfavourable biology.","caveats":["Non-randomised risk-adapted design."],"changedPractice":true,"participants":915},{"id":"paper-siegel-crc-incidence-1974-2013-jnci-2017","kind":"paper","name":"Colorectal cancer incidence patterns in the United States, 1974 to 2013","aka":[],"tldr":"Analysing four decades of US registry data, this study showed colorectal cancer incidence rising steeply in adults under 50 while falling in older adults, with people born around 1990 having double the colon cancer risk and quadruple the rectal cancer risk of those born around 1950.","summary":"Age-period-cohort analysis of colorectal cancer incidence from SEER registries between 1974 and 2013, showing increases of 1 to 2 percent per year in adults aged 20 to 39 and rising rectal cancer incidence in those aged 40 to 54, alongside declines in adults 55 and older attributed to screening.","asOf":"2026-09-17","links":[{"label":"J Natl Cancer Inst 2017","url":"https://doi.org/10.1093/jnci/djw322"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28376186/"}],"tags":[],"related":[],"cancers":["early-onset-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jnci"],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":2017,"doi":"10.1093/jnci/djw322","pmid":"28376186","authors":"Siegel RL, Fedewa SA, Anderson WF, et al.","paperType":"observational","findings":["Colon cancer incidence rising 1 to 2.4 percent per year in adults aged 20 to 39 since the mid-1980s.","Rectal cancer incidence rising about 3.2 percent per year in adults aged 20 to 29 and 30 to 39."],"whatItMeans":"This is the paper that made early-onset colorectal cancer a public health issue and drove the change in screening age.","caveats":["Registry analysis cannot identify causes.","Some increase may reflect greater detection through colonoscopy for symptoms."],"changedPractice":true},{"id":"paper-columbus-lancet-oncol-2018","kind":"paper","name":"COLUMBUS: encorafenib plus binimetinib versus vemurafenib or encorafenib in BRAF-mutant melanoma","aka":[],"tldr":"The third BRAF-MEK combination, encorafenib plus binimetinib, delayed progression more than vemurafenib and produced the longest median survival of any targeted regimen in BRAF-mutant melanoma, with less fever than dabrafenib-trametinib.","summary":"Phase 3 trial of 577 patients with advanced BRAF V600-mutant melanoma randomised to encorafenib plus binimetinib, encorafenib alone or vemurafenib alone.\n\nMedian progression-free survival was 14.9 months with the combination against 7.3 months with vemurafenib (hazard ratio 0.54), and median overall survival 33.6 versus 16.9 months on later analysis; the combination had a distinct toxicity profile with less pyrexia and photosensitivity.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2018","url":"https://doi.org/10.1016/S1470-2045(18)30142-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29573941/"}],"tags":[],"related":[],"cancers":["braf-v600-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["binimetinib","encorafenib","vemurafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["columbus"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2018,"doi":"10.1016/S1470-2045(18)30142-6","pmid":"29573941","authors":"Dummer R, Ascierto PA, Gogas HJ, et al.","paperType":"rct","findings":["Median progression-free survival 14.9 vs 7.3 months; hazard ratio 0.54.","Median overall survival 33.6 vs 16.9 months."],"whatItMeans":"Encorafenib-binimetinib is one of three standard BRAF-MEK doublets for advanced melanoma and is often chosen for its tolerability.","caveats":["Open-label; vemurafenib monotherapy is a dated comparator."],"changedPractice":true,"participants":577},{"id":"paper-combi-ad-nejm-2017","kind":"paper","name":"COMBI-AD: adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma","aka":[],"tldr":"A year of dabrafenib plus trametinib after surgery for stage III BRAF-mutant melanoma cut the risk of relapse by more than half, giving patients with BRAF mutations a targeted alternative to adjuvant immunotherapy.","summary":"Phase 3 placebo-controlled trial of 870 patients with completely resected stage III BRAF V600E or V600K melanoma randomised to 12 months of dabrafenib plus trametinib or placebo.\n\nThree-year relapse-free survival was 58 versus 39 percent (hazard ratio 0.47) with an early overall survival benefit (hazard ratio 0.57); five-year relapse-free survival was 52 versus 36 percent. Pyrexia and fatigue led to discontinuation in about a quarter.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1708539"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28891408/"}],"tags":[],"related":[],"cancers":["braf-v600-melanoma","stage-iii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["combi-ad"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1708539","pmid":"28891408","authors":"Long GV, Hauschild A, Santinami M, et al.","paperType":"rct","findings":["Three-year relapse-free survival 58 percent vs 39 percent; hazard ratio 0.47.","Five-year relapse-free survival 52 percent vs 36 percent."],"whatItMeans":"Adjuvant dabrafenib-trametinib is a standard for resected stage III BRAF-mutant melanoma alongside adjuvant PD-1 blockade; the choice weighs a finite year of oral therapy against immune side effects.","caveats":["Final overall survival analysis pending.","Discontinuation for adverse events in 26 percent."],"changedPractice":true,"participants":870},{"id":"paper-combi-d-long-lancet-2015","kind":"paper","name":"COMBI-d: dabrafenib and trametinib versus dabrafenib alone for BRAF V600-mutant melanoma","aka":[],"tldr":"Adding the MEK inhibitor trametinib to the BRAF inhibitor dabrafenib lengthened survival and reduced the skin cancers caused by BRAF inhibition alone in metastatic BRAF-mutant melanoma, establishing dual blockade as the standard for targeted therapy.","summary":"Phase 3 double-blind trial of 423 patients with untreated BRAF V600E or V600K metastatic melanoma randomised to dabrafenib plus trametinib or dabrafenib plus placebo.\n\nMedian overall survival was 25.1 versus 18.7 months (hazard ratio 0.71), median progression-free survival 11.0 versus 8.8 months and response 69 versus 53 percent; cutaneous squamous cell carcinomas were fewer with the combination, while pyrexia was more common.","asOf":"2026-09-17","links":[{"label":"Lancet 2015","url":"https://doi.org/10.1016/S0140-6736(15)60898-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26037941/"}],"tags":[],"related":[],"cancers":["braf-v600-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["combi-d"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2015,"doi":"10.1016/S0140-6736(15)60898-4","pmid":"26037941","authors":"Long GV, Stroyakovskiy D, Gogas H, et al.","paperType":"rct","findings":["Median overall survival 25.1 vs 18.7 months; hazard ratio 0.71.","Objective response 69 percent vs 53 percent."],"whatItMeans":"BRAF plus MEK inhibitor doublets replaced BRAF monotherapy, and dabrafenib-trametinib became the reference regimen for BRAF-mutant melanoma, later extended to adjuvant use in COMBI-AD.","caveats":["Pyrexia in over half of combination patients.","Long-term follow-up shows a plateau of about one third of patients alive at five years."],"changedPractice":true,"participants":423},{"id":"paper-fushimi-androgen-deprivation-salivary-duct-ann-oncol-2018","kind":"paper","name":"Combined androgen blockade in androgen receptor-positive salivary gland carcinoma","aka":[],"tldr":"Hormone therapy of the kind used in prostate cancer shrank or controlled tumours in most patients with androgen receptor-positive salivary duct carcinoma, a treatment with far less toxicity than chemotherapy.","summary":"Prospective phase 2 study of 36 patients with androgen receptor-positive locally advanced or metastatic salivary gland carcinoma (predominantly salivary duct carcinoma) treated with leuprorelin and bicalutamide.\n\nObjective response was 41.7 percent with a clinical benefit rate of 75 percent, median progression-free survival 8.8 months and median overall survival 30.5 months, and toxicity was mild.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2018","url":"https://doi.org/10.1093/annonc/mdx771"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29211833/"}],"tags":[],"related":[],"cancers":["salivary-duct-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2018,"doi":"10.1093/annonc/mdx771","pmid":"29211833","authors":"Fushimi C, Tada Y, Takahashi H, et al.","paperType":"observational","findings":["Objective response 41.7 percent; clinical benefit 75 percent.","Median progression-free survival 8.8 months; median overall survival 30.5 months."],"whatItMeans":"Androgen receptor testing and androgen deprivation therapy are now standard options for salivary duct carcinoma, often before chemotherapy in slowly progressing disease.","caveats":["Small single-arm trial; a subsequent randomised comparison with chemotherapy showed similar efficacy with less toxicity."],"changedPractice":true,"participants":36},{"id":"paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","kind":"paper","name":"COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis","aka":[],"tldr":"Ruxolitinib shrank the enlarged spleen by more than a third in 42% of myelofibrosis patients versus under 1% on placebo, and halved symptom scores in nearly half.","summary":"COMFORT-I was a double-blind phase 3 trial that randomised 309 patients with intermediate-2 or high-risk myelofibrosis to the JAK1/JAK2 inhibitor ruxolitinib or placebo. The primary endpoint was the proportion with at least a 35% reduction in spleen volume at 24 weeks by imaging. This was 41.9% versus 0.7%, and a 50% or greater improvement in total symptom score was seen in 45.9% versus 5.3%. Anaemia and thrombocytopenia were the main toxicities. A parallel trial, COMFORT-II, showed similar spleen responses against best available therapy. Later analyses suggested a survival advantage for ruxolitinib despite crossover. It was the first drug approved for myelofibrosis and the first approved JAK inhibitor for a malignancy.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1110557"},{"label":"ClinicalTrials.gov NCT00952289","url":"https://clinicaltrials.gov/study/NCT00952289"}],"tags":[],"related":["paper-momentum-momelotinib-lancet-2023"],"cancers":["myeloproliferative-neoplasms"],"sections":[],"technologies":[],"targets":["jak2"],"drugs":["ruxolitinib","fedratinib","pacritinib","momelotinib"],"companies":["incyte","novartis"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-rare-cancers"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1110557","authors":"Verstovsek S, Mesa RA, Gotlib J, et al.","paperType":"rct","findings":["309 patients with intermediate-2 or high-risk myelofibrosis; ruxolitinib vs placebo, double-blind.","Spleen volume reduction of at least 35% at week 24: 41.9% vs 0.7%.","Symptom score improvement of at least 50%: 45.9% vs 5.3%.","Grade 3-4 anaemia 45% and thrombocytopenia 13% with ruxolitinib; rarely led to discontinuation.","Pooled COMFORT analyses later showed an overall survival advantage (hazard ratio about 0.7) despite extensive crossover."],"whatItMeans":"COMFORT-I turned the 2005 discovery of the JAK2 V617F mutation into the first effective medicine for myelofibrosis, transforming symptom control for a disease with no prior standard. Ruxolitinib is still the reference first-line therapy, with fedratinib, pacritinib and momelotinib as alternatives for cytopenic patients. It does not eliminate the malignant clone or reverse fibrosis in most patients.","caveats":["Primary endpoint was spleen volume, a surrogate; survival gains were shown only in later, crossover-confounded analyses.","Ruxolitinib worsens anaemia, limiting use in already-anaemic patients.","Benefit is largely symptomatic; molecular responses are uncommon.","Discontinuation is followed by rapid symptom rebound."],"changedPractice":true,"participants":309},{"id":"paper-commands-luspatercept-mds-lancet-2023","kind":"paper","name":"COMMANDS: luspatercept versus epoetin alfa as first treatment for anaemia in lower-risk MDS needing transfusions","aka":[],"tldr":"In COMMANDS, luspatercept, a drug that frees late-stage red cell production from TGF-beta-family braking, freed 59% of transfusion-dependent MDS patients from transfusions for at least 12 weeks, against 31% with the standard erythropoietin injection.","summary":"COMMANDS randomised patients with lower-risk MDS (the three lowest risk categories) who were red-cell transfusion dependent and had not received erythropoiesis-stimulating agents to subcutaneous luspatercept every three weeks or weekly epoetin alfa. The primary endpoint was red-cell transfusion independence for at least 12 weeks with a concurrent haemoglobin rise of at least 1.5 g/dL within the first 24 weeks. In the interim analysis of 301 patients this was achieved by 58.5% versus 31.2%, with benefit in both ring-sideroblast-positive and negative disease, although the difference was smaller in patients without ring sideroblasts. Adverse events were similar, with fatigue, diarrhoea and hypertension more common with luspatercept.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=COMMANDS%20luspatercept%20epoetin%20alfa%20lower-risk%20MDS%20Platzbecker%20Lancet%202023"},{"label":"ClinicalTrials.gov NCT03682536","url":"https://clinicaltrials.gov/study/NCT03682536"}],"tags":[],"related":["paper-imerge-imetelstat-mds-lancet-2024"],"cancers":["mds"],"sections":[],"technologies":[],"targets":["tgf-beta"],"drugs":["luspatercept","imetelstat"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["orr"],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-drug-pricing"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"authors":"Platzbecker U, Della Porta MG, Santini V, et al.","paperType":"rct","findings":["Interim analysis of 301 ESA-naive, transfusion-dependent, lower-risk MDS patients; luspatercept vs epoetin alfa.","Primary endpoint (12-week transfusion independence plus haemoglobin rise of at least 1.5 g/dL in weeks 1-24): 58.5% vs 31.2%.","Benefit in ring-sideroblast-positive disease was largest; the effect in ring-sideroblast-negative disease was smaller and less certain.","Median duration of transfusion independence was longer with luspatercept.","Safety comparable; no increase in progression to AML."],"whatItMeans":"COMMANDS moved luspatercept from second line (after ESA failure, MEDALIST trial) to first line, offering transfusion-dependent lower-risk MDS patients a better chance of transfusion freedom from the start. It changed guidelines and labels in 2023. Erythropoietin remains a reasonable and cheaper option for patients without ring sideroblasts or with low transfusion burden.","caveats":["Interim analysis of an open-label trial; the composite primary endpoint is a surrogate for quality of life and survival.","Uncertain benefit in ring-sideroblast-negative and SF3B1-unmutated disease.","Excluded patients with del(5q) and those with high transfusion burden plus low erythropoietin only partially represented.","Cost is far higher than epoetin."],"changedPractice":true,"participants":301},{"id":"paper-tcga-gastric-nature-2014","kind":"paper","name":"Comprehensive molecular characterisation of gastric adenocarcinoma (The Cancer Genome Atlas)","aka":[],"tldr":"Sequencing 295 stomach cancers divided them into four molecular groups, Epstein-Barr virus-positive, microsatellite unstable, genomically stable and chromosomally unstable, each with distinct drivers and potential therapies.","summary":"Integrated genomic analysis by The Cancer Genome Atlas of 295 primary gastric adenocarcinomas identifying four subtypes: Epstein-Barr virus-positive (PIK3CA mutations, PD-L1/2 amplification), microsatellite unstable (hypermutation), genomically stable (diffuse histology, RHOA and CLDN18-ARHGAP fusions) and chromosomal instability (TP53 mutation, receptor tyrosine kinase amplifications).","asOf":"2026-09-17","links":[{"label":"Nature 2014","url":"https://doi.org/10.1038/nature13480"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25079317/"}],"tags":[],"related":[],"cancers":["gastric-msi-high"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2014,"doi":"10.1038/nature13480","pmid":"25079317","authors":"Cancer Genome Atlas Research Network.","paperType":"translational","findings":["Four molecular subtypes with distinct genomic features.","Microsatellite-unstable tumours in about 22 percent and Epstein-Barr virus-positive in about 9 percent of the cohort."],"whatItMeans":"The immunotherapy sensitivity of microsatellite-unstable and Epstein-Barr virus-positive gastric cancer and the claudin 18.2 and HER2 targets map onto these subtypes.","caveats":["Subtypes are not yet used directly to choose treatment beyond microsatellite status and HER2."],"changedPractice":true,"participants":295},{"id":"paper-tcga-papillary-rcc-nejm-2016","kind":"paper","name":"Comprehensive molecular characterisation of papillary renal cell carcinoma (The Cancer Genome Atlas)","aka":[],"tldr":"Genomic analysis of 161 papillary kidney cancers showed that type 1 tumours are driven by MET alterations while type 2 tumours are a mixture of distinct diseases including CDKN2A-silenced, SETD2-mutated, fumarate hydratase-deficient and a CpG island methylator phenotype with very poor survival.","summary":"Integrated genomic study by The Cancer Genome Atlas of 161 papillary renal cell carcinomas showing MET alterations in 81 percent of type 1 tumours, and in type 2 tumours CDKN2A loss, SETD2 and other chromatin modifier mutations, TFE3 fusions, NRF2-ARE pathway activation and a CpG island methylator phenotype associated with fumarate hydratase deficiency and the worst outcomes.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2016","url":"https://doi.org/10.1056/NEJMoa1505917"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26536169/"}],"tags":[],"related":[],"cancers":["papillary-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1505917","pmid":"26536169","authors":"Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, et al.","paperType":"translational","findings":["MET alterations in 81 percent of type 1 tumours.","CpG island methylator phenotype subgroup with fumarate hydratase loss and poor survival among type 2 tumours."],"whatItMeans":"Papillary renal cell carcinoma is several diseases; the finding of MET dependence in type 1 tumours underpins the use of cabozantinib and savolitinib, and the 2022 WHO classification dropped the type 1 and 2 split in favour of molecular entities.","caveats":["Treatment-naive primary tumours; metastatic disease may differ."],"changedPractice":true,"participants":161},{"id":"paper-promise-talhouk-cancer-2017","kind":"paper","name":"Confirmation of ProMisE: a genomics-based clinical classifier for endometrial cancer","aka":[],"tldr":"The ProMisE classifier uses three tests, mismatch repair and p53 immunohistochemistry plus POLE sequencing, to sort endometrial cancers into four molecular groups that reproduce the Cancer Genome Atlas subtypes and predict outcome.","summary":"Confirmation study in 319 endometrial cancers of the Proactive Molecular Risk Classifier for Endometrial Cancer, assigning tumours to POLE-mutated, mismatch repair-deficient, p53-abnormal or p53 wild-type (no specific molecular profile) groups using immunohistochemistry and targeted sequencing.\n\nThe classifier was reproducible, could be applied to biopsy material and stratified survival, with POLE tumours faring best and p53-abnormal worst, independent of traditional risk factors.","asOf":"2026-09-17","links":[{"label":"Cancer 2017","url":"https://doi.org/10.1002/cncr.30496"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28061006/"}],"tags":[],"related":[],"cancers":["endometrial-nsmp","endometrial-mmr-deficient","endometrial-p53-abnormal","endometrial-pole-ultramutated"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-wiley"],"dependsOn":[],"notes":[],"journal":"Cancer","year":2017,"doi":"10.1002/cncr.30496","pmid":"28061006","authors":"Talhouk A, McConechy MK, Leung S, et al.","paperType":"translational","findings":["Four molecular groups with distinct survival; p53-abnormal worst, POLE best.","Classifier reproducible on diagnostic biopsies with high concordance to hysterectomy specimens."],"whatItMeans":"Molecular classification of every endometrial cancer, now embedded in the WHO classification and the ESGO/ESTRO/ESP guideline, rests on ProMisE; it decides adjuvant therapy and identifies candidates for immunotherapy.","caveats":["Tumours with more than one classifying feature (multiple classifiers) need hierarchical assignment rules.","POLE sequencing is not yet universally available."],"changedPractice":true,"participants":319},{"id":"paper-conroy-folfirinox-pancreatic-nejm-2011","kind":"paper","name":"Conroy 2011: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer (PRODIGE 4/ACCORD 11)","aka":[],"tldr":"A four-drug chemotherapy combination gave fit patients with metastatic pancreatic cancer clearly longer survival than the standard gemcitabine, the first real improvement in the disease in over a decade, at the cost of more side effects.","summary":"This French phase 2-3 trial randomised 342 patients with metastatic pancreatic adenocarcinoma and good performance status to FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and fluorouracil) or gemcitabine. FOLFIRINOX improved overall survival, progression-free survival and response rate, and delayed the decline in quality of life despite more grade 3 and 4 toxicity, particularly neutropenia, febrile neutropenia, diarrhoea and sensory neuropathy. It made FOLFIRINOX a first-line standard for fit patients and the backbone later moved into the adjuvant setting.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1011923"},{"label":"ClinicalTrials.gov NCT00112658","url":"https://clinicaltrials.gov/study/NCT00112658"}],"tags":[],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":[],"drugs":["oxaliplatin","irinotecan","fluorouracil","gemcitabine"],"companies":[],"institutions":[],"pathways":[],"terms":["os","pfs","febrile-neutropenia"],"trials":["prodige-24"],"people":["thierry-conroy"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1011923","authors":"Conroy T, Desseigne F, Ychou M, et al.","paperType":"rct","findings":["342 patients with metastatic pancreatic cancer and ECOG performance status 0 or 1; FOLFIRINOX vs gemcitabine.","Median overall survival 11.1 vs 6.8 months, hazard ratio 0.57.","Median progression-free survival 6.4 vs 3.3 months, hazard ratio 0.47; response rate 31.6% vs 9.4%.","Grade 3 or 4 neutropenia 45.7% vs 21.0%, febrile neutropenia 5.4% vs 1.2%, sensory neuropathy 9.0% vs 0%."],"whatItMeans":"FOLFIRINOX and, soon after, gemcitabine plus nab-paclitaxel ended the era of single-agent gemcitabine for metastatic pancreatic cancer. The regimen's modified form later improved survival after surgery in PRODIGE 24, and its toxicity is why fitness, not just stage, decides which treatment a patient is offered.","caveats":["Restricted to fit patients under 76 with good performance status; most patients with pancreatic cancer are not eligible.","Toxicity is substantial and needs experienced supportive care.","Open-label design."],"changedPractice":true,"participants":342},{"id":"paper-cou-aa-301-abiraterone-de-bono-nejm-2011","kind":"paper","name":"COU-AA-301: abiraterone and increased survival in metastatic castration-resistant prostate cancer after docetaxel","aka":[],"tldr":"Abiraterone, a pill that blocks androgen synthesis throughout the body, lengthened survival in men with metastatic prostate cancer that had progressed after docetaxel, proving that the disease remains hormone-driven even when castration-resistant.","summary":"Phase 3 placebo-controlled trial of 1,195 men with metastatic castration-resistant prostate cancer previously treated with docetaxel randomised 2:1 to abiraterone plus prednisone or placebo plus prednisone.\n\nMedian overall survival was 14.8 versus 10.9 months (hazard ratio 0.65), with improvements in PSA response, radiographic progression and pain; mineralocorticoid excess (fluid retention, hypokalaemia, hypertension) was the characteristic toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2011","url":"https://doi.org/10.1056/NEJMoa1014618"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21612468/"}],"tags":[],"related":[],"cancers":["prostate-mcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1014618","pmid":"21612468","authors":"de Bono JS, Logothetis CJ, Molina A, et al.","paperType":"rct","findings":["Median overall survival 14.8 vs 10.9 months; hazard ratio 0.65.","PSA response 29 percent vs 6 percent."],"whatItMeans":"Abiraterone became a standard treatment for metastatic castration-resistant prostate cancer and, after later trials, for hormone-sensitive and high-risk localised disease.","caveats":["Requires concurrent prednisone.","Cross-resistance with enzalutamide limits sequential use."],"changedPractice":true,"participants":1195},{"id":"paper-coussens-werb-inflammation-cancer-nature-2002","kind":"paper","name":"Coussens and Werb 2002: inflammation and cancer","aka":[],"tldr":"The review that made the immune cells inside a tumour part of the disease: long-running inflammation, whether from infection, irritation or the tumour's own signals, supplies growth factors, blood vessels and DNA damage that help cancers start and spread.","summary":"Coussens and Werb drew together epidemiology and mouse genetics to argue that chronic inflammation is a cause of cancer rather than a bystander. They reviewed the infections and inflammatory conditions tied to specific cancers, such as Helicobacter pylori and stomach cancer, hepatitis viruses and liver cancer, and inflammatory bowel disease and bowel cancer, and described how macrophages, neutrophils and mast cells in the tumour microenvironment release cytokines, proteases, reactive oxygen species and angiogenic factors that promote proliferation, invasion and new blood vessels. They cited estimates that about 15% of cancers worldwide are linked to infection and proposed that anti-inflammatory strategies could prevent or treat cancer.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature01322"}],"tags":[],"related":["paper-hallmarks-of-cancer-cell-2000"],"cancers":["gastric","hcc","colorectal"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["inflammation","immune-system"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2002,"doi":"10.1038/nature01322","authors":"Coussens LM, Werb Z.","paperType":"review","findings":["Chronic inflammation from infection or irritation precedes many cancers; the authors cite estimates that about 15% of cancers worldwide are attributable to infections.","Innate immune cells recruited to tumours supply cytokines, growth factors, proteases and reactive oxygen species that drive proliferation, angiogenesis, invasion and DNA damage.","Mouse models in which inflammatory cells or their mediators are removed develop fewer or slower tumours."],"whatItMeans":"This paper is why the tumour microenvironment is studied as intensely as the cancer cell itself. It underpins vaccination against HPV and hepatitis B as cancer prevention, aspirin and anti-inflammatory trials in bowel cancer, and the current work on macrophages and myeloid cells as immunotherapy targets.","caveats":["A review, so it synthesises rather than tests; several proposed mechanisms rested on mouse models.","Inflammation is also part of effective anti-tumour immunity, and the balance between the two is still being worked out."],"changedPractice":false},{"id":"paper-cpx-351-study-301-lancet-je-jco-2018","kind":"paper","name":"CPX-351 versus 7+3 chemotherapy in older adults with newly diagnosed secondary acute myeloid leukaemia","aka":[],"tldr":"A liposomal formulation locking cytarabine and daunorubicin in a fixed ratio lengthened survival compared with standard 7+3 chemotherapy in patients aged 60 to 75 with secondary or therapy-related acute myeloid leukaemia, and more of them reached transplant.","summary":"Phase 3 trial of 309 patients aged 60 to 75 with newly diagnosed high-risk or secondary AML randomised to CPX-351 or conventional cytarabine plus daunorubicin (7+3).\n\nMedian overall survival was 9.56 months with CPX-351 against 5.95 months with 7+3 (hazard ratio 0.69); remission rates were higher and outcomes after transplant were better, with a longer recovery of blood counts as the main cost.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2018","url":"https://doi.org/10.1200/JCO.2017.77.6112"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30024784/"}],"tags":[],"related":[],"cancers":["aml-secondary"],"sections":[],"technologies":[],"targets":[],"drugs":["cytarabine","daunorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2018,"doi":"10.1200/JCO.2017.77.6112","pmid":"30024784","authors":"Lancet JE, Uy GL, Cortes JE, et al.","paperType":"rct","findings":["Median overall survival 9.56 vs 5.95 months; hazard ratio 0.69.","Complete remission (with or without incomplete recovery) 47.7 percent vs 33.3 percent."],"whatItMeans":"CPX-351 is the preferred intensive induction for fit older patients with secondary or therapy-related AML in many centres, mainly as a bridge to allogeneic transplant.","caveats":["Open-label; longer neutropenia and thrombocytopenia with CPX-351.","Benefit in patients under 60 and in de novo AML is not established."],"changedPractice":true,"participants":309},{"id":"paper-shaw-crizotinib-ros1-nejm-2014","kind":"paper","name":"Crizotinib in ROS1-rearranged non-small-cell lung cancer","aka":[],"tldr":"Crizotinib shrank tumours in almost three quarters of patients with ROS1-rearranged lung cancer and controlled the disease for a median of 19 months, establishing ROS1 as a targetable driver and leading to the first approval.","summary":"Expansion cohort of a phase 1 study treating 50 patients with advanced ROS1-rearranged non-small-cell lung cancer with crizotinib 250 mg twice daily.\n\nObjective response was 72 percent with median duration of response 17.6 months and median progression-free survival 19.2 months; the safety profile matched that seen in ALK-positive disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2014","url":"https://doi.org/10.1056/NEJMoa1406766"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25264305/"}],"tags":[],"related":[],"cancers":["ros1-positive-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["crizotinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/NEJMoa1406766","pmid":"25264305","authors":"Shaw AT, Ou SH, Bang YJ, et al.","paperType":"observational","findings":["Objective response 72 percent.","Median progression-free survival 19.2 months."],"whatItMeans":"ROS1 testing became standard in lung adenocarcinoma; crizotinib was the first approved ROS1 inhibitor and remains an option, though entrectinib, repotrectinib and taletrectinib now offer brain penetration and resistance coverage.","caveats":["Single-arm study of 50 patients.","Poor brain penetration and the G2032R resistance mutation limit crizotinib."],"changedPractice":true,"participants":50},{"id":"paper-cross-nejm-2012","kind":"paper","name":"CROSS: preoperative chemoradiotherapy for oesophageal or junctional cancer","aka":[],"tldr":"Five weeks of carboplatin-paclitaxel with radiotherapy before oesophagectomy lengthened median survival from 24 to 49 months in oesophageal cancer compared with surgery alone, with a complete pathological response in almost half of squamous cancers.","summary":"Phase 3 trial of 366 patients with resectable oesophageal or junctional cancer (75 percent adenocarcinoma) randomised to weekly carboplatin-paclitaxel with 41.4 Gy radiotherapy followed by surgery, or surgery alone.\n\nMedian overall survival was 49.4 versus 24.0 months (hazard ratio 0.657), complete resection 92 versus 69 percent and pathological complete response 29 percent overall (49 percent in squamous cell carcinoma); the ten-year update confirmed the benefit.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2012","url":"https://doi.org/10.1056/NEJMoa1112088"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22646630/"}],"tags":[],"related":[],"cancers":["oesophageal-adenocarcinoma","oesophageal-squamous-cell-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["cross"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1112088","pmid":"22646630","authors":"van Hagen P, Hulshof MC, van Lanschot JJ, et al.","paperType":"rct","findings":["Median overall survival 49.4 vs 24.0 months; hazard ratio 0.657.","Pathological complete response 29 percent overall; 49 percent in squamous cell carcinoma."],"whatItMeans":"CROSS chemoradiotherapy is a standard for locally advanced oesophageal cancer, particularly squamous cell carcinoma; for adenocarcinoma, perioperative FLOT is now often preferred after ESOPEC.","caveats":["Adenocarcinoma benefit was smaller than in squamous cell carcinoma.","Postoperative morbidity was not increased but the regimen requires fitness for surgery."],"changedPractice":true,"participants":366},{"id":"paper-crown-nejm-2020","kind":"paper","name":"CROWN: lorlatinib versus crizotinib as first treatment for ALK-positive lung cancer","aka":[],"tldr":"The third-generation ALK inhibitor lorlatinib kept ALK-positive lung cancer under control for years longer than crizotinib and largely prevented brain metastases; at five years most patients on lorlatinib had still not progressed.","summary":"Open-label phase 3 trial of 296 patients with untreated advanced ALK-positive NSCLC randomised to lorlatinib or crizotinib. Primary endpoint was PFS by blinded review.\n\nAt the interim analysis, 12-month PFS was 78% vs 39% (HR 0.28) with intracranial responses in 82% of patients with measurable brain metastases. The 2024 five-year update reported 5-year PFS of 60% vs 8% (HR 0.19), with median PFS still not reached, the longest PFS recorded for a targeted therapy in metastatic NSCLC.","asOf":"2026-09-08","links":[{"label":"NEJM 2020","url":"https://doi.org/10.1056/NEJMoa2027187"},{"label":"ClinicalTrials.gov NCT03052608","url":"https://clinicaltrials.gov/study/NCT03052608"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["alk"],"drugs":["lorlatinib"],"companies":["pfizer"],"institutions":["peter-mac"],"pathways":[],"terms":["oncogene-addiction","gene-fusion","pfs","resistance"],"trials":[],"people":["solomon-benjamin","enriqueta-felip","kim-dong-wan"],"bottlenecks":["b-brain-delivery","b-resistance","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2027187","authors":"Shaw AT, Bauer TM, de Marinis F, et al.","paperType":"rct","findings":["12-month PFS 78% vs 39%; HR 0.28 (95% CI 0.19-0.41).","Intracranial objective response 82% vs 23% in patients with measurable brain metastases.","Five-year update (JCO 2024): 5-year PFS 60% vs 8%, HR 0.19; median PFS not reached; time to intracranial progression HR 0.06.","Grade 3-4 adverse events 72% vs 56%, driven by hyperlipidaemia, weight gain, oedema and cognitive or mood effects."],"whatItMeans":"For ALK-positive advanced lung cancer, lorlatinib as the first drug offers the possibility of many years without progression and strong protection against brain metastases. Alectinib and brigatinib remain alternatives with a gentler side-effect profile; the choice weighs lorlatinib's cognitive, metabolic and weight effects against its unmatched duration of control.","caveats":["Open-label; no direct comparison with alectinib or brigatinib, the other first-line standards.","Neurocognitive and mood adverse events require counselling and sometimes dose reduction.","Overall survival data remain immature because so few patients have progressed.","Small trial; crizotinib is no longer a relevant comparator."],"changedPractice":true,"participants":296},{"id":"paper-falini-npm1-nejm-2005","kind":"paper","name":"Cytoplasmic nucleophosmin in acute myeloid leukaemia with a normal karyotype","aka":[],"tldr":"This study discovered that about a third of acute myeloid leukaemias, and most with normal chromosomes, carry a mutation in the NPM1 gene that displaces its protein into the cytoplasm, defining a distinct and relatively favourable form of the disease.","summary":"Immunohistochemical and sequencing study of 591 AML cases showing cytoplasmic nucleophosmin in 35 percent, almost always caused by mutations in exon 12 of NPM1, concentrated in normal-karyotype AML (about 50 to 60 percent), associated with monocytic features, CD34 negativity and a good response to induction chemotherapy in the absence of FLT3-ITD.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2005","url":"https://doi.org/10.1056/NEJMoa041974"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15659725/"}],"tags":[],"related":[],"cancers":["aml-npm1-kmt2a"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2005,"doi":"10.1056/NEJMoa041974","pmid":"15659725","authors":"Falini B, Mecucci C, Tiacci E, et al.","paperType":"translational","findings":["Cytoplasmic NPM1 in 35.2 percent of primary AML and in the majority of normal-karyotype cases.","Associated with higher complete remission rates and mutual exclusivity with recurrent translocations."],"whatItMeans":"NPM1-mutated AML is now its own WHO category. The mutation is a stable target for measurable residual disease monitoring and the disease is one of the two indications for menin inhibitors.","caveats":["Prognostic benefit is lost when FLT3-ITD is co-mutated at high allelic ratio.","Discovery study; clinical management implications developed over the following decade."],"changedPractice":true,"participants":591},{"id":"paper-yan-peritoneal-mesothelioma-crs-hipec-jco-2009","kind":"paper","name":"Cytoreductive surgery and HIPEC for malignant peritoneal mesothelioma: multi-institutional registry","aka":[],"tldr":"Pooling eight centres, this registry showed that removing all visible peritoneal mesothelioma and washing the abdomen with heated chemotherapy gave a median survival of over four years, transforming the outlook for selected patients.","summary":"Retrospective multi-institutional registry of 405 patients with diffuse malignant peritoneal mesothelioma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at eight specialised centres.\n\nMedian overall survival was 53 months with three- and five-year survival of 60 and 47 percent; epithelioid histology, absence of nodal metastases, completeness of cytoreduction and use of HIPEC were independently associated with survival, while perioperative mortality was 2 percent.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2009","url":"https://doi.org/10.1200/JCO.2009.23.9640"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19917862/"}],"tags":[],"related":[],"cancers":["peritoneal-mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2009,"doi":"10.1200/JCO.2009.23.9640","pmid":"19917862","authors":"Yan TD, Deraco M, Baratti D, et al.","paperType":"observational","findings":["Median overall survival 53 months; five-year survival 47 percent.","Completeness of cytoreduction and epithelioid subtype were the strongest prognostic factors."],"whatItMeans":"Cytoreductive surgery with HIPEC in an experienced centre is the standard for fit patients with resectable epithelioid peritoneal mesothelioma, a disease that had a median survival of about a year on chemotherapy alone.","caveats":["Retrospective registry with selection of fit patients with resectable disease.","No randomised comparison with systemic therapy exists."],"changedPractice":true,"participants":405},{"id":"paper-damico-risk-groups-jama-1998","kind":"paper","name":"D'Amico risk groups: biochemical outcome after radical prostatectomy, external beam radiotherapy or brachytherapy","aka":[],"tldr":"This analysis of nearly 1,900 men introduced the low, intermediate and high-risk groups for localised prostate cancer based on PSA, Gleason score and stage, a classification still used to choose between surveillance, surgery and radiotherapy.","summary":"Retrospective cohort study of 1,872 men treated with radical prostatectomy, external beam radiotherapy or brachytherapy, stratified into low (PSA 10 or less, Gleason 6 or less, T1c to T2a), intermediate and high (PSA over 20, Gleason 8 to 10, or T2c) risk groups by five-year PSA failure.\n\nLow-risk men had equivalent outcomes with all three treatments; intermediate- and high-risk men did worse with brachytherapy alone than with surgery or external beam radiotherapy.","asOf":"2026-09-17","links":[{"label":"JAMA 1998","url":"https://doi.org/10.1001/jama.280.11.969"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/9749478/"}],"tags":[],"related":[],"cancers":["prostate-high-risk","prostate-intermediate-risk","prostate-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":1998,"doi":"10.1001/jama.280.11.969","pmid":"9749478","authors":"D'Amico AV, Whittington R, Malkowicz SB, et al.","paperType":"observational","findings":["Three risk groups with distinct five-year PSA failure-free survival.","Brachytherapy alone inferior for intermediate- and high-risk disease."],"whatItMeans":"The D'Amico system, refined by the NCCN, remains the framework for the very-low to very-high-risk categories used on this site's prostate pages.","caveats":["Retrospective, PSA-based endpoint; modern imaging and genomics refine the groups."],"changedPractice":true,"participants":1872},{"id":"paper-subbiah-dabrafenib-trametinib-atc-jco-2018","kind":"paper","name":"Dabrafenib and trametinib in BRAF V600E-mutant anaplastic thyroid cancer (ROAR)","aka":[],"tldr":"In one of the most lethal cancers known, dabrafenib plus trametinib shrank BRAF-mutant anaplastic thyroid cancer in about two thirds of patients, leading to the first ever drug approval for the disease.","summary":"Anaplastic thyroid cancer cohort of the phase 2 ROAR basket trial: 16 patients with BRAF V600E-mutant locally advanced or metastatic anaplastic thyroid cancer treated with dabrafenib plus trametinib.\n\nObjective response was 69 percent with responses lasting more than a year in most, twelve-month overall survival of about 80 percent in an updated analysis, and manageable toxicity; the approval followed in 2018.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2018","url":"https://doi.org/10.1200/JCO.2017.73.6785"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29072975/"}],"tags":[],"related":[],"cancers":["anaplastic-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2018,"doi":"10.1200/JCO.2017.73.6785","pmid":"29072975","authors":"Subbiah V, Kreitman RJ, Wainberg ZA, et al.","paperType":"observational","findings":["Objective response 69 percent (11 of 16).","Median duration of response and survival substantially exceeding historical months."],"whatItMeans":"Rapid BRAF testing is mandatory at diagnosis of anaplastic thyroid cancer, and BRAF-MEK inhibition, increasingly with pembrolizumab and as neoadjuvant therapy, is the standard for BRAF-mutant disease.","caveats":["Very small cohort; only about 40 percent of anaplastic thyroid cancers carry BRAF V600E."],"changedPractice":true,"participants":16},{"id":"paper-planchard-dabrafenib-trametinib-braf-nsclc-lancet-oncol-2016","kind":"paper","name":"Dabrafenib plus trametinib in previously treated BRAF V600E-mutant metastatic non-small-cell lung cancer","aka":[],"tldr":"Combining a BRAF inhibitor with a MEK inhibitor shrank tumours in about two thirds of previously treated patients with BRAF V600E-mutant lung cancer, far more than BRAF inhibition alone, leading to the first approval for this driver.","summary":"Phase 2 multicohort study; this cohort treated 57 patients with previously treated BRAF V600E-mutant metastatic non-small-cell lung cancer with dabrafenib plus trametinib.\n\nObjective response was 63.2 percent with a median progression-free survival of 9.7 months, compared with 33 percent for dabrafenib alone in an earlier cohort; pyrexia, nausea and fatigue were common.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2016","url":"https://doi.org/10.1016/S1470-2045(16)30146-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27283860/"}],"tags":[],"related":[],"cancers":["braf-v600e-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2016,"doi":"10.1016/S1470-2045(16)30146-2","pmid":"27283860","authors":"Planchard D, Besse B, Groen HJM, et al.","paperType":"observational","findings":["Objective response 63.2 percent.","Median progression-free survival 9.7 months."],"whatItMeans":"BRAF V600E is a routinely tested lung cancer driver, and BRAF plus MEK inhibition is the standard targeted therapy for it.","caveats":["Single-arm study with 57 patients.","Non-V600 BRAF mutations do not respond."],"changedPractice":true,"participants":57},{"id":"paper-planchard-dabrafenib-trametinib-first-line-lancet-oncol-2017","kind":"paper","name":"Dabrafenib plus trametinib in previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer","aka":[],"tldr":"Used as first treatment, dabrafenib plus trametinib shrank tumours in almost two thirds of patients with BRAF V600E-mutant lung cancer and controlled the disease for over a year, supporting its use before chemotherapy.","summary":"First-line cohort of the phase 2 multicohort study: 36 patients with untreated BRAF V600E-mutant metastatic non-small-cell lung cancer received dabrafenib plus trametinib.\n\nObjective response was 64 percent with a median progression-free survival of 10.9 months and median overall survival of 24.6 months at the initial report; updated analyses showed durable benefit.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2017","url":"https://doi.org/10.1016/S1470-2045(17)30679-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28919011/"}],"tags":[],"related":[],"cancers":["braf-v600e-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2017,"doi":"10.1016/S1470-2045(17)30679-4","pmid":"28919011","authors":"Planchard D, Smit EF, Groen HJM, et al.","paperType":"observational","findings":["Objective response 64 percent.","Median progression-free survival 10.9 months; median overall survival 24.6 months."],"whatItMeans":"BRAF plus MEK inhibition is a standard first-line option for BRAF V600E lung cancer, with chemo-immunotherapy as the alternative or subsequent line.","caveats":["Small single-arm cohort; no comparison with chemo-immunotherapy."],"changedPractice":true,"participants":36},{"id":"paper-hargrave-dabrafenib-trametinib-paediatric-hgg-jco-2023","kind":"paper","name":"Dabrafenib plus trametinib in relapsed or refractory BRAF V600-mutant paediatric high-grade glioma","aka":[],"tldr":"In children whose BRAF V600-mutant high-grade glioma had relapsed, the combination of dabrafenib and trametinib shrank tumours in more than half and gave responses lasting well over a year, far better than historical chemotherapy.","summary":"Phase 2 study of 41 children and adolescents with relapsed or refractory BRAF V600-mutant high-grade glioma treated with dabrafenib plus trametinib.\n\nObjective response by independent review was 56 percent with a median duration of response of 22.2 months and median progression-free survival of 9.0 months, compared with expected responses of under 20 percent with chemotherapy; toxicity was mostly fever, rash and gastrointestinal.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2023","url":"https://doi.org/10.1200/JCO.23.00558"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37643378/"}],"tags":[],"related":[],"cancers":["paediatric-high-grade-glioma"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2023,"doi":"10.1200/JCO.23.00558","pmid":"37643378","authors":"Hargrave DR, Terashima K, Hara J, et al.","paperType":"observational","findings":["Objective response 56 percent; median duration of response 22.2 months.","Median overall survival 32.8 months."],"whatItMeans":"BRAF V600E testing is mandatory in childhood high-grade glioma and the combination is a standard at relapse and, increasingly, alongside or before radiotherapy in newly diagnosed disease; it supported the tumour-agnostic approval in children.","caveats":["Small single-arm cohort.","Resistance eventually develops in most patients."],"changedPractice":true,"participants":41},{"id":"paper-darnell-jak-stat-science-1994","kind":"paper","name":"Darnell, Kerr and Stark 1994: JAK-STAT pathways and transcriptional activation by interferons","aka":[],"tldr":"The review that defined the JAK-STAT pathway, the direct route by which interferons and many other cytokines tell a cell's genes to respond, and which is now the target of JAK inhibitors used in blood cancers.","summary":"Darnell, Kerr and Stark drew together the genetics and biochemistry that revealed how interferons signal: receptor binding activates Janus kinases (JAKs), which phosphorylate STAT proteins that dimerise, move to the nucleus and switch on genes within minutes. They showed that the same JAK-STAT logic is shared by many cytokines and growth factors, each using a particular combination of JAKs and STATs. The paper gave the pathway its name and set out the model that has held since.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.8197455"}],"tags":[],"related":["paper-grivennikov-immunity-inflammation-cancer-cell-2010"],"cancers":[],"sections":[],"technologies":[],"targets":["jak2","ifnar1"],"drugs":[],"companies":[],"institutions":[],"pathways":["jak-stat"],"terms":["cytokine","signalling-pathway"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":1994,"doi":"10.1126/science.8197455","authors":"Darnell JE Jr, Kerr IM, Stark GR.","paperType":"review","findings":["Interferon receptors activate JAK kinases, which phosphorylate STAT transcription factors that move directly to the nucleus.","Different cytokines use distinct combinations of the JAK and STAT family members.","The pathway provides a rapid, direct route from cell surface to gene activation."],"whatItMeans":"The JAK-STAT pathway explains how interferon and interleukin signals act in immunity and cancer. Its discovery underlies ruxolitinib and other JAK inhibitors in myeloproliferative neoplasms, the role of STAT3 in tumour-promoting inflammation, and the interferon-gamma signalling that determines whether tumours respond to checkpoint inhibitors.","caveats":["A review from the pathway's early days; negative regulators such as SOCS proteins were described later.","Focused on interferons; oncogenic JAK2 mutations were discovered in 2005."],"changedPractice":false},{"id":"paper-dart-nivolumab-ipilimumab-nec-patel-ccr-2020","kind":"paper","name":"DART (SWOG 1609): nivolumab plus ipilimumab in rare tumours, non-pancreatic neuroendocrine neoplasms cohort","aka":[],"tldr":"In a basket trial of rare cancers, dual immunotherapy shrank tumours in about a quarter of patients with non-pancreatic neuroendocrine neoplasms, almost all of them high-grade carcinomas, giving an immunotherapy option for a disease with few treatments.","summary":"Neuroendocrine cohort of the phase 2 DART basket trial: 32 patients with non-pancreatic neuroendocrine neoplasms treated with nivolumab plus ipilimumab.\n\nObjective response was 25 percent overall and 44 percent in high-grade neuroendocrine carcinoma, with no responses in low- or intermediate-grade tumours; median progression-free survival was 4 months and overall survival 11 months.","asOf":"2026-09-17","links":[{"label":"Clin Cancer Res 2020","url":"https://doi.org/10.1158/1078-0432.CCR-19-3356"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31969335/"}],"tags":[],"related":[],"cancers":["extrapulmonary-nec"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2020,"doi":"10.1158/1078-0432.CCR-19-3356","pmid":"31969335","authors":"Patel SP, Othus M, Chae YK, et al.","paperType":"observational","findings":["Objective response 25 percent overall; 44 percent in high-grade neuroendocrine carcinoma.","No responses in grade 1 to 2 neuroendocrine tumours."],"whatItMeans":"Nivolumab plus ipilimumab is a guideline-listed option for extrapulmonary neuroendocrine carcinoma after platinum chemotherapy, whereas well-differentiated tumours do not respond.","caveats":["Very small cohort; responses were not always durable.","A subsequent expansion cohort reported lower response rates."],"changedPractice":true,"participants":32},{"id":"paper-dasatinib-vs-imatinib-ph-positive-all-shen-jama-oncol-2020","kind":"paper","name":"Dasatinib versus imatinib with chemotherapy for paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (CCCG-ALL-2015)","aka":[],"tldr":"In Chinese children with Philadelphia-positive leukaemia, dasatinib given at a high dose with chemotherapy improved four-year event-free survival compared with imatinib and reduced central nervous system relapses, without cranial irradiation or routine transplant.","summary":"Phase 3 trial of 189 children with Ph-positive ALL randomised to dasatinib 80 mg per square metre or imatinib 300 mg per square metre daily with intensive chemotherapy, without prophylactic cranial irradiation.\n\nFour-year event-free survival was 71.0 percent with dasatinib against 48.9 percent with imatinib, overall survival 88.4 versus 69.2 percent, and the cumulative risk of isolated central nervous system relapse was 2.7 versus 8.4 percent.","asOf":"2026-09-17","links":[{"label":"JAMA Oncol 2020","url":"https://doi.org/10.1001/jamaoncol.2019.5868"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31944221/"}],"tags":[],"related":[],"cancers":["all-paediatric-ph-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["dasatinib","imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2020,"doi":"10.1001/jamaoncol.2019.5868","pmid":"31944221","authors":"Shen S, Chen X, Cai J, et al.","paperType":"rct","findings":["Four-year event-free survival 71.0 percent vs 48.9 percent.","Isolated central nervous system relapse 2.7 percent vs 8.4 percent."],"whatItMeans":"Dasatinib is preferred over imatinib for paediatric Ph-positive ALL in many protocols because of its central nervous system penetration and superior outcomes in this trial.","caveats":["Open-label single-country trial with a higher dasatinib dose than used elsewhere."],"changedPractice":true,"participants":189},{"id":"paper-de-escalate-lancet-2019","kind":"paper","name":"De-ESCALaTE HPV: radiotherapy plus cisplatin or cetuximab in low-risk HPV-positive oropharyngeal cancer","aka":[],"tldr":"This European trial, like its American counterpart, found that replacing cisplatin with cetuximab in low-risk HPV-positive oropharyngeal cancer caused more recurrences and deaths without reducing severe toxicity.","summary":"Phase 3 trial of 334 patients with low-risk HPV-positive oropharyngeal cancer (non-smokers or light smokers) randomised to radiotherapy 70 Gy with cisplatin or with cetuximab, with severe toxicity as the primary endpoint.\n\nSevere toxicity did not differ, while two-year overall survival was 97.5 percent with cisplatin against 89.4 percent with cetuximab (hazard ratio 5.0) and recurrence was 6.0 versus 16.1 percent.","asOf":"2026-09-17","links":[{"label":"Lancet 2019","url":"https://doi.org/10.1016/S0140-6736(18)32752-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30449623/"}],"tags":[],"related":[],"cancers":["hpv-positive-oropharyngeal-cancer","oropharyngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["cetuximab","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["de-escalate"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2019,"doi":"10.1016/S0140-6736(18)32752-1","pmid":"30449623","authors":"Mehanna H, Robinson M, Hartley A, et al.","paperType":"rct","findings":["Two-year overall survival 97.5 percent (cisplatin) vs 89.4 percent (cetuximab).","Two-year recurrence 6.0 percent vs 16.1 percent."],"whatItMeans":"Cetuximab is not an acceptable substitute for cisplatin in HPV-positive disease; de-escalation must be tested through other routes such as dose reduction after response or surgery-based pathways.","caveats":["Small trial powered for toxicity rather than survival."],"changedPractice":true,"participants":334},{"id":"paper-decision-sorafenib-lancet-2014","kind":"paper","name":"DECISION: sorafenib in radioactive iodine-refractory differentiated thyroid cancer","aka":[],"tldr":"Sorafenib was the first drug shown to delay progression in iodine-refractory differentiated thyroid cancer, adding about five months compared with placebo and opening the era of kinase inhibitors for the disease.","summary":"Phase 3 placebo-controlled trial of 417 patients with progressive radioactive iodine-refractory differentiated thyroid cancer randomised to sorafenib or placebo.\n\nMedian progression-free survival was 10.8 versus 5.8 months (hazard ratio 0.59) with response 12.2 versus 0.5 percent; hand-foot skin reaction, diarrhoea, alopecia and rash were common.","asOf":"2026-09-17","links":[{"label":"Lancet 2014","url":"https://doi.org/10.1016/S0140-6736(14)60421-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24768112/"}],"tags":[],"related":[],"cancers":["follicular-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["sorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["decision-sorafenib"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2014,"doi":"10.1016/S0140-6736(14)60421-9","pmid":"24768112","authors":"Brose MS, Nutting CM, Jarzab B, et al.","paperType":"rct","findings":["Median progression-free survival 10.8 vs 5.8 months; hazard ratio 0.59.","Objective response 12.2 percent vs 0.5 percent."],"whatItMeans":"Sorafenib is an approved option for iodine-refractory thyroid cancer, now usually used after or instead of lenvatinib depending on tolerability.","caveats":["No overall survival benefit; response rate low compared with lenvatinib."],"changedPractice":true,"participants":417},{"id":"paper-depmap-tsherniak-cell-2017","kind":"paper","name":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without","aka":[],"tldr":"Genome-scale RNAi screens across 501 cancer cell lines, analysed with the DEMETER algorithm to remove off-target noise, identified 769 genes on which subsets of cancers depend and showed that most dependencies can be predicted from the cell's molecular features.","summary":"The Broad Institute's Project Achilles knocked down 17,098 genes in 501 cell lines drawn from a broad range of cancer types using pooled shRNA libraries. A new computational method, DEMETER, separated on-target from seed-sequence off-target effects, a longstanding problem of RNAi screens.\n\nThe analysis identified 769 genes with strong differential dependency across lines; more than 90% of lines depended on at least one such gene, and 426 of the 769 dependencies could be predicted from mutation, copy number or expression features. Predictive markers were often not the gene itself but paralog loss, lineage or pathway activity, pointing to synthetic-lethal and lineage-specific targets.\n\nThe paper defined the goal of the Cancer Dependency Map (DepMap), which has since moved to genome-wide CRISPR screens (Meyers 2017, Behan 2019) in over 1,000 lines with matched multi-omics, and is the most-used resource for target discovery and biomarker hypothesis generation.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/j.cell.2017.06.010"},{"label":"CRISPR-based DepMap (Meyers 2017)","url":"https://doi.org/10.1038/ng.3984"},{"label":"DepMap portal","url":"https://depmap.org"}],"tags":[],"related":["depmap","high-throughput-screening-libraries"],"cancers":[],"sections":["drug-discovery"],"technologies":["crispr-screens","synthetic-lethality-approaches","functional-drug-testing"],"targets":["wrn","prmt5-mtap"],"drugs":[],"companies":[],"institutions":["broad-institute","dana-farber"],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":["b-preclinical-models","b-undruggable-targets","b-translational-valley"],"keyPapers":[],"journals":["cell"],"dependsOn":[],"notes":[],"journal":"Cell","year":2017,"doi":"10.1016/j.cell.2017.06.010","pmid":"28753430","authors":"Tsherniak A, Vazquez F, Montgomery PG, et al.","paperType":"basic","findings":["501 cell lines screened with 17,098-gene shRNA library; DEMETER algorithm removed seed-based off-target effects","769 genes with differential dependency; over 90% of lines depended on at least one","426 dependencies (55%) predictable from genomic or expression features, often via paralogs or lineage factors","Dependencies on WRN in MSI-high lines and on paralogs (for example SMARCA2 in SMARCA4-mutant lines) emerged from these and follow-on screens"],"whatItMeans":"DepMap is the lookup table drug hunters use to ask: which cancers would die if we blocked this gene, and how would we recognise them? It generated targets such as WRN and PRMT5-MTAP now in clinical trials, and it is public.","caveats":["Cell lines lack microenvironment, immune context and drug pharmacology; many in vitro dependencies do not translate","RNAi knockdown is partial; CRISPR knockout can give different results for essential genes","Lineages and ancestries are unevenly represented; some cancers have few lines","Dependency does not equal druggability; most dependencies are transcription factors or lineage genes"],"changedPractice":false},{"id":"paper-mullighan-ikzf1-nejm-2009","kind":"paper","name":"Deletion of IKZF1 and prognosis in acute lymphoblastic leukaemia","aka":[],"tldr":"Deletion or mutation of the IKZF1 gene marked a subgroup of childhood B-cell acute lymphoblastic leukaemia with a threefold higher risk of relapse, and these cases shared a gene expression signature with Philadelphia-positive leukaemia.","summary":"Genomic study of 221 children with high-risk B-ALL identifying IKZF1 deletions or mutations in 28.6 percent, associated with a hazard ratio of about 3.5 for relapse, poor outcome independent of other factors, and a gene expression profile resembling BCR-ABL1-positive ALL; findings were validated in a second cohort.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2009","url":"https://doi.org/10.1056/NEJMoa0808253"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19129520/"}],"tags":[],"related":[],"cancers":["all-ph-like"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2009,"doi":"10.1056/NEJMoa0808253","pmid":"19129520","authors":"Mullighan CG, Su X, Zhang J, et al.","paperType":"translational","findings":["IKZF1 alterations in 28.6 percent of high-risk B-ALL.","Hazard ratio for relapse about 3.5 with IKZF1 alteration."],"whatItMeans":"IKZF1 status is part of risk stratification in several paediatric ALL protocols and is a hallmark of Ph-like ALL.","caveats":["Prognostic effect is attenuated by measurable residual disease-directed therapy and co-occurring favourable lesions."],"changedPractice":true,"participants":221},{"id":"paper-dellphi-301-nejm-2023","kind":"paper","name":"DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer","aka":[],"tldr":"A bispecific antibody that pulls T cells onto small-cell lung cancer cells produced responses in 40% of patients whose cancer had come back after chemotherapy, lasting far longer than any previous drug in this setting.","summary":"Open-label phase 2 trial of 220 patients with small-cell lung cancer that had progressed after platinum-based chemotherapy (and usually immunotherapy), testing tarlatamab, a DLL3 x CD3 bispecific T-cell engager, at 10 mg or 100 mg every two weeks. Primary endpoint was objective response rate.\n\nAt 10 mg the response rate was 40%, median PFS 4.9 months and median OS 14.3 months, with cytokine release syndrome in about half of patients, mostly grade 1-2 and mainly during the first cycle. It led to accelerated FDA approval in 2024 and was confirmed by the phase 3 DeLLphi-304 trial, which showed a survival benefit over chemotherapy (median OS 13.6 vs 8.3 months, HR 0.60).","asOf":"2026-09-08","links":[{"label":"NEJM 2023","url":"https://doi.org/10.1056/NEJMoa2307980"},{"label":"ClinicalTrials.gov NCT05060016","url":"https://clinicaltrials.gov/study/NCT05060016"}],"tags":[],"related":[],"cancers":["sclc"],"sections":[],"technologies":["t-cell-engager","bispecific-antibody"],"targets":["dll3","cd3"],"drugs":["tarlatamab"],"companies":["amgen"],"institutions":["samsung-medical-center"],"pathways":[],"terms":["orr","crs","icans","accelerated-approval"],"trials":["dellphi-304"],"people":["ahn-myung-ju","cho-byoung-chul","enriqueta-felip","juergen-wolf","fiona-blackhall"],"bottlenecks":["b-undruggable-targets","b-dose-optimisation","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2307980","authors":"Ahn MJ, Cho BC, Felip E, et al.","paperType":"rct","findings":["Objective response 40% at 10 mg and 32% at 100 mg; median duration of response over 9 months.","At 10 mg: median PFS 4.9 months; median overall survival 14.3 months in a population with a historical OS of 6-8 months.","Cytokine release syndrome 51% (10 mg) and 61% (100 mg), mostly grade 1-2 in cycle 1; ICANS or associated neurological events in about 8% (10 mg).","Discontinuation for treatment-related adverse events 3% at the 10 mg dose, which was selected for further development.","DeLLphi-304 phase 3 (2025): OS 13.6 vs 8.3 months versus chemotherapy, HR 0.60."],"whatItMeans":"Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.","caveats":["Single-arm phase 2 with a randomised dose comparison, not a randomised comparison against chemotherapy (that came with DeLLphi-304).","Cytokine release syndrome and neurotoxicity require hospital-based step-up dosing and limit use in frail patients or centres without experience.","Every-two-week intravenous dosing is burdensome for patients with a short life expectancy.","DLL3 expression was not required for entry and was not predictive, so there is no selection biomarker."],"changedPractice":true,"participants":220},{"id":"paper-va-larynx-induction-chemotherapy-nejm-1991","kind":"paper","name":"Department of Veterans Affairs Laryngeal Cancer Study: induction chemotherapy plus radiation versus surgery plus radiation","aka":[],"tldr":"This landmark trial showed that advanced laryngeal cancer could be treated with chemotherapy followed by radiotherapy instead of total laryngectomy, with the same survival and preservation of the larynx in about two thirds of survivors.","summary":"Phase 3 trial of 332 patients with stage III to IV laryngeal squamous cell carcinoma randomised to induction cisplatin-fluorouracil followed by radiotherapy in responders (with surgery for non-responders or relapse) or total laryngectomy with postoperative radiotherapy.\n\nTwo-year survival was 68 percent in both arms and the larynx was preserved in 64 percent of surviving patients in the chemotherapy arm, with fewer distant metastases but more local recurrences.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 1991","url":"https://doi.org/10.1056/NEJM199106133242402"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/2034244/"}],"tags":[],"related":[],"cancers":["laryngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1991,"doi":"10.1056/NEJM199106133242402","pmid":"2034244","authors":"Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, et al.","paperType":"rct","findings":["Two-year overall survival 68 percent in both arms.","Larynx preserved in 64 percent of surviving patients treated with chemotherapy and radiotherapy."],"whatItMeans":"Organ preservation became a legitimate goal in laryngeal cancer; RTOG 91-11 later refined the approach to concurrent chemoradiation.","caveats":["Predates concurrent chemoradiation and modern imaging.","Salvage laryngectomy after radiotherapy carries higher complication rates."],"changedPractice":true,"participants":332},{"id":"paper-simon-col1a1-pdgfb-dfsp-nat-genet-1997","kind":"paper","name":"Deregulation of the platelet-derived growth factor B-chain gene via fusion with COL1A1 in dermatofibrosarcoma protuberans","aka":[],"tldr":"This study discovered that dermatofibrosarcoma protuberans is driven by a fusion of the collagen gene COL1A1 to the growth factor gene PDGFB, which explains its response to imatinib and gives the tumour a diagnostic marker.","summary":"Molecular characterisation of the ring chromosomes and t(17;22) translocation of dermatofibrosarcoma protuberans and giant cell fibroblastoma, identifying fusion of COL1A1 to PDGFB placing PDGFB under collagen promoter control and leading to autocrine PDGF receptor activation.","asOf":"2026-09-17","links":[{"label":"Nat Genet 1997","url":"https://doi.org/10.1038/ng0197-95"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/8988177/"}],"tags":[],"related":[],"cancers":["dermatofibrosarcoma-protuberans"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":1997,"doi":"10.1038/ng0197-95","pmid":"8988177","authors":"Simon MP, Pedeutour F, Sirvent N, et al.","paperType":"basic","findings":["COL1A1-PDGFB fusion identified as the driver of dermatofibrosarcoma protuberans and giant cell fibroblastoma."],"whatItMeans":"COL1A1-PDGFB fusion testing confirms the diagnosis, and the fusion's dependence on PDGF receptor beta signalling is the rationale for imatinib.","caveats":["Rare cases carry alternative PDGFD fusions."],"changedPractice":true},{"id":"paper-desktop-iii-nejm-2021","kind":"paper","name":"DESKTOP III: secondary cytoreductive surgery for recurrent platinum-sensitive ovarian cancer","aka":[],"tldr":"In women with a first platinum-sensitive relapse selected by a simple score predicting complete resectability, surgery before chemotherapy lengthened survival by about a year, but only when all visible disease was removed.","summary":"Phase 3 trial of 407 patients with first relapse of ovarian cancer after a platinum-free interval of six months or more and a positive AGO score (good performance status, complete resection at first surgery, ascites under 500 ml), randomised to secondary cytoreductive surgery followed by chemotherapy or chemotherapy alone.\n\nMedian overall survival was 53.7 versus 46.0 months (hazard ratio 0.75) and progression-free survival 18.4 versus 14.0 months; patients with complete resection had a median survival of 61.9 months, while incomplete resection was worse than no surgery.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2021","url":"https://doi.org/10.1056/NEJMoa2103294"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34874631/"}],"tags":[],"related":[],"cancers":["platinum-sensitive-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["desktop-iii"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2103294","pmid":"34874631","authors":"Harter P, Sehouli J, Vergote I, et al.","paperType":"rct","findings":["Median overall survival 53.7 vs 46.0 months; hazard ratio 0.75.","Complete resection in 75 percent of surgical patients; median survival 61.9 months in that group."],"whatItMeans":"Secondary cytoreduction is recommended for AGO score-positive patients at first platinum-sensitive relapse in centres where complete resection can be achieved in most cases.","caveats":["The GOG-0213 trial found no benefit, possibly because of less stringent selection and bevacizumab use.","Requires high-volume surgical expertise."],"changedPractice":true,"participants":407},{"id":"paper-destiny-breast03-nejm-2022","kind":"paper","name":"DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer","aka":[],"tldr":"A newer antibody-drug conjugate, trastuzumab deruxtecan, kept HER2-positive metastatic breast cancer under control roughly four times longer than the previous standard, T-DM1, and later lengthened survival.","summary":"Open-label phase 3 trial of 524 patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, randomised 1:1 to trastuzumab deruxtecan (T-DXd, 5.4 mg/kg) or trastuzumab emtansine (T-DM1). Primary endpoint was progression-free survival by blinded independent central review.\n\nAt the interim analysis, 12-month PFS was 75.8% vs 34.1% (HR 0.28). The 2023 update reported median PFS 28.8 vs 6.8 months and a significant overall survival benefit (HR 0.64). It moved T-DXd into the second line and is the clearest head-to-head demonstration that ADC design (payload, drug-to-antibody ratio, bystander effect) determines clinical outcome.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2115022"},{"label":"ClinicalTrials.gov NCT03529110","url":"https://clinicaltrials.gov/study/NCT03529110"}],"tags":[],"related":["idea-payload-switching"],"cancers":["breast-her2-positive"],"sections":[],"technologies":["adc","topoisomerase-inhibitors"],"targets":["her2"],"drugs":["trastuzumab-deruxtecan","trastuzumab-emtansine"],"companies":["daiichi-sankyo","astrazeneca"],"institutions":[],"pathways":[],"terms":["pfs","os","payload","dar","bystander-effect","ild","adc-sequencing"],"trials":["destiny-breast03"],"people":["javier-cortes","kim-sung-bae","im-seock-ah","park-yeon-hee","giuseppe-curigliano","xu-binghe","sara-hurvitz"],"bottlenecks":["b-resistance","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2115022","authors":"Cortes J, Kim SB, Chung WP, et al.","paperType":"rct","findings":["12-month progression-free survival 75.8% with T-DXd vs 34.1% with T-DM1; HR 0.28 (95% CI 0.22-0.37).","Confirmed objective response 79.7% vs 34.2%.","Updated analysis (Lancet 2023): median PFS 28.8 vs 6.8 months; overall survival HR 0.64.","Drug-related interstitial lung disease/pneumonitis in roughly one in ten T-DXd patients, mostly low grade, with no grade 4-5 events in the primary report."],"whatItMeans":"For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.","caveats":["Open-label design, though the primary endpoint was assessed by blinded central review.","Interstitial lung disease requires proactive CT surveillance and dose interruption; fatal cases occurred in other T-DXd trials.","Many patients had not received pertuzumab-based first-line therapy, so the population differs slightly from today's second line.","What to give after T-DXd, and whether a TOP1-payload ADC can follow another, remains unresolved."],"changedPractice":true,"participants":524},{"id":"paper-destiny-breast04-nejm-2022","kind":"paper","name":"DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group","aka":[],"tldr":"Breast cancers with only a little HER2 on their surface, long called HER2-negative, responded to trastuzumab deruxtecan and patients lived about six months longer than on chemotherapy. It created the HER2-low category.","summary":"Open-label phase 3 trial of 557 patients with HER2-low (IHC 1+ or IHC 2+/ISH-negative) metastatic breast cancer after one or two lines of chemotherapy, randomised 2:1 to trastuzumab deruxtecan or physician's choice chemotherapy. About 89% were hormone-receptor positive. Primary endpoint was PFS in the HR-positive cohort.\n\nMedian PFS was 10.1 vs 5.4 months (HR 0.51) in the HR-positive cohort and overall survival 23.9 vs 17.5 months (HR 0.64); results in the whole population were similar. Roughly half of all breast cancers are HER2-low, so the trial redefined HER2 testing and opened ADC therapy to a very large population.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2203690"},{"label":"ClinicalTrials.gov NCT03734029","url":"https://clinicaltrials.gov/study/NCT03734029"}],"tags":[],"related":["idea-payload-switching"],"cancers":["breast-hr-positive","tnbc"],"sections":[],"technologies":["adc","histopathology-ihc","companion-diagnostic"],"targets":["her2"],"drugs":["trastuzumab-deruxtecan"],"companies":["daiichi-sankyo","astrazeneca"],"institutions":[],"pathways":[],"terms":["her2-low","ihc","bystander-effect","ild","pfs","os"],"trials":["destiny-breast04"],"people":["sohn-joohyuk","park-yeon-hee","xu-binghe","im-seock-ah","hope-rugo","kim-sung-bae","david-cameron"],"bottlenecks":["b-biomarker-validation","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2203690","authors":"Modi S, Jacot W, Yamashita T, et al.","paperType":"rct","findings":["HR-positive cohort: median PFS 10.1 vs 5.4 months, HR 0.51 (95% CI 0.40-0.64); median OS 23.9 vs 17.5 months, HR 0.64.","All patients: median PFS 9.9 vs 5.1 months (HR 0.50); median OS 23.4 vs 16.8 months (HR 0.64).","Benefit was similar for IHC 1+ and IHC 2+/ISH-negative tumours, questioning whether HER2 level is the true predictor.","The small HR-negative (triple-negative) cohort of about 58 patients showed a consistent trend (PFS HR 0.46).","Drug-related interstitial lung disease in 12.1% of T-DXd patients, including three deaths."],"whatItMeans":"Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.","caveats":["HER2-low scoring by immunohistochemistry is poorly reproducible between pathologists, and the assay was never designed to distinguish 0 from 1+.","Fatal pneumonitis occurred; patients need CT surveillance and rapid steroid treatment of symptoms.","The triple-negative cohort was exploratory and small.","DESTINY-Breast06 later showed activity in HER2-ultralow (faint staining) tumours, suggesting the biomarker threshold is arbitrary."],"changedPractice":true,"participants":557},{"id":"paper-destiny-breast06-nejm-2024","kind":"paper","name":"DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer","aka":[],"tldr":"Given as the first chemotherapy-type treatment after hormone therapy stopped working, trastuzumab deruxtecan delayed progression by about five months compared with standard chemotherapy, including in tumours with barely detectable HER2.","summary":"Open-label phase 3 trial of 866 patients with hormone-receptor-positive metastatic breast cancer that was HER2-low (IHC 1+ or 2+/ISH-negative) or HER2-ultralow (IHC 0 with faint membrane staining), who had progressed on endocrine therapy but had not received chemotherapy for metastatic disease. Patients were randomised to trastuzumab deruxtecan or physician's choice chemotherapy (capecitabine, paclitaxel or nab-paclitaxel). Primary endpoint was PFS in the HER2-low group.\n\nMedian PFS was 13.2 vs 8.1 months (HR 0.62) in HER2-low patients, with a similar effect in the ultralow subgroup. It moved T-DXd one line earlier and pushed the HER2 threshold down to almost any detectable staining.","asOf":"2026-09-08","links":[{"label":"PubMed search: DESTINY-Breast06","url":"https://pubmed.ncbi.nlm.nih.gov/?term=DESTINY-Breast06+trastuzumab+deruxtecan+HER2-low+chemotherapy-naive"},{"label":"ClinicalTrials.gov NCT04494425","url":"https://clinicaltrials.gov/study/NCT04494425"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":["adc","histopathology-ihc"],"targets":["her2"],"drugs":["trastuzumab-deruxtecan"],"companies":["daiichi-sankyo","astrazeneca"],"institutions":[],"pathways":[],"terms":["her2-low","ihc","pfs","ild","first-line"],"trials":["destiny-breast06"],"people":["hu-xichun","yonemori-kan","barrios-carlos","sohn-joohyuk","im-seock-ah","giuseppe-curigliano"],"bottlenecks":["b-biomarker-validation","b-drug-pricing","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"authors":"Bardia A, Hu X, Dent R, et al.","paperType":"rct","findings":["HER2-low: median PFS 13.2 vs 8.1 months, HR 0.62 (95% CI 0.51-0.74).","HER2-ultralow (about 150 patients): median PFS 13.2 vs 8.3 months, HR 0.78, consistent with the HER2-low result.","Objective response rate roughly 57% vs 31% in the HER2-low group.","Overall survival was immature at the primary analysis and not significantly different.","Interstitial lung disease in about 11% of T-DXd patients, with a small number of fatal cases."],"whatItMeans":"Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.","caveats":["No overall survival benefit was demonstrated at the primary analysis, so the case for using it earlier rests on PFS and response.","HER2-ultralow scoring is even less reproducible than HER2-low, and the ultralow subgroup was small and exploratory.","Comparator chemotherapy was single-agent and the trial was open-label.","Cost and pneumonitis risk are much higher than for capecitabine, which many patients tolerate well for a long time."],"changedPractice":true,"participants":866},{"id":"paper-destiny-crc01-lancet-oncol-2021","kind":"paper","name":"DESTINY-CRC01: trastuzumab deruxtecan in HER2-expressing metastatic colorectal cancer","aka":[],"tldr":"Trastuzumab deruxtecan shrank tumours in about 45 percent of patients with HER2-high colorectal cancer, including those who had already received other HER2 drugs, but did nothing for tumours with low HER2 expression and carried a risk of lung inflammation.","summary":"Phase 2 study of 86 patients with HER2-expressing, RAS and BRAF wild-type metastatic colorectal cancer after at least two regimens, treated with trastuzumab deruxtecan 6.4 mg/kg in three cohorts by HER2 level.\n\nIn the HER2 immunohistochemistry 3+ or 2+ with amplification cohort, objective response was 45.3 percent with median progression-free survival 6.9 months, including responses after prior HER2 therapy; no responses were seen in the low-expression cohorts, and interstitial lung disease occurred in 9 percent with some deaths.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(21)00086-3"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33961795/"}],"tags":[],"related":[],"cancers":["her2-amplified-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["crc01","trastuzumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00086-3","pmid":"33961795","authors":"Siena S, Di Bartolomeo M, Raghav K, et al.","paperType":"observational","findings":["Objective response 45.3 percent in HER2-positive cohort A; median progression-free survival 6.9 months.","No responses in HER2 2+ non-amplified or 1+ cohorts; interstitial lung disease 9.3 percent."],"whatItMeans":"Trastuzumab deruxtecan is an option for HER2-positive colorectal cancer after HER2 antibodies, and it contributed to the tumour-agnostic approval for HER2 3+ solid tumours; lung monitoring is essential.","caveats":["Single-arm; interstitial lung disease including fatal cases.","The 6.4 mg/kg dose is higher than that used in breast cancer."],"changedPractice":true,"participants":86},{"id":"paper-destiny-gastric01-nejm-2020","kind":"paper","name":"DESTINY-Gastric01: trastuzumab deruxtecan in previously treated HER2-positive gastric cancer","aka":[],"tldr":"Trastuzumab deruxtecan shrank tumours in half of patients with HER2-positive gastric cancer that had progressed after trastuzumab, compared with 14 percent on chemotherapy, and lengthened survival by over four months.","summary":"Randomised phase 2 trial in Japan and South Korea of 187 patients with HER2-positive advanced gastric or junctional adenocarcinoma after at least two prior regimens including trastuzumab, randomised 2:1 to trastuzumab deruxtecan 6.4 mg/kg or physician's choice of irinotecan or paclitaxel.\n\nObjective response was 51 versus 14 percent and median overall survival 12.5 versus 8.4 months (hazard ratio 0.59); interstitial lung disease occurred in 10 percent, with myelosuppression as the other main toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa2004413"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32469182/"}],"tags":[],"related":[],"cancers":["gastric-her2-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-gastric01","destiny-gastric02"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2004413","pmid":"32469182","authors":"Shitara K, Bang YJ, Iwasa S, et al.","paperType":"rct","findings":["Objective response 51 percent vs 14 percent.","Median overall survival 12.5 vs 8.4 months; hazard ratio 0.59."],"whatItMeans":"Trastuzumab deruxtecan is the standard second- or third-line treatment for HER2-positive gastric cancer, later confirmed against ramucirumab-paclitaxel in DESTINY-Gastric04.","caveats":["Asian population; the Western DESTINY-Gastric02 study showed a lower response rate.","Interstitial lung disease requires monitoring."],"changedPractice":true,"participants":187},{"id":"paper-destiny-lung01-nejm-2022","kind":"paper","name":"DESTINY-Lung01: trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer","aka":[],"tldr":"Trastuzumab deruxtecan shrank tumours in more than half of patients with previously treated HER2-mutant lung cancer, a driver with no approved therapy until this study, though lung inflammation was a serious side effect.","summary":"Phase 2 study of 91 patients with previously treated HER2-mutant metastatic non-small-cell lung cancer treated with trastuzumab deruxtecan 6.4 mg/kg.\n\nObjective response was 55 percent with median duration of response 9.3 months, median progression-free survival 8.2 months and median overall survival 17.8 months; drug-related interstitial lung disease occurred in 26 percent with two deaths.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2112431"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34534430/"}],"tags":[],"related":[],"cancers":["her2-mutant-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-lung01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2112431","pmid":"34534430","authors":"Li BT, Smit EF, Goto Y, et al.","paperType":"observational","findings":["Objective response 55 percent; median duration of response 9.3 months.","Median overall survival 17.8 months; interstitial lung disease 26 percent."],"whatItMeans":"HER2 mutations, present in about 3 percent of lung adenocarcinomas, became actionable; trastuzumab deruxtecan received the first approval for a HER2-mutant lung cancer, at the lower 5.4 mg/kg dose validated in DESTINY-Lung02.","caveats":["High rate of interstitial lung disease at 6.4 mg/kg.","Single-arm study."],"changedPractice":true,"participants":91},{"id":"paper-destiny-lung02-goto-jco-2023","kind":"paper","name":"DESTINY-Lung02: two doses of trastuzumab deruxtecan in HER2-mutant metastatic non-small-cell lung cancer","aka":[],"tldr":"Comparing two doses of trastuzumab deruxtecan in HER2-mutant lung cancer showed that the lower 5.4 mg/kg dose gave the same response rate of about half with far less lung toxicity, fixing the approved dose.","summary":"Randomised phase 2 trial of 152 patients with previously treated HER2-mutant metastatic non-small-cell lung cancer randomised 2:1 to trastuzumab deruxtecan 5.4 or 6.4 mg/kg.\n\nObjective response was 49.0 percent at 5.4 mg/kg and 56.0 percent at 6.4 mg/kg, with median durations of 16.8 and 5.9 months; adjudicated interstitial lung disease was 12.9 versus 28.0 percent.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2023","url":"https://doi.org/10.1200/JCO.23.01361"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37694347/"}],"tags":[],"related":[],"cancers":["her2-mutant-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-lung02"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2023,"doi":"10.1200/JCO.23.01361","pmid":"37694347","authors":"Goto K, Goto Y, Kubo T, et al.","paperType":"rct","findings":["Objective response 49.0 percent (5.4 mg/kg) vs 56.0 percent (6.4 mg/kg).","Interstitial lung disease 12.9 percent vs 28.0 percent."],"whatItMeans":"Trastuzumab deruxtecan 5.4 mg/kg is the approved regimen for HER2-mutant lung cancer after platinum chemotherapy, and the trial is a rare example of dose optimisation improving safety without losing efficacy.","caveats":["Not powered to compare efficacy between doses formally."],"changedPractice":true,"participants":152},{"id":"paper-destiny-pantumor02-jco-2024","kind":"paper","name":"DESTINY-PanTumor02: trastuzumab deruxtecan in HER2-expressing solid tumours","aka":[],"tldr":"Across seven tumour types including endometrial, cervical and ovarian cancers, trastuzumab deruxtecan shrank tumours in about 37 percent of patients overall and 61 percent of those with the highest HER2 expression, leading to a tumour-agnostic approval.","summary":"Phase 2 study of 267 patients with previously treated HER2-expressing (immunohistochemistry 3+ or 2+) advanced solid tumours in seven cohorts (endometrial, cervical, ovarian, bladder, biliary, pancreatic and other) treated with trastuzumab deruxtecan 5.4 mg/kg.\n\nObjective response was 37.1 percent overall and 61.3 percent in immunohistochemistry 3+ tumours, with median duration of response 11.3 and 22.1 months respectively; endometrial (57.5 percent) and cervical (50.0 percent) cohorts responded best. Interstitial lung disease occurred in 10.5 percent.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2024","url":"https://doi.org/10.1200/JCO.23.02005"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37870536/"}],"tags":[],"related":[],"cancers":["endometrial-p53-abnormal","recurrent-metastatic-cervical-cancer","uterine-carcinosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-pantumor02"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2024,"doi":"10.1200/JCO.23.02005","pmid":"37870536","authors":"Meric-Bernstam F, Makker V, Oaknin A, et al.","paperType":"observational","findings":["Objective response 37.1 percent overall; 61.3 percent in immunohistochemistry 3+.","Endometrial cohort response 57.5 percent; cervical 50.0 percent."],"whatItMeans":"HER2 immunohistochemistry is now worth doing in advanced gynaecological and other cancers, since trastuzumab deruxtecan is approved for HER2 3+ solid tumours after prior therapy.","caveats":["Single-arm across heterogeneous tumours; responses in 2+ tumours were modest (27 percent).","Interstitial lung disease including fatal cases."],"changedPractice":true,"participants":267},{"id":"paper-detect-a-science-2020","kind":"paper","name":"DETECT-A: a blood test plus PET-CT found treatable cancers in 10,000 women with no symptoms","aka":[],"tldr":"The first prospective interventional study of a multi-analyte blood test (CancerSEEK) in asymptomatic people: 26 cancers were first detected by the blood test, most of them localised, and the test roughly doubled the number of cancers caught by standard screening.","summary":"DETECT-A enrolled 10,006 women aged 65-75 with no history of cancer in the Geisinger health system. A blood test measuring mutations in cell-free DNA and protein markers (CancerSEEK) was performed; a confirmed positive led to whole-body PET-CT, and imaging-positive participants were referred for diagnosis.\n\nTwenty-six cancers were detected by the blood test, of which 17 were localised or regional and 12 were treated with surgery with intent to cure. Standard-of-care screening detected a further 24 cancers, so combining the blood test with existing screening roughly doubled detection (from about a quarter to about half of incident cancers). Fewer than 1% of participants had an unnecessary invasive procedure.\n\nIt proved that a blood-first screening pathway can be safely operationalised and that many blood-detected cancers are at a curable stage.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1126/science.abb9601"},{"label":"ClinicalTrials.gov NCT03934866","url":"https://clinicaltrials.gov/study/NCT03934866"}],"tags":[],"related":["paper-pathfinder-lancet-2023"],"cancers":[],"sections":["early-detection"],"technologies":["mced","liquid-biopsy","pet-ct"],"targets":[],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":[],"terms":["ppv","ctdna","stage-shift"],"trials":[],"people":["bert-vogelstein","kenneth-kinzler"],"bottlenecks":["b-early-detection","b-overdiagnosis"],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2020,"doi":"10.1126/science.abb9601","pmid":"32345712","authors":"Lennon AM, Buchanan AH, Kinde I, et al.","paperType":"observational","findings":["Blood test alone detected 26 of 96 incident cancers (about 27% sensitivity); with standard screening the combined sensitivity was about 52%","17 of 26 blood-detected cancers were localised or regional; 12 patients had surgery with curative intent","The blood test found cancers in organs with no standard screening (ovary, kidney, appendix, uterus, lymphoma)","Participants did not reduce their uptake of standard screening after joining the study"],"whatItMeans":"A blood test can find early, treatable cancers in people who feel well, including cancers for which no screening exists. It is not a replacement for mammography or colonoscopy but a possible addition. Larger randomised trials are needed to show benefit outweighs harm.","caveats":["Single-arm, single health system, women only; no mortality endpoint","Sensitivity of about a quarter for all incident cancers means most cancers were missed","PET-CT confirmation for all positives is costly and exposes participants to radiation","CancerSEEK's commercial successor tests differ in design, so performance does not transfer directly"],"changedPractice":false,"participants":10006},{"id":"paper-curtin-melanoma-genetic-alterations-nejm-2005","kind":"paper","name":"Distinct sets of genetic alterations in melanoma","aka":[],"tldr":"Comparing melanomas from sun-damaged skin, non-sun-damaged skin, palms and soles, and mucosal surfaces showed each carries a different pattern of BRAF, NRAS and copy-number changes, establishing that melanoma is several genetically distinct diseases.","summary":"Comparative genomic hybridisation and mutation analysis of 126 melanomas grouped by anatomical site and sun exposure, showing BRAF mutations concentrated in melanomas on skin without chronic sun damage, and frequent focal amplifications with few BRAF mutations in acral and mucosal melanomas.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2005","url":"https://doi.org/10.1056/NEJMoa050092"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16291983/"}],"tags":[],"related":[],"cancers":["acral-melanoma","mucosal-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2005,"doi":"10.1056/NEJMoa050092","pmid":"16291983","authors":"Curtin JA, Fridlyand J, Kageshita T, et al.","paperType":"translational","findings":["BRAF mutations in 59 percent of melanomas on non-chronically sun-damaged skin vs 11 percent in chronically sun-damaged, 23 percent acral and 11 percent mucosal.","Frequent focal copy-number amplifications in acral and mucosal melanoma."],"whatItMeans":"This paper founded the site-based molecular classification of melanoma that underpins separate pages for acral and mucosal disease and their different treatment responses.","caveats":["Low-resolution copy-number technology by current standards."],"changedPractice":true,"participants":126},{"id":"paper-beltran-nepc-divergent-evolution-nat-med-2016","kind":"paper","name":"Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer","aka":[],"tldr":"Sequencing showed that neuroendocrine prostate cancer arises from the same cells as ordinary prostate adenocarcinoma but diverges through loss of RB1 and TP53 and changes in DNA methylation rather than new mutations, explaining how the cancer escapes hormone therapy by changing identity.","summary":"Whole-exome and methylation analysis of 114 metastatic biopsies from patients with castration-resistant prostate cancer, comparing adenocarcinoma with neuroendocrine prostate cancer.\n\nNeuroendocrine tumours shared clonal origin with adenocarcinoma, showed frequent RB1 loss and TP53 mutation, low androgen receptor signalling, distinct epigenetic profiles and overexpression of EZH2, with a lineage-switch rather than a distinct mutational driver.","asOf":"2026-09-17","links":[{"label":"Nat Med 2016","url":"https://doi.org/10.1038/nm.4045"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26855148/"}],"tags":[],"related":[],"cancers":["prostate-nepc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2016,"doi":"10.1038/nm.4045","pmid":"26855148","authors":"Beltran H, Prandi D, Mosquera JM, et al.","paperType":"translational","findings":["RB1 loss and TP53 alteration enriched in neuroendocrine prostate cancer.","Epigenetic divergence with shared clonal ancestry from adenocarcinoma."],"whatItMeans":"Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation.","caveats":["Biopsy cohort from selected patients; therapeutic implications are still being tested."],"changedPractice":true,"participants":114},{"id":"paper-sahm-meningioma-methylation-lancet-oncol-2017","kind":"paper","name":"DNA methylation-based classification and grading system for meningioma","aka":[],"tldr":"Profiling the chemical marks on meningioma DNA separated the tumours into six classes that predicted recurrence better than the traditional microscope-based grade, especially for the many grade 1 and 2 tumours that behave unexpectedly.","summary":"Retrospective study of 497 meningiomas (with 309 validation cases) using genome-wide DNA methylation profiling to define six methylation classes and three combined groups (benign, intermediate, malignant), compared with WHO grading for prediction of recurrence.\n\nMethylation classes identified aggressive tumours among WHO grade 1 and 2 cases and benign behaviour among some grade 2 tumours, outperforming histological grade for progression-free survival.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2017","url":"https://doi.org/10.1016/S1470-2045(17)30155-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28314689/"}],"tags":[],"related":[],"cancers":["meningioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2017,"doi":"10.1016/S1470-2045(17)30155-9","pmid":"28314689","authors":"Sahm F, Schrimpf D, Stichel D, et al.","paperType":"translational","findings":["Six methylation classes with distinct recurrence risk; methylation grouping predicted progression better than WHO grade."],"whatItMeans":"Molecular classification is entering meningioma diagnosis (the 2021 WHO classification incorporates CDKN2A/B deletion and TERT promoter mutation) and is used to select grade 2 patients for or against adjuvant radiotherapy and trials.","caveats":["Retrospective; methylation profiling is not universally available.","Combined integrated grading systems have since refined this approach."],"changedPractice":true,"participants":497},{"id":"paper-doll-hill-smoking-lung-cancer-bmj-1950","kind":"paper","name":"Doll and Hill 1950: the case-control study that tied smoking to lung cancer","aka":[],"tldr":"Comparing 649 men with lung cancer to matched hospital controls in London, Doll and Hill found that almost none of the cancer patients were non-smokers and that risk rose steeply with the amount smoked.","summary":"Richard Doll and Austin Bradford Hill interviewed patients with lung cancer and matched controls with other diseases in 20 London hospitals between 1948 and 1949. The preliminary report analysed 649 men and 60 women with lung cancer.\n\nOnly 0.3% of male lung cancer patients were non-smokers, compared with 4.2% of controls, and heavy smokers (25 or more cigarettes a day) were far over-represented among cases. The authors concluded that smoking was a factor, and an important factor, in the production of carcinoma of the lung, and set out the case for a prospective study, which became the British Doctors Study in 1951.\n\nAlong with Wynder and Graham's US study the same year, it launched the modern epidemiology of tobacco and eventually the tobacco control policies that have prevented more cancer deaths than any treatment.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1136/bmj.2.4682.739"},{"label":"British Doctors Study preliminary report (1954)","url":"https://doi.org/10.1136/bmj.1.4877.1451"}],"tags":[],"related":["paper-doll-peto-50-year-doctors-bmj-2004","idea-prev-smokefree-generation-evaluation","idea-prev-clean-air-never-smoker-endpoints"],"cancers":["nsclc","sclc"],"sections":["prevention"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-misinformation","b-incentive-misalignment"],"keyPapers":[],"journals":["bmj"],"dependsOn":[],"notes":[],"journal":"BMJ","year":1950,"doi":"10.1136/bmj.2.4682.739","pmid":"14772469","authors":"Doll R, Hill AB","paperType":"observational","findings":["Non-smokers: 2 of 649 male lung cancer cases (0.3%) vs 27 of 649 controls (4.2%)","Proportion of heavy smokers (25 or more cigarettes a day) was about twice as high among cases as controls","Association was specific to lung cancer, not to other cancers or diseases in the same hospitals","Estimated risk in heavy smokers about 50 times that of non-smokers"],"whatItMeans":"Doll and Hill's 1950 study is where the evidence that smoking causes cancer begins. Everything from cigarette warnings and tax to smoke-free laws and lung screening eligibility descends from this study and the cohort that followed it.","caveats":["Case-control design with hospital controls; recall and selection bias were the main criticisms at the time","Causation was not accepted by many, including Fisher, until the prospective cohort and animal data accumulated","Women were too few for separate analysis","Exposure was self-reported and unverified"],"changedPractice":true,"participants":1465},{"id":"paper-dunleavy-da-epoch-r-pmbcl-nejm-2013","kind":"paper","name":"Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma","aka":[],"tldr":"Infusional dose-adjusted EPOCH with rituximab cured almost every patient with primary mediastinal B-cell lymphoma without any radiotherapy, sparing young patients the heart and breast cancer risks of chest irradiation.","summary":"Prospective single-centre phase 2 study of 51 patients with untreated primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-rituximab for six to eight cycles without radiotherapy, with a retrospective validation cohort of 16 patients at Stanford.\n\nAt a median follow-up of 5 years, event-free survival was 93 percent and overall survival 97 percent; only two patients received radiotherapy, and PET scans after treatment had a low positive predictive value.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2013","url":"https://doi.org/10.1056/NEJMoa1214561"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23574119/"}],"tags":[],"related":[],"cancers":["primary-mediastinal-b-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2013,"doi":"10.1056/NEJMoa1214561","pmid":"23574119","authors":"Dunleavy K, Pittaluga S, Maeda LS, et al.","paperType":"observational","findings":["Five-year event-free survival 93 percent; overall survival 97 percent.","Radiotherapy avoided in 96 percent of patients."],"whatItMeans":"Dose-adjusted EPOCH-R without radiotherapy became a standard for primary mediastinal B-cell lymphoma, particularly in the United States, and the IELSG37 trial later confirmed radiotherapy can be omitted after a negative PET.","caveats":["Single-arm study from one centre with a small validation cohort.","Six-day infusional regimen is demanding; R-CHOP with PET-guided radiotherapy is an alternative."],"changedPractice":true,"participants":51},{"id":"paper-cercek-dmmr-rectal-nejm-2022","kind":"paper","name":"Dostarlimab alone cures mismatch-repair-deficient rectal cancer without surgery or radiotherapy","aka":[],"tldr":"Six months of the PD-1 antibody dostarlimab made every tumour disappear in a small group of patients with mismatch-repair-deficient rectal cancer, allowing them to avoid chemotherapy, radiotherapy and surgery.","summary":"Single-arm phase 2 trial of patients with stage II-III mismatch-repair-deficient locally advanced rectal adenocarcinoma treated with dostarlimab 500 mg every three weeks for six months, with the plan to proceed to chemoradiotherapy and surgery only if disease persisted.\n\nAll 12 patients who completed treatment at the time of the report had a clinical complete response on endoscopy, MRI and PET, and none had needed chemoradiotherapy or surgery at a follow-up of 6-25 months. Later expansions confirmed sustained complete responses in over 40 patients. It showed that a subset of solid tumours can be cured by immunotherapy alone with total organ preservation, and led to guideline endorsement and a breakthrough designation.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2201445"},{"label":"ClinicalTrials.gov NCT04165772","url":"https://clinicaltrials.gov/study/NCT04165772"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor","mri"],"targets":["pd1"],"drugs":["dostarlimab"],"companies":["gsk"],"institutions":["mskcc"],"pathways":[],"terms":["msi","pcr","neoadjuvant-adjuvant","breakthrough-designation"],"trials":[],"people":["andrea-cercek","luis-diaz"],"bottlenecks":["b-immunotherapy-response","b-surgery-radiation-innovation","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2201445","authors":"Cercek A, Lumish M, Sinopoli J, et al.","paperType":"rct","findings":["Clinical complete response in 12 of 12 patients (100%) who completed six months of dostarlimab.","No patient required chemoradiotherapy or surgery, and no progression or recurrence during follow-up (6-25 months at publication).","No grade 3 or higher adverse events.","Subsequent expansion (2024-2025) reported sustained complete responses in over 40 rectal patients, with the approach extended to other dMMR tumour types."],"whatItMeans":"Patients with rectal cancer whose tumour is mismatch-repair deficient (about 5-10% of rectal cancers) can now be offered immunotherapy alone with the realistic expectation of avoiding surgery, radiotherapy and a permanent stoma. This requires mismatch repair testing on the diagnostic biopsy, close endoscopic and MRI surveillance, and treatment in an experienced centre. It does not apply to the 90% of rectal cancers that are mismatch-repair proficient.","caveats":["Very small single-centre study with short follow-up at publication; durability beyond a few years is still being established.","Clinical complete response is not the same as pathological complete response; surveillance must be rigorous and long-term.","Most patients were treated at one specialist centre; reproducibility in routine practice is uncertain.","Six months of dostarlimab is expensive and access is uneven."],"changedPractice":true,"participants":12},{"id":"paper-dreamseq-jco-2023","kind":"paper","name":"DREAMseq (ECOG-ACRIN EA6134): sequencing dabrafenib-trametinib and nivolumab-ipilimumab in BRAF-mutant metastatic melanoma","aka":[],"tldr":"Starting with nivolumab plus ipilimumab and switching to BRAF-MEK inhibitors at progression gave 20 percentage points better two-year survival than the reverse order in BRAF-mutant advanced melanoma, settling the question of which to use first.","summary":"Phase 3 trial of 265 patients with treatment-naive BRAF V600-mutant metastatic melanoma randomised to nivolumab-ipilimumab followed by dabrafenib-trametinib at progression, or the reverse sequence.\n\nTwo-year overall survival was 71.8 percent with immunotherapy first against 51.5 percent with targeted therapy first; the trial was stopped early for this difference, and responses to immunotherapy were more durable while responses to targeted therapy after immunotherapy were preserved.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2023","url":"https://doi.org/10.1200/JCO.22.01763"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36166727/"}],"tags":[],"related":[],"cancers":["advanced-melanoma","braf-v600-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","ipilimumab","nivolumab","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["dreamseq"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2023,"doi":"10.1200/JCO.22.01763","pmid":"36166727","authors":"Atkins MB, Lee SJ, Chmielowski B, et al.","paperType":"rct","findings":["Two-year overall survival 71.8 percent (immunotherapy first) vs 51.5 percent (targeted therapy first).","Median progression-free survival after crossover favoured targeted therapy given second."],"whatItMeans":"Immunotherapy first is the standard for BRAF-mutant advanced melanoma in patients who can wait for a response; targeted therapy is reserved for rapid control or after immunotherapy.","caveats":["Open-label and stopped early.","Does not address newer first-line options such as nivolumab-relatlimab."],"changedPractice":true,"participants":265},{"id":"paper-duo-e-jco-2023","kind":"paper","name":"DUO-E: durvalumab with carboplatin-paclitaxel and maintenance durvalumab with or without olaparib in advanced endometrial cancer","aka":[],"tldr":"Adding durvalumab to first-line chemotherapy delayed progression in advanced endometrial cancer, and adding the PARP inhibitor olaparib to durvalumab maintenance helped further in mismatch repair-proficient tumours.","summary":"Phase 3 trial of 718 patients with newly diagnosed advanced or recurrent endometrial cancer randomised to carboplatin-paclitaxel alone, with durvalumab followed by durvalumab maintenance, or with durvalumab followed by durvalumab plus olaparib maintenance.\n\nProgression-free survival hazard ratios were 0.71 for durvalumab and 0.55 for durvalumab plus olaparib versus control; in mismatch repair-deficient disease both immunotherapy arms performed similarly (hazard ratio about 0.42), whereas olaparib added benefit in proficient disease (0.57 versus 0.77).","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2024","url":"https://doi.org/10.1200/JCO.23.02132"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37864337/"}],"tags":[],"related":[],"cancers":["advanced-recurrent-endometrial-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["carboplatin","durvalumab","olaparib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["duo-e"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2024,"doi":"10.1200/JCO.23.02132","pmid":"37864337","authors":"Westin SN, Moore K, Chon HS, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.71 (durvalumab) and 0.55 (durvalumab plus olaparib).","Mismatch repair-proficient: hazard ratio 0.77 vs 0.57 with olaparib added."],"whatItMeans":"Durvalumab-based chemo-immunotherapy is a third first-line option with RUBY and NRG-GY018, and durvalumab plus olaparib maintenance is approved for mismatch repair-proficient disease in some regions.","caveats":["The contribution of olaparib in proficient disease may be concentrated in p53-abnormal tumours; overall survival immature.","Anaemia and neutropenia increased with olaparib."],"changedPractice":true,"participants":718},{"id":"paper-ivosidenib-idh1-dinardo-nejm-2018","kind":"paper","name":"Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory acute myeloid leukaemia","aka":[],"tldr":"The oral IDH1 inhibitor ivosidenib put about a third of patients with relapsed or refractory IDH1-mutated acute myeloid leukaemia into remission, with some clearing the mutation altogether, leading to its approval.","summary":"Phase 1 dose-escalation and expansion study of 258 patients with IDH1-mutated advanced haematological cancers, including 179 with relapsed or refractory AML treated at 500 mg daily.\n\nIn the primary efficacy population the rate of complete remission or complete remission with partial haematological recovery was 30.4 percent, median duration of response 8.2 months, and 21 percent of responders had no detectable IDH1 mutation. Differentiation syndrome occurred in about one in ten.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1716984"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29860938/"}],"tags":[],"related":[],"cancers":["aml-idh"],"sections":[],"technologies":[],"targets":[],"drugs":["ivosidenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1716984","pmid":"29860938","authors":"DiNardo CD, Stein EM, de Botton S, et al.","paperType":"observational","findings":["Complete remission or complete remission with partial haematological recovery in 30.4 percent; overall response 41.6 percent.","Median overall survival 8.8 months in relapsed or refractory AML."],"whatItMeans":"IDH1 testing at diagnosis and relapse now directs patients to a targeted oral drug; ivosidenib went on to be combined with azacitidine in newly diagnosed disease (AGILE).","caveats":["Single-arm study; responses were partial for most and relapse common.","Differentiation syndrome and QT prolongation need monitoring."],"changedPractice":true,"participants":258},{"id":"paper-dynamic-nejm-2022","kind":"paper","name":"DYNAMIC: a blood test safely halved chemotherapy use after surgery for stage II colon cancer","aka":[],"tldr":"Giving chemotherapy only to patients with tumour DNA in their blood after surgery cut chemotherapy use from 28% to 15% with no loss in recurrence-free survival at two years.","summary":"DYNAMIC randomised 455 patients with resected stage II colon cancer 2:1 to ctDNA-guided management or standard management. In the ctDNA arm, plasma taken at weeks 4 and 7 after surgery was tested with a tumour-informed assay; ctDNA-positive patients received oxaliplatin-based or fluoropyrimidine chemotherapy and ctDNA-negative patients were observed. The primary endpoint was recurrence-free survival at 2 years, tested for non-inferiority.\n\nAdjuvant chemotherapy was given to 15% of ctDNA-guided patients versus 28% of standard-management patients. Two-year recurrence-free survival was 93.5% versus 92.4%, meeting non-inferiority. ctDNA-positive patients treated with chemotherapy had a 3-year RFS of 86.4%, and untreated ctDNA-negative patients 92.5%.\n\nIt was the first randomised evidence that ctDNA can safely de-escalate adjuvant treatment.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa2200075"},{"label":"ANZCTR ACTRN12615000381583","url":"https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368271"}],"tags":[],"related":["idea-ctdna-guided-adjuvant-crc","ctdna-mrd-to-adjuvant"],"cancers":["colorectal"],"sections":["diagnostics","chemotherapy"],"technologies":["mrd-testing","liquid-biopsy"],"targets":[],"drugs":[],"companies":[],"institutions":["peter-mac","johns-hopkins"],"pathways":[],"terms":["mrd","ctdna","neoadjuvant-adjuvant"],"trials":["dynamic"],"people":["bert-vogelstein","kenneth-kinzler"],"bottlenecks":["b-dormancy-mrd","b-toxicity-qol","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2200075","pmid":"35657320","authors":"Tie J, Cohen JD, Lahouel K, et al.","paperType":"rct","findings":["Adjuvant chemotherapy use 15% vs 28% (relative risk 1.82 for standard management)","Two-year recurrence-free survival 93.5% vs 92.4% (absolute difference 1.1 percentage points; 95% CI -4.1 to 6.2), non-inferior","ctDNA-positive patients treated with chemotherapy: 3-year RFS 86.4%; ctDNA-negative untreated: 92.5%","About 15% of patients were ctDNA-positive after surgery"],"whatItMeans":"For stage II colon cancer, where most patients are cured by surgery alone, a blood test can identify the minority who benefit from chemotherapy and spare everyone else its side effects. It does not yet prove that treating ctDNA-positive patients improves survival compared with not treating them.","caveats":["Non-inferiority margin of 8.5 percentage points was generous; the trial was not powered to detect small losses","Stage II only; DYNAMIC-III in stage III showed that escalation for ctDNA-positive patients did not clearly improve outcomes","Assay (Safe-SeqS on 15 tumour-specific mutations) is not the commercial assays used elsewhere","Two-year follow-up is short for colon cancer recurrence"],"changedPractice":true,"participants":455},{"id":"paper-e3a06-lenalidomide-smouldering-lonial-jco-2020","kind":"paper","name":"E3A06: lenalidomide versus observation in smouldering multiple myeloma","aka":[],"tldr":"Lenalidomide alone delayed progression to active myeloma in people with intermediate- or high-risk smouldering disease, but side effects led many to stop, and it did not improve survival.","summary":"Phase 2/3 trial randomising 182 patients with intermediate- or high-risk smouldering myeloma to lenalidomide 25 mg or observation.\n\nThree-year progression-free survival was 91 percent with lenalidomide against 66 percent with observation (hazard ratio 0.28), with the largest benefit in high-risk patients; about half of treated patients discontinued for toxicity.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2020","url":"https://doi.org/10.1200/JCO.19.01740"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31652094/"}],"tags":[],"related":[],"cancers":["smouldering-myeloma"],"sections":[],"technologies":[],"targets":[],"drugs":["lenalidomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"doi":"10.1200/JCO.19.01740","pmid":"31652094","authors":"Lonial S, Jacobus S, Fonseca R, et al.","paperType":"rct","findings":["Three-year progression-free survival 91 percent vs 66 percent; hazard ratio 0.28.","Grade 3 to 4 adverse events in 28 percent of the lenalidomide arm."],"whatItMeans":"Lenalidomide showed that intervening before symptoms can delay end-organ damage, supporting later trials such as AQUILA, but tolerability limits its use as a single agent.","caveats":["No overall survival benefit shown.","Progression was defined by end-organ damage, and imaging at baseline was not modern PET or MRI in all patients."],"changedPractice":true,"participants":182},{"id":"paper-eano-meningioma-goldbrunner-neuro-oncology-2021","kind":"paper","name":"EANO guideline on the diagnosis and management of meningiomas (2021)","aka":[],"tldr":"The European neuro-oncology guideline on meningioma sets out when to watch, when to operate, when to use radiosurgery or fractionated radiotherapy by grade and extent of resection, and the limited place of drug therapy.","summary":"Evidence-based guideline from the European Association of Neuro-Oncology covering imaging and molecular diagnosis of meningioma (including methylation and mutational classification), observation of incidental tumours, surgical goals and Simpson grading, radiosurgery and fractionated radiotherapy indications for grade 1 to 3 tumours, systemic therapy for refractory disease, and follow-up schedules.","asOf":"2026-09-17","links":[{"label":"Neuro Oncol 2021","url":"https://doi.org/10.1093/neuonc/noab150"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34181733/"}],"tags":[],"related":[],"cancers":["meningioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["neuro-oncology"],"dependsOn":[],"notes":[],"journal":"Neuro-Oncology","year":2021,"doi":"10.1093/neuonc/noab150","pmid":"34181733","authors":"Goldbrunner R, Stavrinou P, Jenkinson MD, et al.","paperType":"guideline","findings":[],"whatItMeans":"Observation for small asymptomatic tumours, adjuvant radiotherapy for incompletely resected grade 2 and all grade 3 tumours, and the referral of refractory cases to trials on this site's meningioma page follow this guideline.","caveats":["Randomised evidence for adjuvant radiotherapy in grade 2 meningioma is still awaited from ongoing trials."],"changedPractice":true},{"id":"paper-echelon-1-brentuximab-avd-nejm-2018","kind":"paper","name":"ECHELON-1: brentuximab vedotin replacing bleomycin in first-line chemotherapy for advanced Hodgkin lymphoma","aka":[],"tldr":"Swapping bleomycin for the CD30 antibody-drug conjugate brentuximab vedotin modestly improved disease control in advanced Hodgkin lymphoma and, at six years, improved survival.","summary":"ECHELON-1 randomised 1334 patients with previously untreated stage III or IV classical Hodgkin lymphoma to brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A+AVD) or standard ABVD for six cycles. The primary endpoint was modified PFS by independent review. At two years modified PFS was 82.1% versus 77.2% (hazard ratio 0.77). A+AVD caused more peripheral neuropathy (67% versus 43%) and febrile neutropenia (19% versus 8%) but eliminated bleomycin lung toxicity. The six-year update (Ansell et al., NEJM 2022) showed an overall survival benefit: 93.9% versus 89.4% (hazard ratio 0.59), the first OS improvement in front-line advanced Hodgkin lymphoma.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1708984"},{"label":"6-year overall survival (Ansell 2022)","url":"https://doi.org/10.1056/NEJMoa2206125"},{"label":"ClinicalTrials.gov NCT01712490","url":"https://clinicaltrials.gov/study/NCT01712490"}],"tags":[],"related":["paper-swog-s1826-nivolumab-avd-nejm-2024"],"cancers":["hodgkin-lymphoma"],"sections":[],"technologies":["adc"],"targets":["cd30"],"drugs":["brentuximab-vedotin","doxorubicin"],"companies":["pfizer","takeda"],"institutions":[],"pathways":[],"terms":["pfs","os"],"trials":["echelon-1","hd21","swog-s1826"],"people":[],"bottlenecks":["b-toxicity-qol","b-survivorship"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1708984","authors":"Connors JM, Jurczak W, Straus DJ, et al.","paperType":"rct","findings":["1334 patients with stage III-IV classical Hodgkin lymphoma; A+AVD vs ABVD.","2-year modified PFS 82.1% vs 77.2%; hazard ratio 0.77.","Peripheral neuropathy 67% vs 43%; febrile neutropenia 19% vs 8%; pulmonary toxicity lower with A+AVD.","6-year overall survival 93.9% vs 89.4%; hazard ratio 0.59.","Fewer second malignancies and fewer patients needing subsequent therapy with A+AVD."],"whatItMeans":"ECHELON-1 made a targeted antibody-drug conjugate part of first-line Hodgkin therapy and eventually showed that this saves lives, not just relapses. It set the reference arm against which nivolumab-AVD (SWOG S1826) and BrECADD (HD21) were later compared. Neuropathy is the main price and needs proactive dose modification.","caveats":["Modified PFS was a novel composite endpoint counting incomplete response followed by further therapy as an event.","Early absolute benefit was small (about 5 points) and OS emerged only with long follow-up.","Excluded early-stage disease; older patients (over 60) had high toxicity with A+AVD.","Cost of brentuximab restricts use in lower-income settings."],"changedPractice":true,"participants":1334},{"id":"paper-e1910-blinatumomab-mrd-negative-all-nejm-2024","kind":"paper","name":"ECOG-ACRIN E1910: adding blinatumomab to chemotherapy for adults with B-cell ALL already in MRD-negative remission","aka":[],"tldr":"Giving the bispecific blinatumomab to adults whose leukaemia was already undetectable after chemotherapy raised three-year survival from 68% to 85%.","summary":"E1910 enrolled adults aged 30-70 with newly diagnosed Philadelphia-chromosome-negative B-cell ALL. Those who reached MRD-negative remission after induction and intensification (224 patients) were randomised to four cycles of blinatumomab interleaved with consolidation chemotherapy or chemotherapy alone, followed by maintenance. The primary endpoint in this group was overall survival. At three years OS was 85% versus 68% (hazard ratio 0.41) and relapse-free survival 80% versus 64%. Neuropsychiatric events were more frequent with blinatumomab but mostly low grade. The result led to approval of blinatumomab in consolidation for CD19-positive B-ALL regardless of MRD status.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2312948"},{"label":"ClinicalTrials.gov NCT02003222","url":"https://clinicaltrials.gov/study/NCT02003222"}],"tags":[],"related":["blinatumomab-frontline-consolidation","paper-aall1731-blinatumomab-children-nejm-2025"],"cancers":["all-leukemia"],"sections":[],"technologies":["bispecific-antibody","t-cell-engager","mrd-testing"],"targets":["cd19","cd3"],"drugs":["blinatumomab"],"companies":["amgen"],"institutions":["ecog-acrin"],"pathways":[],"terms":["mrd","os","mrd-negative-cr"],"trials":["e1910"],"people":["mark-litzow"],"bottlenecks":["b-dormancy-mrd"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2312948","authors":"Litzow MR, Sun Z, Mattison RJ, et al.","paperType":"rct","findings":["488 adults enrolled; 224 MRD-negative patients randomised to blinatumomab plus chemotherapy or chemotherapy alone.","3-year overall survival 85% vs 68%; hazard ratio 0.41.","3-year relapse-free survival 80% vs 64%.","Benefit seen across age groups, including patients aged 55-70.","Grade 3 or higher neuropsychiatric events higher with blinatumomab; no excess treatment-related deaths."],"whatItMeans":"E1910 changed the standard of care for adult B-ALL: immunotherapy is now part of front-line consolidation even for patients with no detectable leukaemia, because MRD-negative by flow cytometry does not mean cured. It also demonstrated that a T-cell engager can improve overall survival in a curative setting. Chemotherapy-light or chemotherapy-free regimens built on blinatumomab and inotuzumab are the next step.","caveats":["MRD was assessed by flow cytometry at 10^-4 sensitivity; more sensitive NGS assays might identify who truly needs blinatumomab.","Adults under 30 were excluded (treated on paediatric-inspired protocols).","Randomised sample was modest and the OS benefit emerged at interim analysis.","Blinatumomab requires continuous 28-day infusions, a logistical burden."],"changedPractice":true,"participants":224},{"id":"paper-e3311-transoral-surgery-ferris-jco-2022","kind":"paper","name":"ECOG-ACRIN E3311: transoral surgery followed by reduced-dose radiotherapy for HPV-positive oropharyngeal cancer","aka":[],"tldr":"In HPV-positive oropharyngeal cancer removed by transoral robotic surgery, patients with intermediate-risk pathology did just as well with a reduced 50 Gy dose of radiotherapy as with the standard 60 Gy, supporting surgery-based de-escalation.","summary":"Phase 2 trial of 495 patients with resectable HPV-positive oropharyngeal cancer treated with transoral surgery and neck dissection, then allocated by pathology: observation for low risk, randomisation to 50 or 60 Gy radiotherapy for intermediate risk, and chemoradiotherapy for high risk.\n\nTwo-year progression-free survival was 96.9 percent with observation, 94.9 percent with 50 Gy and 96.0 percent with 60 Gy, and 90.7 percent with chemoradiation, with better swallowing outcomes at lower doses.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2022","url":"https://doi.org/10.1200/JCO.21.01752"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34699271/"}],"tags":[],"related":[],"cancers":["hpv-positive-oropharyngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2022,"doi":"10.1200/JCO.21.01752","pmid":"34699271","authors":"Ferris RL, Flamand Y, Weinstein GS, et al.","paperType":"rct","findings":["Two-year progression-free survival 94.9 percent with 50 Gy vs 96.0 percent with 60 Gy in intermediate-risk patients.","Low-risk patients observed after surgery had 96.9 percent two-year progression-free survival."],"whatItMeans":"Transoral surgery with pathology-guided reduced-dose radiotherapy is a validated de-escalation pathway for HPV-positive oropharyngeal cancer in experienced centres.","caveats":["Phase 2 with no non-surgical comparator.","Requires surgical expertise with low positive-margin rates."],"changedPractice":true,"participants":495},{"id":"paper-sankaranarayanan-oral-screening-lancet-2005","kind":"paper","name":"Effect of screening on oral cancer mortality in Kerala, India","aka":[],"tldr":"Visual examination of the mouth by trained health workers reduced oral cancer deaths by a third among tobacco and alcohol users in Kerala, the only randomised evidence that oral cancer screening works.","summary":"Cluster-randomised trial in 13 clusters of Trivandrum district: 96,517 people in seven intervention clusters received three rounds of oral visual inspection by trained health workers and 95,356 in six control clusters received usual care. Oral cancer deaths were 77 versus 87 (mortality rate ratio 0.79; 95% CI 0.51-1.22 overall), with a significant reduction in tobacco or alcohol users (0.66; 95% CI 0.45-0.95) and in male users (0.57; 0.35-0.93). The 15-year follow-up (Oral Oncology 2013) showed a 24% mortality reduction in users after four rounds and 81% (69-89%) in users who attended all four rounds.","asOf":"2026-09-10","links":[{"label":"Lancet 2005","url":"https://doi.org/10.1016/S0140-6736(05)66658-5"},{"label":"15-year follow-up (Oral Oncology 2013)","url":"https://doi.org/10.1016/j.oraloncology.2012.11.004"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":["chemoprevention"],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":[],"trials":["kerala-oral-screening"],"people":["sankaranarayanan-rengaswamy"],"bottlenecks":["b-early-detection","b-prevention-adoption"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2005,"doi":"10.1016/S0140-6736(05)66658-5","authors":"Sankaranarayanan R, Ramadas K, Thomas G, et al.","paperType":"rct","findings":["Oral cancer mortality rate ratio 0.79 overall (not significant) and 0.66 in tobacco or alcohol users (significant).","Male tobacco or alcohol users: rate ratio 0.57.","15-year follow-up: 81% lower oral cancer mortality in users who attended all four screening rounds, and 38% lower incidence.","Screening was done by trained non-medical health workers, not dentists or doctors."],"whatItMeans":"Targeted visual screening of tobacco and alcohol users is a cheap, workable way to cut oral cancer deaths in high-incidence countries, and is the basis for India's national oral cancer screening component. Its effect depends on people attending repeatedly and on treatment being available.","caveats":["Overall (all-comer) mortality reduction was not statistically significant; the benefit is concentrated in high-risk users.","Cluster trial with 13 clusters, which limits precision.","Compliance with referral and treatment was incomplete, so real programmes may achieve less."],"changedPractice":true,"participants":191873},{"id":"paper-demetri-imatinib-gist-nejm-2002","kind":"paper","name":"Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours","aka":[],"tldr":"Imatinib produced responses in more than half of patients with advanced gastrointestinal stromal tumours, a cancer that had been completely resistant to chemotherapy, and turned a lethal disease into a chronic one.","summary":"Phase 2 trial of 147 patients with unresectable or metastatic KIT-positive gastrointestinal stromal tumour randomised to imatinib 400 or 600 mg daily.\n\nPartial response occurred in 53.7 percent and stable disease in 27.9 percent, with only 13.6 percent early progression; oedema, nausea, diarrhoea and myalgia were common but serious toxicity was uncommon. Long-term follow-up showed median survival of about five years.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2002","url":"https://doi.org/10.1056/NEJMoa020461"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12181401/"}],"tags":[],"related":[],"cancers":["gist-kit-exon-11"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2002,"doi":"10.1056/NEJMoa020461","pmid":"12181401","authors":"Demetri GD, von Mehren M, Blanke CD, et al.","paperType":"rct","findings":["Partial response 53.7 percent; stable disease 27.9 percent.","No significant difference between 400 and 600 mg doses."],"whatItMeans":"Imatinib is the standard first-line treatment for advanced GIST and the model for kinase-targeted therapy in solid tumours.","caveats":["Randomised between doses only, without a control arm.","Response assessment by size criteria underestimates benefit (Choi criteria came later)."],"changedPractice":true,"participants":147},{"id":"paper-el-deiry-waf1-p21-cell-1993","kind":"paper","name":"El-Deiry 1993: WAF1, the gene through which p53 stops cell division","aka":[],"tldr":"The discovery of p21, the gene p53 switches on to halt cell division, which explained for the first time how the most commonly mutated cancer gene actually stops damaged cells from growing.","summary":"El-Deiry, Vogelstein and colleagues searched for genes activated by wild-type p53 and identified WAF1, now called CDKN1A or p21, whose expression was induced by wild-type but not mutant p53 in human cells. Introducing WAF1 into cancer cell lines suppressed their growth. Independently identified at the same time as an inhibitor of cyclin-dependent kinases, p21 turned out to be the link between p53 activation and arrest of the cell cycle at the G1 checkpoint.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/0092-8674(93)90500-P"}],"tags":[],"related":["paper-levine-p53-gatekeeper-cell-1997"],"cancers":[],"sections":[],"technologies":[],"targets":["tp53","cdk4-6"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":["p53-cell-cycle","cell-cycle-engine-cdks"],"terms":["cell-cycle","tumour-suppressor-gene"],"trials":[],"people":["bert-vogelstein"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cell","year":1993,"doi":"10.1016/0092-8674(93)90500-P","authors":"El-Deiry WS, Tokino T, Velculescu VE, et al.","paperType":"basic","findings":["WAF1 (p21, CDKN1A) was identified as a gene induced by wild-type p53 and not by tumour-derived mutant p53.","Expression of WAF1 suppressed the growth of human tumour cell lines.","p21 was shown by parallel work to inhibit cyclin-dependent kinases, providing the mechanism for p53-mediated cell cycle arrest."],"whatItMeans":"This paper closed the loop between DNA damage, p53 and the cell cycle machinery. p21 is now a standard marker of p53 activity, part of how chemotherapy and radiotherapy stop cells dividing, and a component of the senescence response that CDK4/6 inhibitors exploit.","caveats":["Cell line study; the in vivo roles of p21 in tumour suppression proved more complex.","p21 is also induced by p53-independent signals."],"changedPractice":false},{"id":"paper-dcruz-elective-neck-dissection-nejm-2015","kind":"paper","name":"Elective versus therapeutic neck dissection in node-negative oral cancer","aka":[],"tldr":"Removing the neck lymph nodes at the first operation for early mouth cancer, rather than waiting to see if they become involved, raised three-year survival from 67.5% to 80%.","summary":"Randomised trial at Tata Memorial Hospital of 596 patients with early (T1-T2) node-negative oral squamous cell cancer, 500 analysed (245 elective, 255 therapeutic neck dissection), median follow-up 39 months. Elective dissection gave 81 recurrences and 50 deaths versus 146 and 79; 3-year overall survival 80.0% versus 67.5% (hazard ratio 0.64; 95% CI 0.45-0.92; P=0.01) and disease-free survival 69.5% versus 45.9% (P<0.001); adverse events 6.6% versus 3.6%.","asOf":"2026-09-10","links":[{"label":"NEJM 2015","url":"https://doi.org/10.1056/NEJMoa1506007"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":["sentinel-node"],"targets":[],"drugs":[],"companies":[],"institutions":["tata-memorial"],"pathways":[],"terms":[],"trials":["elective-neck-dissection-tmh"],"people":["dcruz-anil"],"bottlenecks":["b-surgery-radiation-innovation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1506007","authors":"D'Cruz AK, Vaish R, Kapre N, et al.","paperType":"rct","findings":["3-year overall survival 80.0% with elective neck dissection versus 67.5% with watchful waiting (HR 0.64).","3-year disease-free survival 69.5% versus 45.9%.","Recurrences 81 versus 146; deaths 50 versus 79.","Adverse events were higher with elective dissection (6.6% versus 3.6%) but modest."],"whatItMeans":"Elective neck dissection is now the standard for early oral cancer everywhere. The trial shows what high-volume Indian centres can contribute: a definitive answer to a surgical question that had been debated for half a century and that Western centres, with far fewer oral cancers, could not resolve.","caveats":["Ultrasound and clinical staging of the neck were used; modern imaging or sentinel node biopsy may change the trade-off.","Single-centre trial in a predominantly tobacco-related oral cancer population.","Quality of life and morbidity outcomes were secondary."],"changedPractice":true,"participants":596},{"id":"paper-elevate-tn-acalabrutinib-lancet-2020","kind":"paper","name":"ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL","aka":[],"tldr":"In ELEVATE-TN, acalabrutinib, a second-generation BTK inhibitor, with or without an antibody, cut the risk of progression by 80-90% compared with chlorambucil-obinutuzumab in older or unfit patients with CLL.","summary":"ELEVATE-TN was a three-arm phase 3 trial of 535 treatment-naive patients aged 65 or older, or younger with comorbidities. Patients were randomised to acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, or chlorambucil plus obinutuzumab; the primary endpoint was PFS for the combination versus chemo-immunotherapy. At a median follow-up of 28.3 months median PFS was not reached in either acalabrutinib arm versus 22.6 months with chemo-immunotherapy, with hazard ratios of 0.10 for the combination and 0.20 for monotherapy. Acalabrutinib caused less atrial fibrillation and bleeding than reported with ibrutinib, and the trial supported its front-line approval.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=ELEVATE-TN%20acalabrutinib%20obinutuzumab%20chlorambucil%20Sharman%20Lancet%202020"},{"label":"ClinicalTrials.gov NCT02475681","url":"https://clinicaltrials.gov/study/NCT02475681"}],"tags":[],"related":[],"cancers":["cll"],"sections":[],"technologies":[],"targets":["btk","cd20"],"drugs":["acalabrutinib","obinutuzumab","ibrutinib","zanubrutinib"],"companies":["astrazeneca"],"institutions":[],"pathways":[],"terms":["pfs"],"trials":["elevate-tn","sequoia"],"people":[],"bottlenecks":["b-toxicity-qol","b-drug-pricing"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2020,"authors":"Sharman JP, Egyed M, Jurczak W, et al.","paperType":"rct","findings":["535 patients; acalabrutinib + obinutuzumab (179), acalabrutinib (179), chlorambucil + obinutuzumab (177).","Median PFS not reached in both acalabrutinib arms vs 22.6 months; hazard ratio 0.10 (combination) and 0.20 (monotherapy).","Estimated 24-month PFS about 93% (combination), 87% (monotherapy) and 47% (chemo-immunotherapy).","Headache and diarrhoea were the commonest acalabrutinib adverse events; atrial fibrillation was uncommon.","Adding obinutuzumab to acalabrutinib improved PFS further in longer follow-up but was not the primary comparison."],"whatItMeans":"ELEVATE-TN put a more selective BTK inhibitor into first-line CLL and, with the head-to-head ELEVATE-RR trial, showed it is as effective as ibrutinib with fewer cardiac side effects. Continuous acalabrutinib became one of the two main front-line options alongside fixed-duration venetoclax combinations. The trade-off is indefinite therapy and cost versus a time-limited course.","caveats":["The comparator, chlorambucil-obinutuzumab, was already being superseded when the trial reported.","Continuous therapy until progression; no MRD-guided stopping.","Cross-trial comparisons with venetoclax regimens are indirect.","Overall survival was not significantly different at early follow-up."],"changedPractice":true,"participants":535},{"id":"paper-eliana-tisagenlecleucel-nejm-2018","kind":"paper","name":"ELIANA: the global trial that made tisagenlecleucel the first approved CAR-T therapy for children and young adults with relapsed ALL","aka":[],"tldr":"Across 25 centres, 81% of children and young adults with relapsed or refractory ALL went into remission after a single tisagenlecleucel infusion, and half were still event-free a year later.","summary":"ELIANA was a single-arm, multicentre phase 2 trial of tisagenlecleucel in patients aged 3-21 with CD19-positive relapsed or refractory B-cell ALL. Of 92 enrolled, 75 received an infusion; the rest could not because of manufacturing failure, death or adverse events. The overall remission rate within three months was 81%, all MRD-negative; event-free survival was 73% at six months and 50% at 12 months, with overall survival 90% and 76%. Cytokine release syndrome occurred in 77% (grade 3-4 in about 46%) and neurological events in 40%. The trial supported FDA approval in August 2017, the first gene therapy and first CAR-T approved in the United States, and demonstrated that a centrally manufactured autologous cell product could be delivered across continents.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1709866"},{"label":"ClinicalTrials.gov NCT02435849","url":"https://clinicaltrials.gov/study/NCT02435849"}],"tags":[],"related":["paper-maude-ctl019-all-nejm-2014","apheresis-starting-material"],"cancers":["all-leukemia","all-paediatric-relapsed"],"sections":[],"technologies":["car-t"],"targets":["cd19"],"drugs":["tisagenlecleucel","obecabtagene-autoleucel"],"companies":["novartis"],"institutions":["penn-abramson"],"pathways":[],"terms":["crs","icans","efs"],"trials":["eliana"],"people":["carl-june","bruce-levine"],"bottlenecks":["b-manufacturing-cell-therapy","b-drug-pricing","b-global-access"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1709866","authors":"Maude SL, Laetsch TW, Buechner J, et al.","paperType":"translational","findings":["92 enrolled, 75 infused; 25 centres in 11 countries; median age 11.","Overall remission rate within 3 months 81%; all remissions MRD-negative.","Event-free survival 73% at 6 months and 50% at 12 months; overall survival 90% and 76%.","CRS 77% (grade 3-4 in about 46%; 48% needed tocilizumab; 47% intensive care); neurological events 40%.","Manufacturing failed in 7 of 92 and 17 enrolled patients were never infused, highlighting the vein-to-vein problem."],"whatItMeans":"ELIANA turned CAR-T from a single-centre experiment into a licensed product and created the regulatory and logistical template every later cell therapy has followed. For children with refractory leukaemia it offers a chance of durable remission without transplant. The trial also exposed the gaps: manufacturing failures, patients dying while waiting, and roughly half relapsing within a few years.","caveats":["Single-arm; no randomised comparator and outcomes reported on infused rather than enrolled patients in most analyses.","Severe CRS rates were high by later standards, before prophylactic strategies.","Long-term relapse, often CD19-negative, affects about half; some patients still proceed to transplant.","List price around 475,000 US dollars at launch raised affordability and access questions."],"changedPractice":true,"participants":75},{"id":"paper-eln-2022-aml-dohner-blood-2022","kind":"paper","name":"ELN 2022: diagnosis and management of acute myeloid leukaemia in adults","aka":[],"tldr":"The European LeukemiaNet 2022 recommendations define how acute myeloid leukaemia is classified by its genetics into favourable, intermediate and adverse risk, and how those groups should be treated and monitored.","summary":"International expert panel recommendations updating the 2017 European LeukemiaNet guidance on AML diagnosis, genetic risk classification, response criteria, measurable residual disease and treatment, aligned with the 2022 WHO and International Consensus classifications.\n\nKey changes include FLT3-ITD moving to intermediate risk regardless of allelic ratio, the addition of adverse-risk myelodysplasia-related gene mutations, and new criteria for measurable residual disease assessment.","asOf":"2026-09-17","links":[{"label":"Blood 2022","url":"https://doi.org/10.1182/blood.2022016867"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35797463/"}],"tags":[],"related":[],"cancers":["aml-older-unfit","aml-flt3","aml-npm1-kmt2a","aml-idh","aml-secondary"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2022,"doi":"10.1182/blood.2022016867","pmid":"35797463","authors":"Döhner H, Wei AH, Appelbaum FR, et al.","paperType":"guideline","findings":[],"whatItMeans":"The risk category on an AML report, and therefore whether a patient is steered towards transplant in first remission, comes from these recommendations.","caveats":["Risk categories were derived largely from intensively treated patients and predict less well under venetoclax-based regimens."],"changedPractice":true},{"id":"paper-embark-nejm-2023","kind":"paper","name":"EMBARK: enzalutamide with or without leuprolide in high-risk biochemically recurrent prostate cancer","aka":[],"tldr":"In men whose PSA was rising fast after surgery or radiotherapy without visible metastases, enzalutamide with or without hormone injections delayed metastases by years compared with hormone injections alone, with treatment paused when the PSA fell to undetectable.","summary":"Phase 3 trial of 1,068 men with high-risk biochemical recurrence (PSA doubling time of nine months or less) after definitive therapy randomised to enzalutamide plus leuprolide, placebo plus leuprolide, or enzalutamide alone, with treatment suspended at week 37 if PSA was undetectable.\n\nFive-year metastasis-free survival was 87.3 percent with the combination against 71.4 percent with leuprolide alone (hazard ratio 0.42) and 80.0 percent with enzalutamide monotherapy (hazard ratio 0.63); later analysis showed an overall survival benefit for the combination.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2303974"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37851874/"}],"tags":[],"related":[],"cancers":["prostate-bcr"],"sections":[],"technologies":[],"targets":[],"drugs":["enzalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["embark"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2303974","pmid":"37851874","authors":"Freedland SJ, de Almeida Luz M, De Giorgi U, et al.","paperType":"rct","findings":["Five-year metastasis-free survival 87.3 percent (combination) vs 71.4 percent (leuprolide alone); hazard ratio 0.42.","Enzalutamide monotherapy 80.0 percent; hazard ratio 0.63."],"whatItMeans":"Enzalutamide, with or without androgen deprivation, is now approved for high-risk biochemical recurrence, and intermittent therapy with treatment suspension is built into the regimen.","caveats":["Conventional imaging defined the population; PSMA PET would reclassify many as metastatic.","Hot flushes, fatigue and gynaecomastia (with monotherapy) are common."],"changedPractice":true,"participants":1068},{"id":"paper-emerald-1-lancet-2025","kind":"paper","name":"EMERALD-1: durvalumab with or without bevacizumab added to transarterial chemoembolisation for embolisation-eligible hepatocellular carcinoma","aka":[],"tldr":"Adding durvalumab and bevacizumab to chemoembolisation lengthened the time to progression by about seven months in liver cancer suitable for embolisation, the first systemic combination to improve on chemoembolisation alone.","summary":"Phase 3 placebo-controlled trial of 616 patients with unresectable hepatocellular carcinoma eligible for embolisation randomised to transarterial chemoembolisation with durvalumab plus bevacizumab, durvalumab alone, or placebo.\n\nMedian progression-free survival was 15.0 months with durvalumab plus bevacizumab against 8.2 months with placebo (hazard ratio 0.77), while durvalumab alone did not significantly improve progression-free survival; grade 3 to 4 adverse events were more frequent with the combination.","asOf":"2026-09-17","links":[{"label":"Lancet 2025","url":"https://doi.org/10.1016/S0140-6736(24)02551-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39798579/"}],"tags":[],"related":[],"cancers":["hcc-intermediate"],"sections":[],"technologies":[],"targets":[],"drugs":["bevacizumab","durvalumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["emerald-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2025,"doi":"10.1016/S0140-6736(24)02551-0","pmid":"39798579","authors":"Sangro B, Kudo M, Erinjeri JP, et al.","paperType":"rct","findings":["Median progression-free survival 15.0 vs 8.2 months; hazard ratio 0.77.","Durvalumab alone with chemoembolisation: 10.0 months (not significant)."],"whatItMeans":"Chemoembolisation combined with durvalumab and bevacizumab is a new option for intermediate-stage hepatocellular carcinoma where approved, though overall survival benefit is not yet shown.","caveats":["Overall survival data immature.","Bleeding risk with bevacizumab requires endoscopic assessment."],"changedPractice":true,"participants":616},{"id":"paper-emerald-elacestrant-jco-2022","kind":"paper","name":"EMERALD: elacestrant versus standard endocrine therapy after a CDK4/6 inhibitor","aka":[],"tldr":"The oral oestrogen receptor degrader elacestrant delayed progression compared with standard hormone therapy in advanced breast cancer that had progressed on a CDK4/6 inhibitor, with the clearest benefit in tumours carrying an ESR1 mutation.","summary":"Phase 3 trial of 477 patients with oestrogen receptor-positive, HER2-negative advanced breast cancer previously treated with one or two lines of endocrine therapy including a CDK4/6 inhibitor, randomised to elacestrant or investigator's choice of fulvestrant or an aromatase inhibitor.\n\nProgression-free survival was improved overall (hazard ratio 0.70) and in the ESR1-mutated group (hazard ratio 0.55), where median progression-free survival was 3.8 versus 1.9 months; benefit was largest in patients with longer prior CDK4/6 inhibitor exposure.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2022","url":"https://doi.org/10.1200/JCO.22.00338"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35584336/"}],"tags":[],"related":[],"cancers":["hr-positive-metastatic-post-cdk46"],"sections":[],"technologies":[],"targets":[],"drugs":["elacestrant"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["emerald"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2022,"doi":"10.1200/JCO.22.00338","pmid":"35584336","authors":"Bidard FC, Kaklamani VG, Neven P, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.70 overall and 0.55 in ESR1-mutated disease.","Median progression-free survival 3.8 vs 1.9 months in ESR1-mutated tumours."],"whatItMeans":"Elacestrant is the first oral selective oestrogen receptor degrader approved, for ESR1-mutated disease after a CDK4/6 inhibitor. Absolute gains are modest and blood testing for ESR1 mutations is now routine at progression.","caveats":["Absolute benefit is small and control-arm performance was poor.","Nausea and lipid changes are common."],"changedPractice":true,"participants":477},{"id":"paper-empower-cervical-1-cemiplimab-nejm-2022","kind":"paper","name":"EMPOWER-Cervical 1: cemiplimab versus chemotherapy in recurrent cervical cancer after platinum","aka":[],"tldr":"The PD-1 antibody cemiplimab lengthened survival compared with single-agent chemotherapy in recurrent cervical cancer after platinum, regardless of PD-L1 expression, the first immunotherapy to show a survival benefit in this disease.","summary":"Phase 3 trial of 608 patients with recurrent cervical cancer progressing after first-line platinum chemotherapy randomised to cemiplimab or investigator's choice single-agent chemotherapy, enrolled irrespective of PD-L1 status.\n\nMedian overall survival was 12.0 versus 8.5 months (hazard ratio 0.69) overall and 11.1 versus 8.8 months in squamous cell carcinoma; response was 16.4 versus 6.3 percent, and benefit was seen across PD-L1 levels.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2112187"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35139273/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["empower-cervical-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2112187","pmid":"35139273","authors":"Tewari KS, Monk BJ, Vergote I, et al.","paperType":"rct","findings":["Median overall survival 12.0 vs 8.5 months; hazard ratio 0.69.","Objective response 16.4 percent vs 6.3 percent."],"whatItMeans":"Cemiplimab is an option for second-line cervical cancer in patients who have not had immunotherapy, though most now receive pembrolizumab first line, moving cemiplimab later or out of sequence.","caveats":["Patients were immunotherapy-naive; applicability after first-line pembrolizumab is unclear."],"changedPractice":true,"participants":608},{"id":"paper-enasidenib-idh2-stein-blood-2017","kind":"paper","name":"Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukaemia","aka":[],"tldr":"Enasidenib, a pill blocking the mutant IDH2 enzyme, produced responses in about four in ten patients with relapsed IDH2-mutated acute myeloid leukaemia by making the leukaemic cells mature, and became the first IDH-targeted drug approved.","summary":"Phase 1/2 study of 239 patients with IDH2-mutated advanced myeloid malignancies, including 176 with relapsed or refractory AML, treated with enasidenib, mostly at 100 mg daily.\n\nOverall response rate was 40.3 percent with complete remission in 19.3 percent and a median overall survival of 9.3 months; responses came through differentiation of blasts rather than cytotoxicity, with differentiation syndrome in a minority.","asOf":"2026-09-17","links":[{"label":"Blood 2017","url":"https://doi.org/10.1182/blood-2017-04-779405"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28588020/"}],"tags":[],"related":[],"cancers":["aml-idh"],"sections":[],"technologies":[],"targets":[],"drugs":["enasidenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2017,"doi":"10.1182/blood-2017-04-779405","pmid":"28588020","authors":"Stein EM, DiNardo CD, Pollyea DA, et al.","paperType":"observational","findings":["Overall response 40.3 percent; complete remission 19.3 percent.","Median overall survival 9.3 months; 19.7 months in complete responders."],"whatItMeans":"IDH2 mutations, present in about one in eight AML cases, became actionable. Enasidenib is an option at relapse; its role in newly diagnosed disease is less established than ivosidenib's.","caveats":["The later randomised IDHENTIFY trial did not show a survival benefit over conventional care.","Indirect hyperbilirubinaemia and differentiation syndrome are characteristic toxicities."],"changedPractice":true,"participants":239},{"id":"paper-enets-lung-net-consensus-caplin-ann-oncol-2015","kind":"paper","name":"ENETS expert consensus on pulmonary neuroendocrine (carcinoid) tumours","aka":[],"tldr":"The European Neuroendocrine Tumor Society consensus on lung carcinoids covers diagnosis, grading into typical and atypical, surgery with node dissection, and the limited evidence for somatostatin analogues, everolimus and radioligand therapy in advanced disease.","summary":"Expert consensus from the European Neuroendocrine Tumor Society on the classification, staging, imaging, surgical and systemic management of typical and atypical lung carcinoids, including recommendations on adjuvant therapy (not indicated), somatostatin analogues, everolimus, temozolomide-based chemotherapy and peptide receptor radionuclide therapy.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2015","url":"https://doi.org/10.1093/annonc/mdv041"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25646366/"}],"tags":[],"related":[],"cancers":["lung-net"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2015,"doi":"10.1093/annonc/mdv041","pmid":"25646366","authors":"Caplin ME, Baudin E, Ferolla P, et al.","paperType":"guideline","findings":[],"whatItMeans":"Surgical resection as the only curative treatment and the sequence of systemic options on the lung neuroendocrine tumour page follow this consensus.","caveats":["Randomised evidence in lung carcinoids remains scarce; RADIANT-4 and CABINET are the main trials since."],"changedPractice":true},{"id":"paper-hpv-vaccine-england-lancet-2021","kind":"paper","name":"England's HPV programme: cervical cancer down 87% in the first cohort vaccinated at 12-13","aka":[],"tldr":"Ten years after England began vaccinating 12- to 13-year-olds with the bivalent HPV vaccine, cervical cancer in that cohort had fallen by 87% and severe precancer (CIN3) by 97%.","summary":"A population-based observational study used English cancer registry data from 2006 to 2019 to compare cervical cancer and CIN3 rates in cohorts offered the bivalent vaccine (Cervarix) at ages 12-13, 14-16 and 16-18 with earlier, unvaccinated cohorts, adjusting for changes in screening.\n\nRelative reductions in cervical cancer were 87% in the cohort offered vaccination at 12-13, 62% at 14-16 and 34% at 16-18. CIN3 fell by 97%, 75% and 39% respectively. The authors estimated about 450 fewer cervical cancers and 17,200 fewer CIN3 cases by mid-2019.\n\nThis confirmed the Swedish finding with a different vaccine and a school-based programme with high coverage.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S0140-6736(21)02178-4"}],"tags":[],"related":["paper-hpv-vaccine-sweden-nejm-2020","idea-prev-hpv-vaccinate-at-screening","idea-prev-hpv-male-catchup-oropharynx"],"cancers":["cervical"],"sections":["prevention"],"technologies":["hpv-vaccine","hpv-testing"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-global-access"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"doi":"10.1016/S0140-6736(21)02178-4","pmid":"34741816","authors":"Falcaro M, Castañon A, Ndlela B, et al.","paperType":"observational","findings":["Cervical cancer reduced 87% (95% CI 72-94) in the cohort offered vaccine at age 12-13","Reduction of 62% (52-71) at 14-16 and 34% (25-41) at 16-18","CIN3 reduced 97% (96-98) in the youngest cohort","An estimated 448 fewer cervical cancers and 17,235 fewer CIN3 cases by June 2019"],"whatItMeans":"School-based vaccination at 12-13 with high uptake nearly abolishes cervical cancer in vaccinated cohorts, even with a vaccine covering only two HPV types. Screening intervals and the future of cervical screening can now be redesigned around vaccination status.","caveats":["Observational with a cohort comparison; changes in screening policy were adjusted for but cannot be fully excluded","Vaccinated cohorts were still young (under 28), so absolute numbers of cancers were small","Bivalent vaccine; England later switched to quadrivalent and nonavalent","Effects in populations with lower coverage will be smaller"],"changedPractice":true},{"id":"paper-doebele-entrectinib-ntrk-lancet-oncol-2020","kind":"paper","name":"Entrectinib in NTRK fusion-positive solid tumours: integrated analysis of three trials","aka":[],"tldr":"Entrectinib, a TRK and ROS1 inhibitor that enters the brain, shrank tumours in more than half of patients with NTRK fusion-positive cancers of ten types and controlled brain metastases, leading to a tumour-agnostic approval alongside larotrectinib.","summary":"Integrated analysis of 54 adults with NTRK fusion-positive solid tumours from the ALKA-372-001, STARTRK-1 and STARTRK-2 trials treated with entrectinib.\n\nObjective response was 57 percent with a median duration of response of 10 months and intracranial response in half of the patients with brain metastases; toxicity included weight gain, dizziness and dysgeusia.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2020","url":"https://doi.org/10.1016/S1470-2045(19)30691-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31838007/"}],"tags":[],"related":[],"cancers":["ntrk-fusion-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["entrectinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2020,"doi":"10.1016/S1470-2045(19)30691-6","pmid":"31838007","authors":"Doebele RC, Drilon A, Paz-Ares L, et al.","paperType":"observational","findings":["Objective response 57 percent; median duration of response 10 months.","Intracranial response in 50 percent of patients with brain metastases."],"whatItMeans":"Entrectinib is an approved tumour-agnostic TRK inhibitor with an advantage in patients with brain metastases, and it is also approved for ROS1-positive lung cancer.","caveats":["Small pooled population; median progression-free survival 11 months."],"changedPractice":true,"participants":54},{"id":"paper-drilon-entrectinib-ros1-lancet-oncol-2020","kind":"paper","name":"Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three trials","aka":[],"tldr":"Entrectinib shrank tumours in more than three quarters of patients with ROS1-positive lung cancer and, unlike crizotinib, controlled brain metastases in most patients who had them, earning approval as a first-line option.","summary":"Integrated analysis of 53 ROS1 inhibitor-naive patients with ROS1 fusion-positive non-small-cell lung cancer from the ALKA-372-001, STARTRK-1 and STARTRK-2 trials treated with entrectinib.\n\nObjective response was 77 percent with median duration of response 24.6 months and median progression-free survival 19.0 months; intracranial response was 55 percent in patients with brain metastases.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2020","url":"https://doi.org/10.1016/S1470-2045(19)30690-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31838015/"}],"tags":[],"related":[],"cancers":["ros1-positive-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["entrectinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2020,"doi":"10.1016/S1470-2045(19)30690-4","pmid":"31838015","authors":"Drilon A, Siena S, Dziadziuszko R, et al.","paperType":"observational","findings":["Objective response 77 percent; median progression-free survival 19.0 months.","Intracranial response 55 percent."],"whatItMeans":"Entrectinib is a first-line ROS1 inhibitor with brain activity, preferred over crizotinib when brain metastases are present, though repotrectinib and taletrectinib now offer longer control.","caveats":["Single-arm pooled analysis; does not cover the G2032R resistance mutation."],"changedPractice":true,"participants":53},{"id":"paper-bolla-eortc-22863-nejm-1997","kind":"paper","name":"EORTC 22863: improved survival with radiotherapy plus goserelin in locally advanced prostate cancer","aka":[],"tldr":"Adding three years of hormone therapy to radiotherapy for locally advanced prostate cancer improved five-year survival from 62 to 79 percent, establishing long-term androgen deprivation with radiotherapy as the standard for high-risk disease.","summary":"Phase 3 trial of 415 men with locally advanced (T3 to T4 or high-grade T1 to T2) prostate cancer randomised to external beam radiotherapy alone or with goserelin started at the beginning of radiotherapy and continued for three years.\n\nFive-year overall survival was 79 versus 62 percent and disease-free survival 85 versus 48 percent; ten-year follow-up confirmed a persistent survival benefit (58.1 versus 39.8 percent).","asOf":"2026-09-17","links":[{"label":"N Engl J Med 1997","url":"https://doi.org/10.1056/NEJM199707313370502"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/9233866/"}],"tags":[],"related":[],"cancers":["prostate-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1997,"doi":"10.1056/NEJM199707313370502","pmid":"9233866","authors":"Bolla M, Gonzalez D, Warde P, et al.","paperType":"rct","findings":["Five-year overall survival 79 percent vs 62 percent.","Ten-year overall survival 58.1 percent vs 39.8 percent."],"whatItMeans":"Long-term androgen deprivation (18 to 36 months) with radiotherapy remains the backbone for high-risk localised prostate cancer, to which abiraterone is now added for the highest-risk men.","caveats":["Radiotherapy doses were lower than modern standards.","Optimal duration of hormone therapy was refined by later trials (EORTC 22961, DART 01/05)."],"changedPractice":true,"participants":415},{"id":"paper-bernier-eortc-22931-nejm-2004","kind":"paper","name":"EORTC 22931: postoperative irradiation with or without concomitant cisplatin for locally advanced head and neck cancer","aka":[],"tldr":"Adding cisplatin to radiotherapy after surgery for high-risk head and neck cancer improved local control and survival, and with the parallel American trial defined extranodal extension and positive margins as the indications for postoperative chemoradiation.","summary":"Phase 3 trial of 334 patients with resected stage III to IV head and neck squamous cell carcinoma with high-risk features randomised to postoperative radiotherapy alone or with three cycles of concurrent cisplatin.\n\nFive-year progression-free survival was 47 versus 36 percent and overall survival 53 versus 40 percent with chemoradiation, with more severe acute mucositis; a combined analysis with RTOG 9501 showed the benefit was confined to patients with extranodal extension or positive margins.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2004","url":"https://doi.org/10.1056/NEJMoa032641"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15128894/"}],"tags":[],"related":[],"cancers":["hpv-negative-head-and-neck-cancer","oral-tongue-cancer","oral-cavity-cancer","buccal-mucosa-cancer","lip-cancer","mucoepidermoid-carcinoma","salivary-duct-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2004,"doi":"10.1056/NEJMoa032641","pmid":"15128894","authors":"Bernier J, Domenge C, Ozsahin M, et al.","paperType":"rct","findings":["Five-year overall survival 53 percent vs 40 percent.","Five-year locoregional relapse 18 percent vs 31 percent."],"whatItMeans":"Cisplatin chemoradiation after surgery is standard for extranodal extension or involved margins; radiotherapy alone suffices for other adverse features.","caveats":["Cisplatin at 100 mg per square metre every three weeks is poorly tolerated; weekly dosing is common in practice.","Trial predates HPV stratification."],"changedPractice":true,"participants":334},{"id":"paper-eortc-24891-larynx-preservation-lefebvre-jnci-1996","kind":"paper","name":"EORTC 24891: larynx preservation with induction chemotherapy in pyriform sinus (hypopharyngeal) cancer","aka":[],"tldr":"In hypopharyngeal cancer that would otherwise require removal of the voice box, induction chemotherapy followed by radiotherapy in responders gave survival equal to immediate laryngectomy and let about half of survivors keep a functioning larynx.","summary":"Phase 3 trial of 202 patients with resectable pyriform sinus or aryepiglottic fold cancer randomised to immediate total laryngectomy with partial pharyngectomy and postoperative radiotherapy, or induction cisplatin-fluorouracil followed by radiotherapy in complete responders and surgery in the rest.\n\nMedian survival was 44 months with induction chemotherapy against 25 months with surgery (not significantly different, meeting the non-inferiority aim), and at three years 42 percent of surviving patients in the chemotherapy arm had a functional larynx; ten-year follow-up confirmed equivalence.","asOf":"2026-09-17","links":[{"label":"J Natl Cancer Inst 1996","url":"https://doi.org/10.1093/jnci/88.13.890"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/8656441/"}],"tags":[],"related":[],"cancers":["hypopharyngeal-cancer","laryngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jnci"],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":1996,"doi":"10.1093/jnci/88.13.890","pmid":"8656441","authors":"Lefebvre JL, Chevalier D, Luboinski B, et al.","paperType":"rct","findings":["Median overall survival 44 vs 25 months (not significant).","Functional larynx preserved in 42 percent of survivors at three years."],"whatItMeans":"Organ preservation is an accepted alternative to laryngectomy for hypopharyngeal cancer; concurrent chemoradiation has largely replaced sequential induction chemotherapy and radiotherapy.","caveats":["Small trial; survival in hypopharyngeal cancer remains poor with either approach.","Sequential rather than concurrent chemoradiation."],"changedPractice":true,"participants":202},{"id":"paper-eortc-26951-van-den-bent-jco-2013","kind":"paper","name":"EORTC 26951: adjuvant PCV after radiotherapy for anaplastic oligodendroglial tumours, long-term follow-up","aka":[],"tldr":"This European trial confirmed, independently of the American RTOG 9402 study, that PCV chemotherapy added to radiotherapy lengthens survival in anaplastic oligodendroglioma, with the largest benefit in tumours carrying the 1p/19q codeletion.","summary":"Phase 3 trial of 368 patients with anaplastic oligodendroglial tumours randomised to radiotherapy alone or radiotherapy followed by six cycles of PCV, reported at a median follow-up of 140 months.\n\nMedian overall survival was 42.3 months with PCV against 30.6 months without (hazard ratio 0.75); in the 80 patients with 1p/19q codeletion median survival was not reached with PCV against 112 months without (hazard ratio 0.56), and IDH mutation and MGMT methylation were also prognostic.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2013","url":"https://doi.org/10.1200/JCO.2012.43.2229"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23071237/"}],"tags":[],"related":[],"cancers":["oligodendroglioma"],"sections":[],"technologies":[],"targets":[],"drugs":["procarbazine","vincristine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["eortc-26951","codel"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2013,"doi":"10.1200/JCO.2012.43.2229","pmid":"23071237","authors":"van den Bent MJ, Brandes AA, Taphoorn MJ, et al.","paperType":"rct","findings":["Median overall survival 42.3 vs 30.6 months overall; hazard ratio 0.75.","1p/19q-codeleted: median survival not reached vs 112 months; hazard ratio 0.56."],"whatItMeans":"Together with RTOG 9402, this trial made radiotherapy followed by PCV the standard for 1p/19q-codeleted anaplastic oligodendroglioma; the CODEL trial is now comparing PCV with temozolomide.","caveats":["Codeleted subgroup was small.","About a third of patients did not complete PCV because of toxicity."],"changedPractice":true,"participants":368},{"id":"paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","kind":"paper","name":"EORTC 62012: doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced soft tissue sarcoma","aka":[],"tldr":"Adding ifosfamide to doxorubicin for advanced soft tissue sarcoma doubled the response rate and delayed progression but did not lengthen survival and caused much more toxicity, so doxorubicin alone remains the default unless shrinkage is needed.","summary":"Phase 3 trial of 455 patients with advanced high-grade soft tissue sarcoma randomised to doxorubicin 75 mg per square metre alone or with ifosfamide 10 g per square metre and growth factor support.\n\nMedian overall survival was 14.3 versus 12.8 months (hazard ratio 0.83, not significant), median progression-free survival 7.4 versus 4.6 months, and response 26 versus 14 percent; febrile neutropenia and other grade 3 to 4 toxicities were far more frequent with the combination.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2014","url":"https://doi.org/10.1016/S1470-2045(14)70063-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24618336/"}],"tags":[],"related":[],"cancers":["malignant-peripheral-nerve-sheath-tumour","extremity-soft-tissue-sarcoma","undifferentiated-pleomorphic-sarcoma","leiomyosarcoma","myxofibrosarcoma","synovial-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["doxorubicin","ifosfamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["eortc-62012"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2014,"doi":"10.1016/S1470-2045(14)70063-4","pmid":"24618336","authors":"Judson I, Verweij J, Gelderblom H, et al.","paperType":"rct","findings":["Median overall survival 14.3 vs 12.8 months (not significant).","Objective response 26 percent vs 14 percent; median progression-free survival 7.4 vs 4.6 months."],"whatItMeans":"Single-agent doxorubicin is the standard first-line palliative treatment for most advanced sarcomas, with doxorubicin-ifosfamide reserved for fit patients in whom tumour shrinkage matters.","caveats":["Excluded some histologies; benefit may differ by subtype (for example synovial sarcoma is ifosfamide-sensitive)."],"changedPractice":true,"participants":455},{"id":"paper-sylvester-eortc-risk-tables-eur-urol-2006","kind":"paper","name":"EORTC risk tables for recurrence and progression in Ta and T1 bladder cancer","aka":[],"tldr":"Pooling seven trials, this analysis produced the scoring tables that clinicians still use to estimate how likely a non-muscle-invasive bladder tumour is to come back or to progress into the muscle.","summary":"Analysis of 2,596 patients with Ta or T1 bladder cancer from seven EORTC trials, mostly treated with transurethral resection and intravesical chemotherapy, to identify factors predicting recurrence and progression.\n\nNumber of tumours, size, prior recurrence rate, T category, carcinoma in situ and grade were combined into scores giving one- and five-year probabilities of recurrence and progression. The tables underpin the low, intermediate and high-risk groups used in guidelines.","asOf":"2026-09-17","links":[{"label":"Eur Urol 2006","url":"https://doi.org/10.1016/j.eururo.2005.12.031"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16442208/"}],"tags":[],"related":[],"cancers":["non-muscle-invasive-bladder-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["european-urology"],"dependsOn":[],"notes":[],"journal":"European Urology","year":2006,"doi":"10.1016/j.eururo.2005.12.031","pmid":"16442208","authors":"Sylvester RJ, van der Meijden AP, Oosterlinck W, et al.","paperType":"observational","findings":["Five-year progression risk ranged from under 1 percent in the lowest score group to 45 percent in the highest.","Five-year recurrence risk ranged from 31 percent to 78 percent."],"whatItMeans":"The risk groups that decide whether a patient gets a single chemotherapy instillation, BCG, or early cystectomy trace back to this work. Later models (CUETO, the 2021 EAU risk groups) refine the estimates for BCG-treated patients.","caveats":["Few patients received BCG maintenance or re-resection, so the tables overestimate risk under modern care.","Grading used the 1973 WHO system."],"changedPractice":true,"participants":2596},{"id":"paper-epcore-nhl-1-epcoritamab-jco-2023","kind":"paper","name":"EPCORE NHL-1: epcoritamab, a subcutaneous CD20 x CD3 bispecific, in relapsed large B-cell lymphoma including after CAR-T","aka":[],"tldr":"In EPCORE NHL-1, the off-the-shelf bispecific antibody epcoritamab, injected under the skin, produced responses in 63% of 157 patients with relapsed large B-cell lymphoma, including the 39% whose CAR-T had failed. Cytokine release syndrome occurred in half, mostly mild, and the drug won accelerated approval in 2023.","summary":"The dose-expansion part of EPCORE NHL-1 treated 157 patients with relapsed or refractory large B-cell lymphoma after at least two prior lines (median three; 39% had prior CAR-T) with subcutaneous epcoritamab given with step-up dosing then weekly, fortnightly and monthly. The overall response rate was 63.1% with complete response in 38.9%; median duration of response was 12.0 months and complete responders had durable remissions. CRS occurred in 49.7% (grade 3 in 2.5%) and ICANS in 6.4% with one fatal event. Responses were similar after CAR-T failure. Epcoritamab received accelerated approval in 2023, alongside the intravenous CD20 x CD3 bispecific glofitamab, whose pivotal study reported complete response in 39% of 155 patients.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=EPCORE%20NHL-1%20epcoritamab%20large%20B-cell%20lymphoma%20Thieblemont%20JCO%202023"},{"label":"ClinicalTrials.gov NCT03625037","url":"https://clinicaltrials.gov/study/NCT03625037"}],"tags":[],"related":["bispecific-plus-adc-lymphoma"],"cancers":["dlbcl","follicular-lymphoma"],"sections":[],"technologies":["bispecific-antibody","t-cell-engager"],"targets":["cd20","cd3"],"drugs":["epcoritamab","glofitamab","mosunetuzumab","odronextamab"],"companies":["abbvie","roche-genentech"],"institutions":[],"pathways":[],"terms":["crs","icans","orr"],"trials":["epcore-nhl-1","epcore-dlbcl-1","starglo"],"people":[],"bottlenecks":["b-manufacturing-cell-therapy","b-resistance"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2023,"authors":"Thieblemont C, Phillips T, Ghesquieres H, et al.","paperType":"translational","findings":["157 patients with relapsed/refractory LBCL after 2 or more lines; 38.9% had prior CAR-T.","Overall response 63.1%; complete response 38.9%.","Median duration of response 12.0 months; most complete responses ongoing at data cut.","CRS 49.7% (grade 3 2.5%), largely confined to cycle 1; ICANS 6.4% (one fatal).","Similar response rates in patients whose CAR-T had failed."],"whatItMeans":"CD20 x CD3 bispecifics gave patients whose lymphoma has failed CAR-T, or who cannot access it, an effective off-the-shelf treatment that can be started within days. Epcoritamab and glofitamab are now standard third-line options and are moving into earlier lines and combinations. They do not yet replace CAR-T, whose remissions appear more durable.","caveats":["Single-arm phase 2; randomised confirmation in earlier lines came later with mixed results in some designs.","Fixed-duration (glofitamab) versus until-progression (epcoritamab) dosing remains a practical difference without head-to-head data.","Infection risk and hypogammaglobulinaemia accumulate with prolonged dosing.","Durability of partial responses is limited."],"changedPractice":true,"participants":157},{"id":"paper-ehe-consensus-stacchiotti-esmo-open-2021","kind":"paper","name":"Epithelioid haemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts","aka":[],"tldr":"An international group of experts and patient advocates produced the first consensus on managing epithelioid haemangioendothelioma, including active surveillance for stable disease, surgery or transplant for localised disease, and sirolimus for progressing tumours.","summary":"Consensus paper from sarcoma experts and the EHE patient community covering diagnosis (including WWTR1-CAMTA1 and YAP1-TFE3 fusions), the highly variable natural history, indications for active surveillance, surgery, liver transplantation and radiotherapy, systemic therapy with mTOR inhibitors and anti-angiogenic agents, and priorities for research.","asOf":"2026-09-17","links":[{"label":"ESMO Open 2021","url":"https://doi.org/10.1016/j.esmoop.2021.100170"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34090171/"}],"tags":[],"related":[],"cancers":["epithelioid-haemangioendothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["esmo-open"],"dependsOn":[],"notes":[],"journal":"ESMO Open","year":2021,"doi":"10.1016/j.esmoop.2021.100170","pmid":"34090171","authors":"Stacchiotti S, Miah AB, Frezza AM, et al.","paperType":"guideline","findings":[],"whatItMeans":"The observation-first approach and the sequencing of sirolimus before other systemic options on the EHE page come from this consensus.","caveats":["Based largely on retrospective series; no randomised trials exist."],"changedPractice":true},{"id":"paper-eribulin-liposarcoma-schoffski-lancet-2016","kind":"paper","name":"Eribulin versus dacarbazine in previously treated advanced liposarcoma or leiomyosarcoma","aka":[],"tldr":"Eribulin lengthened survival by two months compared with dacarbazine in previously treated liposarcoma and leiomyosarcoma, with the entire benefit in liposarcoma, where survival improved by seven months, leading to its approval for that subtype.","summary":"Phase 3 trial of 452 patients with advanced liposarcoma or leiomyosarcoma after at least two prior regimens randomised to eribulin or dacarbazine.\n\nMedian overall survival was 13.5 versus 11.5 months (hazard ratio 0.77) overall, and 15.6 versus 8.4 months in liposarcoma (hazard ratio 0.51) with no difference in leiomyosarcoma; progression-free survival was similar between arms.","asOf":"2026-09-17","links":[{"label":"Lancet 2016","url":"https://doi.org/10.1016/S0140-6736(15)01283-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26874885/"}],"tags":[],"related":[],"cancers":["liposarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["dacarbazine","eribulin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2016,"doi":"10.1016/S0140-6736(15)01283-0","pmid":"26874885","authors":"Schöffski P, Chawla S, Maki RG, et al.","paperType":"rct","findings":["Median overall survival 13.5 vs 11.5 months overall; hazard ratio 0.77.","Liposarcoma: 15.6 vs 8.4 months; hazard ratio 0.51."],"whatItMeans":"Eribulin is an approved later-line treatment for liposarcoma, one of the few sarcoma drugs with a demonstrated survival benefit.","caveats":["No progression-free survival benefit, an unusual pattern.","Dacarbazine is an active comparator in leiomyosarcoma."],"changedPractice":true,"participants":452},{"id":"paper-erivance-vismodegib-sekulic-nejm-2012","kind":"paper","name":"ERIVANCE BCC: efficacy and safety of vismodegib in advanced basal cell carcinoma","aka":[],"tldr":"The hedgehog pathway inhibitor vismodegib shrank tumours in 43 percent of patients with locally advanced and 30 percent with metastatic basal cell carcinoma, becoming the first drug approved for advanced basal cell carcinoma.","summary":"Phase 2 study of 104 patients with metastatic (33) or locally advanced (71) basal cell carcinoma unsuitable for surgery or radiotherapy treated with vismodegib 150 mg daily.\n\nObjective response was 30 percent in metastatic and 43 percent in locally advanced disease (21 percent complete), with median duration of response of 7.6 months; muscle spasms, alopecia, dysgeusia and weight loss were almost universal and led many patients to stop.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2012","url":"https://doi.org/10.1056/NEJMoa1113713"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22670903/"}],"tags":[],"related":[],"cancers":["locally-advanced-bcc"],"sections":[],"technologies":[],"targets":[],"drugs":["vismodegib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["erivance"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1113713","pmid":"22670903","authors":"Sekulic A, Migden MR, Oro AE, et al.","paperType":"observational","findings":["Objective response 43 percent (locally advanced) and 30 percent (metastatic).","Median duration of response 7.6 months."],"whatItMeans":"Vismodegib (and sonidegib) is the first-line systemic treatment for locally advanced or metastatic basal cell carcinoma, often given intermittently to manage side effects.","caveats":["Single-arm; toxicity-related discontinuation is common.","Teratogenic; strict contraception required."],"changedPractice":true,"participants":104},{"id":"paper-esgo-estro-esp-endometrial-concin-ijgc-2021","kind":"paper","name":"ESGO/ESTRO/ESP guidelines for the management of endometrial carcinoma (2021)","aka":[],"tldr":"The European gynaecological oncology, radiotherapy and pathology societies' joint guideline integrates molecular classification into risk groups for endometrial cancer and sets adjuvant treatment for each, including no adjuvant therapy for early POLE-mutated tumours.","summary":"Joint evidence-based guideline covering diagnosis, molecular classification, surgical staging including sentinel node mapping, risk group definitions incorporating molecular class, adjuvant radiotherapy and chemotherapy recommendations, fertility-sparing treatment, and management of advanced and recurrent disease.","asOf":"2026-09-17","links":[{"label":"Int J Gynecol Cancer 2021","url":"https://doi.org/10.1136/ijgc-2020-002230"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33397713/"}],"tags":[],"related":[],"cancers":["endometrial-nsmp","endometrial-pole-ultramutated"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["international-journal-of-gynecological-cancer"],"dependsOn":[],"notes":[],"journal":"International journal of gynecological cancer","year":2021,"doi":"10.1136/ijgc-2020-002230","pmid":"33397713","authors":"Concin N, Matias-Guiu X, Vergote I, et al.","paperType":"guideline","findings":[],"whatItMeans":"The adjuvant recommendations on this site's endometrial subtype pages (observation for stage I to II POLE-mutated disease, chemotherapy for p53-abnormal tumours with myometrial invasion, brachytherapy for intermediate risk) follow this guideline.","caveats":["Some molecular-based de-escalation recommendations await confirmation from the RAINBO trials."],"changedPractice":true},{"id":"paper-esphall-imatinib-biondi-lancet-oncol-2012","kind":"paper","name":"EsPhALL: imatinib after induction for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukaemia","aka":[],"tldr":"In this European trial, adding intermittent imatinib to intensive chemotherapy for childhood Philadelphia-positive leukaemia improved disease-free survival in good-risk patients and supported its use in every child with the disease.","summary":"European intergroup study of 178 children with Ph-positive ALL; 108 good-risk patients were randomised to imatinib or no imatinib in addition to BFM-type chemotherapy, and poor-risk patients all received imatinib; most underwent transplant.\n\nFour-year disease-free survival was 72.9 percent with imatinib against 61.7 percent without in good-risk patients (not statistically significant by intention to treat but significant as treated), and toxicity was acceptable.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2012","url":"https://doi.org/10.1016/S1470-2045(12)70377-7"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22898679/"}],"tags":[],"related":[],"cancers":["all-paediatric-ph-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2012,"doi":"10.1016/S1470-2045(12)70377-7","pmid":"22898679","authors":"Biondi A, Schrappe M, De Lorenzo P, et al.","paperType":"rct","findings":["Four-year disease-free survival 72.9 percent vs 61.7 percent in good-risk patients.","Poor-risk patients on imatinib: four-year disease-free survival 53.5 percent."],"whatItMeans":"Together with AALL0031, EsPhALL established kinase inhibitor plus chemotherapy as standard for paediatric Ph-positive ALL, with later trials giving imatinib continuously and reducing transplant.","caveats":["Randomisation was stopped early after AALL0031 results; intention-to-treat difference not significant.","Intermittent imatinib schedule was later replaced by continuous dosing."],"changedPractice":true,"participants":178},{"id":"paper-esteva-skin-cancer-deep-learning-nature-2017","kind":"paper","name":"Esteva 2017: a deep neural network classifies skin cancer at dermatologist level","aka":[],"tldr":"A single image-recognition network, trained on about 130,000 clinical photographs, told cancerous skin lesions from benign ones as accurately as 21 dermatologists, the first widely cited demonstration that deep learning could match specialists at a cancer diagnosis task.","summary":"Esteva and colleagues at Stanford fine-tuned a convolutional neural network pretrained on everyday images using 129,450 clinical photographs spanning 2,032 skin diseases arranged in a taxonomy. On held-out biopsy-proven images they tested it against 21 board-certified dermatologists on two decisions: keratinocyte carcinomas versus benign seborrheic keratoses, and malignant melanomas versus benign naevi, using both clinical photographs and dermoscopy images. The network's sensitivity and specificity curve matched or exceeded the average dermatologist on each task.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature21056"}],"tags":[],"related":[],"cancers":["melanoma","basal-cell-carcinoma","cutaneous-scc"],"sections":[],"technologies":["dermoscopy-ai"],"targets":[],"drugs":[],"companies":[],"institutions":["stanford"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2017,"doi":"10.1038/nature21056","authors":"Esteva A, Kuprel B, Novoa RA, et al.","paperType":"methods","findings":["Training set of 129,450 clinical images covering 2,032 diseases; the network was pretrained on general images and fine-tuned on skin.","Tested against 21 dermatologists on biopsy-proven images for two binary decisions: keratinocyte carcinoma versus seborrheic keratosis and melanoma versus benign naevus, with and without dermoscopy.","Performance on both tasks was on a par with the dermatologists across the sensitivity and specificity trade-off."],"whatItMeans":"This paper made AI-assisted skin cancer triage a serious clinical prospect and became the template for later work in radiology and pathology. Prospective trials, regulatory clearance and performance across skin tones followed, and are where its promise is now being tested.","caveats":["A retrospective test on curated images, not a prospective clinical study.","Images came largely from lighter-skinned patients, so performance across skin tones was not established.","Dermatologists in practice use history and examination, not a photograph alone."],"changedPractice":false},{"id":"paper-estimabl2-leboulleux-nejm-2022","kind":"paper","name":"ESTIMABL2: thyroidectomy without radioiodine in patients with low-risk thyroid cancer","aka":[],"tldr":"Skipping radioactive iodine after thyroidectomy for low-risk differentiated thyroid cancer gave the same excellent three-year outcomes as giving it, so most low-risk patients can avoid the treatment.","summary":"Phase 3 non-inferiority trial of 776 patients with low-risk differentiated thyroid cancer (pT1a multifocal to pT1b, N0 or Nx) randomised after total thyroidectomy to postoperative radioiodine (1.1 GBq) or no radioiodine.\n\nAt three years, 95.6 percent of the no-radioiodine group and 95.9 percent of the radioiodine group had no event (abnormal imaging, thyroglobulin rise or further treatment), meeting non-inferiority, with no differences in quality of life or adverse events.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2111953"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35263518/"}],"tags":[],"related":[],"cancers":["papillary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["estimabl2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2111953","pmid":"35263518","authors":"Leboulleux S, Bournaud C, Chougnet CN, et al.","paperType":"rct","findings":["Three-year event-free 95.6 percent (no radioiodine) vs 95.9 percent (radioiodine); non-inferior.","Events were mostly biochemical rather than structural."],"whatItMeans":"Radioactive iodine is no longer recommended routinely for low-risk differentiated thyroid cancer, supported also by the UK IoN trial.","caveats":["Follow-up of three years is short for a disease with late recurrences.","Applies to low-risk tumours up to 2 cm without nodal disease."],"changedPractice":true,"participants":776},{"id":"paper-eau-nmibc-guideline-eur-urol-2022","kind":"paper","name":"European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1 and carcinoma in situ)","aka":[],"tldr":"The European urology guideline sets out how to diagnose, resect, risk-group and treat bladder cancers that have not reached the muscle, including when BCG is needed and when to remove the bladder.","summary":"Evidence-based guideline from the European Association of Urology covering diagnosis, transurethral resection, re-resection, risk stratification, intravesical chemotherapy and BCG, management of BCG failure, and follow-up for non-muscle-invasive bladder cancer.\n\nIt introduces the 2021 EAU risk groups with a very-high-risk category for which early radical cystectomy is recommended, and defines BCG-unresponsive disease for trial and treatment purposes.","asOf":"2026-09-17","links":[{"label":"Eur Urol 2022","url":"https://doi.org/10.1016/j.eururo.2021.08.010"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34511303/"}],"tags":[],"related":[],"cancers":["non-muscle-invasive-bladder-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["european-urology"],"dependsOn":[],"notes":[],"journal":"European Urology","year":2022,"doi":"10.1016/j.eururo.2021.08.010","pmid":"34511303","authors":"Babjuk M, Burger M, Capoun O, et al.","paperType":"guideline","findings":[],"whatItMeans":"Most of the decisions on a non-muscle-invasive bladder cancer page (single instillation, BCG maintenance, early cystectomy, bladder-sparing trials) follow this guideline or its American counterpart.","caveats":["Updated yearly; check the current edition for the latest recommendations on new bladder-sparing agents."],"changedPractice":true},{"id":"paper-eln-2020-cml-hochhaus-leukemia-2020","kind":"paper","name":"European LeukemiaNet 2020 recommendations for treating chronic myeloid leukaemia","aka":[],"tldr":"The 2020 European LeukemiaNet recommendations set the response milestones for kinase inhibitor therapy in chronic myeloid leukaemia, when to switch drugs, and how to manage accelerated and blast phase, including transplant.","summary":"Consensus recommendations covering diagnosis, risk scoring (ELTS), first-line and later-line tyrosine kinase inhibitors, molecular response milestones, treatment-free remission, and the management of advanced-phase disease with kinase inhibitors, chemotherapy and allogeneic transplantation.","asOf":"2026-09-17","links":[{"label":"Leukemia 2020","url":"https://doi.org/10.1038/s41375-020-0776-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32127639/"}],"tags":[],"related":[],"cancers":["cml-advanced-phase"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["leukemia"],"dependsOn":[],"notes":[],"journal":"Leukemia","year":2020,"doi":"10.1038/s41375-020-0776-2","pmid":"32127639","authors":"Hochhaus A, Baccarani M, Silver RT, et al.","paperType":"guideline","findings":[],"whatItMeans":"Whether a patient is on track at three, six and twelve months, and when a change of drug or a transplant referral is warranted, is judged against these milestones.","caveats":["Asciminib and later ponatinib dose data postdate the document."],"changedPractice":true},{"id":"paper-eln-apl-sanz-blood-2019","kind":"paper","name":"European LeukemiaNet recommendations for the management of acute promyelocytic leukaemia (2019 update)","aka":[],"tldr":"The expert panel guidance on acute promyelocytic leukaemia covers the emergency first hours, the choice between arsenic-based and chemotherapy-based regimens by risk, differentiation syndrome, and molecular monitoring.","summary":"Updated recommendations from a European LeukemiaNet expert panel on diagnosis, supportive care for coagulopathy, risk-adapted treatment with all-trans retinoic acid and arsenic trioxide or chemotherapy, management of differentiation syndrome, molecular monitoring and treatment of relapse.","asOf":"2026-09-17","links":[{"label":"Blood 2019","url":"https://doi.org/10.1182/blood-2019-01-894980"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30803991/"}],"tags":[],"related":[],"cancers":["apl"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2019,"doi":"10.1182/blood-2019-01-894980","pmid":"30803991","authors":"Sanz MA, Sanz MA, Fenaux P, et al.","paperType":"guideline","findings":[],"whatItMeans":"Starting retinoic acid on morphological suspicion, aggressive blood product support and arsenic-based induction for non-high-risk disease all follow from this document.","caveats":["Oral arsenic and gemtuzumab-based regimens for high-risk disease have evolved since publication."],"changedPractice":true},{"id":"paper-ev-302-nejm-2024","kind":"paper","name":"EV-302: enfortumab vedotin plus pembrolizumab replaces chemotherapy as first treatment for advanced bladder cancer","aka":[],"tldr":"Combining the Nectin-4 antibody-drug conjugate enfortumab vedotin with pembrolizumab nearly doubled survival compared with platinum chemotherapy in advanced urothelial cancer, the biggest advance in this disease in 40 years.","summary":"Open-label phase 3 trial of 886 patients with untreated locally advanced or metastatic urothelial carcinoma, eligible for cisplatin or carboplatin, randomised to enfortumab vedotin plus pembrolizumab or gemcitabine plus platinum. Dual primary endpoints were PFS by blinded review and OS.\n\nMedian PFS was 12.5 vs 6.3 months (HR 0.45) and median OS 31.5 vs 16.1 months (HR 0.47), with benefit regardless of cisplatin eligibility or PD-L1 expression. It displaced platinum chemotherapy as first-line standard of care, the first regimen to do so since the 1980s, and is the first ADC plus checkpoint inhibitor combination to become a first-line standard in any cancer.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2312117"},{"label":"ClinicalTrials.gov NCT04223856","url":"https://clinicaltrials.gov/study/NCT04223856"}],"tags":[],"related":[],"cancers":["urothelial"],"sections":[],"technologies":["adc","checkpoint-inhibitor"],"targets":["nectin4","pd1"],"drugs":["enfortumab-vedotin","pembrolizumab"],"companies":["astellas","pfizer","merck"],"institutions":[],"pathways":[],"terms":["pfs","os","orr","first-line","standard-of-care","payload"],"trials":["ev-302"],"people":["shilpa-gupta","shin-sang-joon"],"bottlenecks":["b-combination-space","b-drug-pricing","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2312117","authors":"Powles T, Valderrama BP, Gupta S, et al.","paperType":"rct","findings":["Median PFS 12.5 vs 6.3 months; HR 0.45 (95% CI 0.38-0.54).","Median overall survival 31.5 vs 16.1 months; HR 0.47 (95% CI 0.38-0.58).","Objective response 67.7% vs 44.4%; complete response 29.1% vs 12.5%.","Benefit consistent in cisplatin-eligible and -ineligible patients and in PD-L1 high and low tumours.","Grade 3 or higher treatment-related adverse events 55.9% vs 69.5%; skin reactions, peripheral neuropathy and hyperglycaemia were the characteristic toxicities of enfortumab vedotin."],"whatItMeans":"Almost every patient newly diagnosed with advanced bladder or urothelial cancer should now be offered enfortumab vedotin plus pembrolizumab rather than chemotherapy, with median survival extended from about 16 months to over two and a half years. Neuropathy and skin toxicity need monitoring and dose adjustment, and patients with severe diabetes or pre-existing neuropathy need care. Platinum chemotherapy remains an option for those who cannot receive the combination.","caveats":["Open-label; PFS by blinded review.","Only about 30% of chemotherapy patients received maintenance avelumab, which is standard, so the control arm may have underperformed.","Peripheral neuropathy is cumulative and often persistent, affecting quality of life in long survivors.","Very high cost; access outside high-income countries is limited."],"changedPractice":true,"participants":886},{"id":"paper-exam-cabozantinib-mtc-elisei-jco-2013","kind":"paper","name":"EXAM: cabozantinib in progressive medullary thyroid cancer","aka":[],"tldr":"Cabozantinib, a kinase inhibitor blocking RET, MET and VEGF receptors, delayed progression by more than seven months compared with placebo in progressive medullary thyroid cancer, at the cost of considerable toxicity.","summary":"Phase 3 placebo-controlled trial of 330 patients with progressive metastatic medullary thyroid cancer randomised 2:1 to cabozantinib 140 mg daily or placebo.\n\nMedian progression-free survival was 11.2 versus 4.0 months (hazard ratio 0.28) and response 28 versus 0 percent, with benefit regardless of RET status; diarrhoea, hand-foot syndrome, weight loss and fistula were notable toxicities.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2013","url":"https://doi.org/10.1200/JCO.2012.48.4659"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24002501/"}],"tags":[],"related":[],"cancers":["medullary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["cabozantinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["exam"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2013,"doi":"10.1200/JCO.2012.48.4659","pmid":"24002501","authors":"Elisei R, Schlumberger MJ, Müller SP, et al.","paperType":"rct","findings":["Median progression-free survival 11.2 vs 4.0 months; hazard ratio 0.28.","Objective response 28 percent vs 0 percent."],"whatItMeans":"Cabozantinib is an option for progressive medullary thyroid cancer, now mainly for RET-negative disease or after selpercatinib.","caveats":["No overall survival benefit overall, though RET M918T carriers may have benefited.","High dose with frequent reductions."],"changedPractice":true,"participants":330},{"id":"paper-extreme-vermorken-nejm-2008","kind":"paper","name":"EXTREME: platinum-based chemotherapy plus cetuximab in recurrent or metastatic head and neck cancer","aka":[],"tldr":"Adding cetuximab to platinum and fluorouracil lengthened survival in recurrent or metastatic head and neck cancer from 7.4 to 10.1 months, the first improvement in first-line treatment in decades.","summary":"Phase 3 trial of 442 patients with untreated recurrent or metastatic head and neck squamous cell carcinoma randomised to cisplatin or carboplatin plus fluorouracil for up to six cycles, with or without cetuximab continued as maintenance.\n\nMedian overall survival was 10.1 versus 7.4 months (hazard ratio 0.80), progression-free survival 5.6 versus 3.3 months and response 36 versus 20 percent, with skin reactions and infusion reactions as the added toxicities.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2008","url":"https://doi.org/10.1056/NEJMoa0802656"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/18784101/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-hnscc"],"sections":[],"technologies":[],"targets":[],"drugs":["cetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["extreme"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2008,"doi":"10.1056/NEJMoa0802656","pmid":"18784101","authors":"Vermorken JB, Mesia R, Rivera F, et al.","paperType":"rct","findings":["Median overall survival 10.1 vs 7.4 months; hazard ratio 0.80.","Objective response 36 percent vs 20 percent."],"whatItMeans":"EXTREME was the first-line standard for a decade and remains the option for patients unsuitable for pembrolizumab; it was the comparator that KEYNOTE-048 improved upon.","caveats":["Fluorouracil infusion is burdensome; TPExtreme showed docetaxel can replace it."],"changedPractice":true,"participants":442},{"id":"paper-drug-dosing-conundrum-nejm-2021","kind":"paper","name":"FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high","aka":[],"tldr":"FDA oncology leaders argued that the maximum tolerated dose paradigm inherited from chemotherapy produces targeted drugs and immunotherapies dosed far above what is needed, using sotorasib (960 mg vs 240 mg) as the case study, and launched Project Optimus to require dose optimisation before approval.","summary":"This NEJM perspective from the FDA Oncology Center of Excellence set out why oncology dose selection had to change. Phase 1 trials find the maximum tolerated dose over one cycle, a rational approach for cytotoxics but not for targeted agents and immunotherapies whose effects plateau at lower exposures and whose chronic, low-grade toxicity drives discontinuation.\n\nThe authors cited sotorasib, approved at 960 mg daily although early data showed similar exposure and activity at 240 mg; the FDA required a randomised post-marketing comparison of the two doses, which did not establish the lower dose as equivalent and left the label at 960 mg. Other examples included post-approval dose reductions of cabozantinib, niraparib, ceritinib and dasatinib.\n\nProject Optimus, launched the same year, now expects sponsors to compare more than one dose before pivotal trials; FDA's 2024 guidance on dose optimisation formalised this.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMp2109826"},{"label":"FDA Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"}],"tags":[],"related":["idea-tr1-randomised-dose-comparison-before-pivotal","idea-tr1-exposure-response-before-dose-selection","idea-moon-post-approval-dose-deescalation","idea-reg-global-dose-optimisation-guideline"],"cancers":[],"sections":["targeted-therapy"],"technologies":["kinase-inhibitors"],"targets":["kras"],"drugs":["sotorasib","niraparib"],"companies":[],"institutions":[],"pathways":[],"terms":["project-optimus","accelerated-approval"],"trials":[],"people":[],"bottlenecks":["b-dose-optimisation","b-toxicity-qol","b-regulatory-fragmentation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMp2109826","pmid":"34623788","authors":"Shah M, Rahman A, Theoret MR, Pazdur R","paperType":"review","findings":["Most targeted agents and immunotherapies have flat exposure-response relationships above a threshold, so the MTD is rarely the optimal dose","Sotorasib: 960 mg chosen despite comparable early activity at 240 mg; a randomised dose comparison was required as a post-marketing commitment","Multiple approved drugs (for example niraparib, cabozantinib, ceritinib, dasatinib) had labelled doses lowered after approval because of toxicity","Proposal: randomised comparison of at least two doses, with patient-reported tolerability, before registrational trials"],"whatItMeans":"The dose on the label is often not the best dose for patients; it is the highest one that was tolerable for a few weeks. Project Optimus means new cancer drugs should arrive with evidence on dose, and it gives clinicians licence to consider dose reduction for toxicity. For older drugs, the evidence gap persists.","caveats":["A perspective rather than a trial; the regulatory shift adds cost and time to development that smaller sponsors resist","Lower doses could under-treat if exposure-response is misjudged; dose comparisons need adequate power","Post-marketing dose studies are slow and often inconclusive, as sotorasib showed","Global regulators have not fully harmonised on dose-optimisation expectations"],"changedPractice":true},{"id":"paper-ferlay-globocan-2012-methods-ijc-2015","kind":"paper","name":"Ferlay 2015: sources, methods and major patterns in GLOBOCAN 2012","aka":[],"tldr":"The methods paper behind the 2012 world cancer estimates, explaining how IARC builds country figures from registries of very different quality, and reporting about 14.1 million new cases and 32.6 million people living within five years of a diagnosis.","summary":"Ferlay and colleagues at IARC described how GLOBOCAN 2012 estimated incidence, mortality and five-year prevalence for 27 cancers in 184 countries. They set out the hierarchy of methods used according to the data available, from national registries with high coverage to modelling from neighbouring countries, and summarised the results: about 14.1 million new cases, 8.2 million deaths and 32.6 million people alive within five years of diagnosis in 2012, with lung, breast and colorectal cancers the most common. The paper is the one to cite for how GLOBOCAN numbers are made and how uncertain they are by country.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1002/ijc.29210"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-torre-global-cancer-statistics-2012-cacancer-2015"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"International Journal of Cancer","year":2015,"doi":"10.1002/ijc.29210","authors":"Ferlay J, Soerjomataram I, Dikshit R, et al.","paperType":"methods","findings":["About 14.1 million new cases, 8.2 million deaths and 32.6 million five-year prevalent cases worldwide in 2012.","Country estimates follow a hierarchy of methods depending on registry coverage and mortality data quality.","Lung, breast and colorectal cancers were the most common; lung, liver and stomach cancers the leading causes of death."],"whatItMeans":"Anyone using GLOBOCAN numbers should know how they are produced; this paper explains the method hierarchy and why figures for countries without good registries carry wide uncertainty.","caveats":["Methods differ by country, so cross-country comparisons mix data of very different quality.","Superseded by the 2018, 2020 and 2022 methods papers."],"changedPractice":false},{"id":"paper-ferlay-globocan-2018-methods-ijc-2019","kind":"paper","name":"Ferlay 2019: GLOBOCAN 2018 sources and methods","aka":[],"tldr":"The methods paper for the 2018 world cancer estimates, describing the registry and mortality data behind the figure of about 18.1 million new cases in 185 countries and how countries without good data were handled.","summary":"Ferlay and colleagues documented the sources and methods for GLOBOCAN 2018, which estimated incidence and mortality for 36 cancers in 185 countries. They described the data available for each country, the methods applied according to data quality and coverage, and the summary results of about 18.1 million new cases and 9.6 million deaths in 2018. The paper accompanies the headline report by Bray and colleagues and is the reference for the quality of the national estimates.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1002/ijc.31937"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-bray-globocan-2018-cacancer-2018"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"International Journal of Cancer","year":2019,"doi":"10.1002/ijc.31937","authors":"Ferlay J, Colombet M, Soerjomataram I, et al.","paperType":"methods","findings":["About 18.1 million new cancer cases and 9.6 million cancer deaths in 2018 across 185 countries and 36 cancers.","Methods for each country were chosen according to the availability and quality of registry and vital statistics data.","A companion to the headline GLOBOCAN 2018 report."],"whatItMeans":"This paper is the place to check how solid a given country's GLOBOCAN 2018 figure is, which matters when the numbers are used to argue for national cancer plans.","caveats":["Estimates for countries without population-based registries rely on modelling from neighbours.","Superseded by the 2020 and 2022 releases."],"changedPractice":false},{"id":"paper-ferlay-cancer-statistics-2020-overview-ijc-2021","kind":"paper","name":"Ferlay 2021: cancer statistics for the year 2020, an overview","aka":[],"tldr":"IARC's overview of the 2020 world cancer estimates, about 19.3 million new cases, presented by cancer type, sex and world region, alongside the methods and data used and a note that the figures predate the effects of the pandemic.","summary":"Ferlay and colleagues presented an overview of GLOBOCAN 2020: the sources and methods for estimating incidence and mortality for 36 cancers in 185 countries and the main patterns by cancer, sex and region. They reported about 19.3 million new cases and about 10 million deaths in 2020, with female breast cancer the most commonly diagnosed cancer and lung cancer the leading cause of death, and they noted that the estimates reflect pre-pandemic trends because registry data lag by several years.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1002/ijc.33588"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-sung-globocan-2020-cacancer-2021"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"International Journal of Cancer","year":2021,"doi":"10.1002/ijc.33588","authors":"Ferlay J, Colombet M, Soerjomataram I, et al.","paperType":"observational","findings":["About 19.3 million new cases and about 10 million cancer deaths worldwide in 2020.","Female breast cancer the most diagnosed cancer; lung cancer the leading cause of cancer death.","Estimates rest on registry data from earlier years and do not capture pandemic disruption to diagnosis."],"whatItMeans":"This is the methods and overview companion to the widely cited Sung 2021 report and the reference for how the 2020 figures were built.","caveats":["Modelled estimates for countries with limited registries.","Superseded by GLOBOCAN 2022."],"changedPractice":false},{"id":"paper-doll-peto-50-year-doctors-bmj-2004","kind":"paper","name":"Fifty years of the British Doctors Study: smokers lose ten years of life, quitting gives most of it back","aka":[],"tldr":"After following 34,439 male doctors for 50 years, lifelong smokers died on average about 10 years earlier than never-smokers, and stopping at 60, 50, 40 or 30 recovered about 3, 6, 9 or the full 10 years.","summary":"The British Doctors Study began in 1951 with questionnaires to male doctors and followed them for mortality until 2001, with periodic resurveys of smoking habits. This 50-year report used the full cohort of 34,439 men.\n\nMen born around 1920 who continued to smoke had about twice the death rate in middle age of never-smokers and lost about 10 years of life expectancy. The excess was largest for lung cancer, chronic obstructive lung disease and vascular disease. Cessation at age 60, 50, 40 or 30 gained about 3, 6, 9 or 10 years of life expectancy respectively.\n\nThe study, together with the 1954 and 1956 reports, was the foundation of tobacco control worldwide.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1136/bmj.38142.554479.AE"}],"tags":[],"related":["paper-doll-hill-smoking-lung-cancer-bmj-1950","idea-prev-opt-out-cessation-in-lung-screening","idea-prev-smokefree-generation-evaluation"],"cancers":["nsclc","sclc","head-and-neck","esophageal","urothelial","pancreatic"],"sections":["prevention"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-incentive-misalignment"],"keyPapers":[],"journals":["bmj"],"dependsOn":[],"notes":[],"journal":"BMJ","year":2004,"doi":"10.1136/bmj.38142.554479.AE","pmid":"15213107","authors":"Doll R, Peto R, Boreham J, Sutherland I","paperType":"observational","findings":["Lifelong cigarette smokers lost about 10 years of life expectancy compared with never-smokers","Stopping at 60, 50, 40 or 30 gained about 3, 6, 9 or 10 years respectively","Probability of dying in middle age (35-69) was about 43% for smokers vs 15% for non-smokers in the 1920 birth cohort","Lung cancer mortality rose with cigarettes per day and fell steadily after cessation"],"whatItMeans":"Smoking is the single largest preventable cause of cancer death, and quitting at any age helps, with the greatest gain from quitting young. Cessation support belongs in every cancer service, including lung screening programmes.","caveats":["Male British doctors only, a homogeneous and affluent group; absolute risks differ in other populations","Historical cohort smoking high-tar cigarettes from youth; modern patterns differ","Cessation effects are observational and subject to healthy-quitter bias","Does not address e-cigarettes or smokeless products"],"changedPractice":true,"participants":34439},{"id":"paper-fight-202-pemigatinib-lancet-oncol-2020","kind":"paper","name":"FIGHT-202: pemigatinib for previously treated cholangiocarcinoma with FGFR2 fusions or rearrangements","aka":[],"tldr":"The FGFR inhibitor pemigatinib shrank tumours in more than a third of patients with previously treated intrahepatic cholangiocarcinoma carrying FGFR2 fusions, the first targeted drug approved for the disease.","summary":"Phase 2 study of 146 patients with previously treated locally advanced or metastatic cholangiocarcinoma, including 107 with FGFR2 fusions or rearrangements, treated with pemigatinib 13.5 mg daily on a two-weeks-on, one-week-off schedule.\n\nIn FGFR2-rearranged patients objective response was 35.5 percent with median duration of response 7.5 months and median progression-free survival 6.9 months; no responses were seen in patients with other FGF/FGFR alterations. Hyperphosphataemia was almost universal.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2020","url":"https://doi.org/10.1016/S1470-2045(20)30109-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32203698/"}],"tags":[],"related":[],"cancers":["intrahepatic-cholangiocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["pemigatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["fight-202"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2020,"doi":"10.1016/S1470-2045(20)30109-1","pmid":"32203698","authors":"Abou-Alfa GK, Sahai V, Hollebecque A, et al.","paperType":"observational","findings":["Objective response 35.5 percent in FGFR2-rearranged cholangiocarcinoma.","Median progression-free survival 6.9 months; median overall survival 21.1 months."],"whatItMeans":"FGFR2 fusion testing is standard in intrahepatic cholangiocarcinoma, and pemigatinib (with futibatinib) is the second-line targeted option for fusion-positive disease.","caveats":["Single-arm; the confirmatory first-line trial (FIGHT-302) is ongoing.","Hyperphosphataemia, eye toxicity and nail changes require monitoring."],"changedPractice":true,"participants":146},{"id":"paper-druker-imatinib-phase1-nejm-2001","kind":"paper","name":"First imatinib trial: a pill that switched off the enzyme driving chronic myeloid leukaemia","aka":[],"tldr":"In the first human study of imatinib, almost every patient with chronic-phase CML who had failed interferon regained normal blood counts, with mild side effects.","summary":"Phase 1 dose-escalation study of the ABL kinase inhibitor STI571 (imatinib) in 83 patients with chronic-phase CML in whom interferon alfa had failed. Doses of 25 to 1000 mg daily were tested and no maximum tolerated dose was reached. At 300 mg or more, complete haematological responses occurred in 53 of 54 patients, usually within four weeks, and cytogenetic responses in 29 of 54 (17 major). It was the first demonstration that a small molecule designed against a defined oncogenic kinase could control a human cancer, and became the template for targeted therapy.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJM200104053441401"}],"tags":[],"related":["paper-iris-imatinib-nejm-2003"],"cancers":["cml"],"sections":[],"technologies":[],"targets":["bcr-abl"],"drugs":["imatinib"],"companies":["novartis"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-translational-valley"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2001,"doi":"10.1056/NEJM200104053441401","authors":"Druker BJ, Talpaz M, Resta DJ, et al.","paperType":"translational","findings":["83 patients with interferon-refractory chronic-phase CML; doses 25-1000 mg/day; no dose-limiting toxicity identified.","Complete haematological response in 53 of 54 patients treated at 300 mg/day or more, typically within 4 weeks.","Cytogenetic responses in 29 of 54 patients at 300 mg or more, 17 of them major (0-35% Ph-positive metaphases).","Adverse events were mostly grade 1-2: nausea, myalgia, oedema and diarrhoea."],"whatItMeans":"Druker's 2001 imatinib paper turned the idea of hitting a cancer's specific molecular engine into a working medicine. For people with CML it began the shift from a fatal disease treated with interferon or transplant to one managed with a daily tablet. It also set expectations, later tempered, that every cancer might have its own imatinib.","caveats":["Single-arm phase 1 with short follow-up and no survival data.","Responses were haematological and cytogenetic; molecular monitoring came later.","CML is unusually dependent on a single fusion kinase, which limits how far the model generalises."],"changedPractice":true,"participants":83},{"id":"paper-lynch-frameshift-vaccine-ccr-2020","kind":"paper","name":"First trial of a vaccine against the shared neoantigens of mismatch-repair-deficient cancers","aka":[],"tldr":"A vaccine of three frameshift peptides shared by almost all microsatellite-unstable tumours was safe and induced immune responses in every patient with MSI colorectal cancer, opening the path to cancer interception vaccines for Lynch syndrome.","summary":"Mismatch-repair-deficient tumours accumulate insertion or deletion mutations in the same coding microsatellites, producing frameshift peptide (FSP) neoantigens that are shared across patients. This phase I/IIa trial vaccinated 22 patients with a history of MSI-high colorectal cancer with three FSP neoantigens (derived from AIM2, HT001 and TAF1B) with Montanide adjuvant.\n\nThe vaccine was well tolerated (injection-site reactions only) and induced humoral and cellular immune responses in all patients who completed the schedule. The study established that shared frameshift neoantigens are immunogenic in humans and are candidates for an off-the-shelf preventive vaccine in Lynch syndrome carriers.\n\nIt seeded the Nous-209 adenoviral vaccine (209 frameshift neoantigens) now in trials in Lynch carriers, and the NCI's Lynch interception programme.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1158/1078-0432.CCR-19-3517"},{"label":"ClinicalTrials.gov NCT05078866","url":"https://clinicaltrials.gov/study/NCT05078866"}],"tags":[],"related":["idea-interception-vaccines","idea-moon-lynch-vaccine-phase3","idea-prev-lynch-frameshift-vaccine-rct"],"cancers":["colorectal","endometrial"],"sections":["prevention","immunotherapy"],"technologies":["interception-vaccination","shared-antigen-vaccine"],"targets":[],"drugs":[],"companies":[],"institutions":["heidelberg-nct","dkfz"],"pathways":[],"terms":["lynch-syndrome","msi","neoantigen"],"trials":[],"people":[],"bottlenecks":["b-hereditary-risk","b-prevention-adoption","b-trial-design"],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2020,"doi":"10.1158/1078-0432.CCR-19-3517","pmid":"32332013","authors":"Kloor M, Reuschenbach M, Pauligk C, et al.","paperType":"translational","findings":["22 patients enrolled; no vaccine-related serious adverse events","Humoral and cellular responses to at least one frameshift peptide in all patients who completed the three-vaccination schedule","Frameshift neoantigens targeted are present in the majority of MSI-high colorectal cancers regardless of patient","The paper provided human proof of principle for a shared-antigen interception vaccine"],"whatItMeans":"Because Lynch syndrome tumours make the same abnormal proteins in almost every patient, a single vaccine could in principle be given to carriers before cancer develops. This small trial showed the concept is safe and immunogenic; whether it prevents cancer requires the randomised trials now being planned.","caveats":["Immune response, not cancer prevention, was the endpoint","Patients had existing or prior cancers, not healthy carriers","Peptide vaccines with Montanide elicit modest T-cell responses compared with viral-vector or mRNA platforms","Efficacy trials in carriers need thousands of participants and years of follow-up"],"changedPractice":false,"participants":22},{"id":"paper-kroep-mpnst-first-line-chemotherapy-ann-oncol-2011","kind":"paper","name":"First-line chemotherapy for malignant peripheral nerve sheath tumour versus other soft tissue sarcomas (EORTC pooled analysis)","aka":[],"tldr":"Pooling twelve EORTC trials showed that malignant peripheral nerve sheath tumours respond to doxorubicin-ifosfamide about as well as other sarcomas, though survival is shorter, and that NF1-associated tumours may respond less.","summary":"Retrospective analysis of 175 patients with malignant peripheral nerve sheath tumour among 2,675 soft tissue sarcoma patients treated with first-line anthracycline-based chemotherapy in EORTC trials.\n\nResponse rate was 21 percent in MPNST compared with 22 percent in other sarcomas, with the highest response to doxorubicin-ifosfamide; median overall survival was 48 weeks against 51 weeks, and NF1-associated tumours tended to respond less.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2011","url":"https://doi.org/10.1093/annonc/mdq338"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20656792/"}],"tags":[],"related":[],"cancers":["malignant-peripheral-nerve-sheath-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2011,"doi":"10.1093/annonc/mdq338","pmid":"20656792","authors":"Kroep JR, Ouali M, Gelderblom H, et al.","paperType":"observational","findings":["Objective response 21 percent in MPNST vs 22 percent in other sarcomas.","Median overall survival 48 weeks; lower response in NF1-associated MPNST."],"whatItMeans":"Doxorubicin-ifosfamide is the standard first-line chemotherapy for advanced MPNST, and the analysis supports treating it like other high-grade sarcomas while recognising its poorer prognosis.","caveats":["Retrospective pooled analysis across trials spanning decades."],"changedPractice":true,"participants":175},{"id":"paper-fitzmaurice-gbd-cancer-2015-jamaoncol-2017","kind":"paper","name":"Fitzmaurice 2017: the Global Burden of Disease estimate of cancer in 2015","aka":[],"tldr":"The Global Burden of Disease collaboration's count for 2015: about 17.5 million new cancer cases worldwide, with cases rising by a third over the previous decade mostly because populations were growing and ageing, and lung cancer the largest cause of years of life lost to cancer.","summary":"The Global Burden of Disease Cancer Collaboration estimated incidence, mortality, years of life lost, years lived with disability and disability-adjusted life-years for 32 cancer groups in 195 countries for 2015 and the trend since 2005. It counted about 17.5 million cases and 8.7 million deaths. Cases increased by 33% between 2005 and 2015, of which most was attributable to population ageing and growth rather than to rising age-specific rates. Tracheal, bronchus and lung cancer was the leading cause of cancer disability-adjusted life-years globally.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1001/jamaoncol.2016.5688"},{"label":"GBD results tool","url":"https://vizhub.healthdata.org/gbd-results/"}],"tags":[],"related":["paper-bray-globocan-2018-cacancer-2018","paper-sung-globocan-2020-cacancer-2021"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2017,"doi":"10.1001/jamaoncol.2016.5688","authors":"Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Allen C, et al.","paperType":"observational","findings":["About 17.5 million cancer cases and 8.7 million cancer deaths worldwide in 2015.","Cases rose 33% from 2005 to 2015: about 16% from population ageing, 13% from population growth and 4% from changing age-specific rates.","Lung cancer was the leading cause of cancer disability-adjusted life-years; cancer was the second leading cause of death worldwide."],"whatItMeans":"GBD is the other major global cancer count alongside GLOBOCAN, using different methods, and its burden measures in years of life lost make the case that cancer control is largely a problem of ageing populations in middle-income countries.","caveats":["Modelled estimates with wide uncertainty where registry data are sparse.","GBD and GLOBOCAN figures differ because of methods, so they should not be mixed in one comparison."],"changedPractice":false},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","aka":[],"tldr":"Starting with the third-generation EGFR drug osimertinib, rather than saving it for later, kept EGFR-mutated lung cancer under control for almost twice as long and later helped patients live longer.","summary":"Double-blind phase 3 trial of 556 patients with untreated advanced non-small-cell lung cancer carrying an EGFR exon 19 deletion or L858R mutation, randomised to osimertinib or a first-generation EGFR inhibitor (gefitinib or erlotinib). Primary endpoint was investigator-assessed PFS.\n\nMedian PFS was 18.9 vs 10.2 months (HR 0.46), with fewer central nervous system progressions and less grade 3 toxicity. The 2020 overall survival report showed 38.6 vs 31.8 months (HR 0.80) despite crossover. It made osimertinib the global first-line standard and the backbone on which FLAURA2 and MARIPOSA later built.","asOf":"2026-09-08","links":[{"label":"NEJM 2018","url":"https://doi.org/10.1056/NEJMoa1713137"},{"label":"NEJM 2020 (OS)","url":"https://doi.org/10.1056/NEJMoa1913662"},{"label":"ClinicalTrials.gov NCT02296125","url":"https://clinicaltrials.gov/study/NCT02296125"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors","cgp"],"targets":["egfr"],"drugs":["osimertinib"],"companies":["astrazeneca"],"institutions":["gustave-roussy"],"pathways":[],"terms":["oncogene-addiction","resistance","pfs","os","first-line"],"trials":["flaura2","mariposa","adaura"],"people":["jean-charles-soria","ohe-yuichiro","zhou-caicun","cho-byoung-chul"],"bottlenecks":["b-resistance","b-brain-delivery","b-global-access"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1713137","authors":"Soria JC, Ohe Y, Vansteenkiste J, et al.","paperType":"rct","findings":["Median PFS 18.9 vs 10.2 months; HR 0.46 (95% CI 0.37-0.57).","CNS progression events were roughly halved with osimertinib.","Grade 3 or higher adverse events 34% vs 45%.","Overall survival (2020): median 38.6 vs 31.8 months, HR 0.80 (95% CI 0.64-1.00), with about 31% of control patients crossing over to osimertinib.","FLAURA2 (2023) later showed adding platinum-pemetrexed to osimertinib extends PFS further (25.5 vs 16.7 months, HR 0.62)."],"whatItMeans":"Anyone diagnosed with advanced lung cancer should have EGFR testing before treatment, because osimertinib as the first drug gives the longest disease control, protects the brain, and is well tolerated. Chemotherapy is not the first step for these patients. The remaining questions are whether to intensify upfront (adding chemotherapy or amivantamab) and how to treat resistance when it develops.","caveats":["The overall survival benefit was borderline (upper confidence limit 1.00) and diluted by crossover to osimertinib.","Asian patients and those with L858R had smaller OS gains in subgroup analyses.","Resistance is universal; the trial did not address what to do after osimertinib.","High drug cost limits access in many countries where EGFR mutations are common."],"changedPractice":true,"participants":556},{"id":"paper-flot4-lancet-2019","kind":"paper","name":"FLOT4-AIO: perioperative FLOT versus ECF/ECX for resectable gastric or gastro-oesophageal junction adenocarcinoma","aka":[],"tldr":"Perioperative chemotherapy with docetaxel, oxaliplatin, fluorouracil and leucovorin (FLOT) lengthened survival compared with the older anthracycline-based regimen in operable stomach and junctional cancers, making FLOT the standard in Europe.","summary":"Phase 2/3 trial of 716 patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (stage cT2 or higher or node-positive) randomised to perioperative FLOT (four cycles before and after surgery) or ECF/ECX (three cycles before and after).\n\nMedian overall survival was 50 versus 35 months (hazard ratio 0.77), five-year survival 45 versus 36 percent, and complete resection rates were higher with FLOT; toxicity profiles differed but were manageable.","asOf":"2026-09-17","links":[{"label":"Lancet 2019","url":"https://doi.org/10.1016/S0140-6736(18)32557-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30982686/"}],"tags":[],"related":[],"cancers":["oesophageal-adenocarcinoma","gastric-pdl1-high","gastric-her2-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["capecitabine","cisplatin","docetaxel","epirubicin","oxaliplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["flot4"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2019,"doi":"10.1016/S0140-6736(18)32557-1","pmid":"30982686","authors":"Al-Batran SE, Homann N, Pauligk C, et al.","paperType":"rct","findings":["Median overall survival 50 vs 35 months; hazard ratio 0.77.","Five-year overall survival 45 percent vs 36 percent."],"whatItMeans":"FLOT is the reference perioperative regimen for gastric and junctional adenocarcinoma, and the backbone onto which durvalumab was added in MATTERHORN.","caveats":["Only about half of patients completed postoperative chemotherapy.","Not compared with CROSS chemoradiotherapy for oesophageal adenocarcinoma until ESOPEC."],"changedPractice":true,"participants":716},{"id":"paper-jones-arid1a-clear-cell-science-2010","kind":"paper","name":"Frequent mutations of the chromatin remodelling gene ARID1A in ovarian clear cell carcinoma","aka":[],"tldr":"Published alongside the parallel New England Journal study, this exome sequencing project independently found ARID1A mutations in more than half of ovarian clear cell carcinomas, cementing the gene as the tumour's most common driver.","summary":"Exome sequencing of eight ovarian clear cell carcinomas followed by validation in 42 additional tumours, identifying ARID1A mutations in 57 percent along with PIK3CA, KRAS and PPP2R1A mutations.","asOf":"2026-09-17","links":[{"label":"Science 2010","url":"https://doi.org/10.1126/science.1196333"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20826764/"}],"tags":[],"related":[],"cancers":["clear-cell-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2010,"doi":"10.1126/science.1196333","pmid":"20826764","authors":"Jones S, Wang TL, Shih IeM, et al.","paperType":"translational","findings":["ARID1A mutations in 57 percent of ovarian clear cell carcinomas.","PPP2R1A mutations identified as a novel recurrent alteration."],"whatItMeans":"Together with the Wiegand study, this defined clear cell ovarian cancer as a chromatin remodelling-driven disease distinct from high-grade serous cancer.","caveats":["Small discovery cohort."],"changedPractice":true},{"id":"paper-hirota-kit-gist-science-1998","kind":"paper","name":"Gain-of-function mutations of c-kit in human gastrointestinal stromal tumours","aka":[],"tldr":"This discovery that gastrointestinal stromal tumours carry activating mutations in the KIT receptor, and express KIT protein, defined the disease and provided the target for imatinib three years later.","summary":"Study showing KIT expression in gastrointestinal stromal tumours, identifying gain-of-function mutations in the KIT juxtamembrane domain (exon 11) in five of six tumours analysed, and demonstrating that the mutant receptors are constitutively activated and transforming, with interstitial cells of Cajal as the likely cell of origin.","asOf":"2026-09-17","links":[{"label":"Science 1998","url":"https://doi.org/10.1126/science.279.5350.577"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/9438854/"}],"tags":[],"related":[],"cancers":["gist-kit-exon-11"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":1998,"doi":"10.1126/science.279.5350.577","pmid":"9438854","authors":"Hirota S, Isozaki K, Moriyama Y, et al.","paperType":"basic","findings":["Activating KIT juxtamembrane domain mutations in five of six GISTs.","KIT protein expression as a diagnostic marker."],"whatItMeans":"KIT immunohistochemistry and mutation testing define GIST, and the exon 11 mutations described here are the ones most sensitive to imatinib.","caveats":["Small discovery series; PDGFRA mutations in KIT-negative GIST were found later."],"changedPractice":true},{"id":"paper-galaxy-signatera-nat-med-2023","kind":"paper","name":"GALAXY: tumour DNA in blood four weeks after bowel cancer surgery predicts relapse tenfold","aka":[],"tldr":"In 1,039 Japanese patients with resected colorectal cancer, a positive Signatera test at week 4 carried a tenfold higher recurrence risk, and only ctDNA-positive patients appeared to benefit from adjuvant chemotherapy.","summary":"GALAXY is the prospective observational arm of the Japanese CIRCULATE platform. Patients with stage II-IV resectable colorectal cancer had serial tumour-informed ctDNA testing (Signatera) after surgery, with treatment at physician discretion.\n\nctDNA positivity at 4 weeks post-surgery was the strongest predictor of recurrence (HR about 10). Among ctDNA-positive patients, adjuvant chemotherapy was associated with markedly better disease-free survival (HR about 6.6 in favour of treatment), whereas ctDNA-negative patients showed no apparent benefit. Clearance of ctDNA during adjuvant therapy predicted good outcomes.\n\nThe study is the largest prospective MRD dataset in colorectal cancer and the basis for the randomised VEGA and ALTAIR trials.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1038/s41591-022-02115-4"}],"tags":[],"related":["paper-dynamic-nejm-2022","idea-ctdna-guided-adjuvant-crc","idea-tr2-ctdna-mrd-qualification"],"cancers":["colorectal"],"sections":["diagnostics"],"technologies":["mrd-testing","liquid-biopsy"],"targets":[],"drugs":["signatera"],"companies":[],"institutions":["ncc-japan"],"pathways":[],"terms":["mrd","ctdna","vaf"],"trials":[],"people":["yoshino-takayuki"],"bottlenecks":["b-dormancy-mrd","b-biomarker-validation","b-real-world-evidence"],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2023,"doi":"10.1038/s41591-022-02115-4","pmid":"36646802","authors":"Kotani D, Oki E, Nakamura Y, et al.","paperType":"observational","findings":["ctDNA positivity at week 4 associated with recurrence: HR 10.0 (95% CI 7.7-14.0)","18-month DFS 38.4% for ctDNA-positive vs 90.5% for ctDNA-negative patients","Adjuvant chemotherapy associated with improved DFS in ctDNA-positive patients (HR 6.59, 95% CI 3.53-12.3) but not in ctDNA-negative patients","ctDNA clearance by week 24 predicted substantially better DFS than persistent positivity"],"whatItMeans":"The blood test stratifies risk far better than stage or pathology. It supports treating ctDNA-positive patients and suggests ctDNA-negative patients gain little from chemotherapy, but because treatment was not randomised the de-escalation claim needs the randomised trials that are now under way.","caveats":["Observational; treatment decisions were not randomised, so the chemotherapy benefit estimate is confounded","Short follow-up at initial publication (median about 17 months)","Japanese population and Japanese adjuvant practice; generalisability to other health systems is untested","Commercial sponsor (Natera) involvement in assay and analysis"],"changedPractice":false,"participants":1039},{"id":"paper-galon-immune-contexture-colorectal-science-2006","kind":"paper","name":"Galon 2006: the type, density and location of immune cells in colorectal tumours predict outcome","aka":[],"tldr":"Counting the T cells inside a bowel cancer and at its edge predicted whether the cancer would return better than the traditional stage did, the discovery behind the Immunoscore test.","summary":"Galon and colleagues analysed immune cells in tumours from 415 patients with colorectal cancer using gene expression and tissue microarrays. A strong presence of adaptive immune cells, in particular CD3, CD8, CD45RO memory and granzyme B-positive cytotoxic T cells, in both the tumour centre and the invasive margin was associated with a much lower rate of early metastasis and longer survival, independently of and more strongly than the TNM stage. The finding led to the standardised Immunoscore, validated internationally in 2018.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.1129139"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tils","immune-system","prognosis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":2006,"doi":"10.1126/science.1129139","authors":"Galon J, Costes A, Sanchez-Cabo F, et al.","paperType":"translational","findings":["Immune profiling of colorectal tumours from 415 patients by gene expression and tissue microarrays.","Tumours without signs of early metastatic invasion had higher densities of adaptive immune cells, especially memory and cytotoxic T cells.","High densities of CD3, CD8 and CD45RO cells in both the tumour centre and invasive margin predicted longer disease-free and overall survival, independently of TNM stage."],"whatItMeans":"This paper showed that the immune response to a cancer is part of its prognosis, not background noise, and it introduced the idea of the immune contexture that underlies both the Immunoscore and the biomarker work in immunotherapy.","caveats":["A single-centre cohort at the time; the Immunoscore was validated in a later international study.","Immunoscore is not yet part of routine staging in most countries."],"changedPractice":false},{"id":"paper-gap70-geriatric-assessment-lancet-2021","kind":"paper","name":"GAP70+: a geriatric assessment before chemotherapy cut serious toxicity in older adults by a fifth","aka":[],"tldr":"When oncologists received a geriatric assessment summary with management recommendations for patients aged 70 or over, grade 3-5 toxicity fell from 71% to 51% with no loss in survival.","summary":"GAP70+ was a cluster-randomised trial in 40 US community oncology practices. Patients aged 70 or over with advanced cancer and at least one impaired geriatric domain who were starting a new palliative chemotherapy or other high-risk regimen were enrolled (718 patients). Intervention practices received a geriatric assessment summary and tailored recommendations; usual-care practices received only alerts for depression and cognitive impairment.\n\nThe primary endpoint, grade 3-5 toxicity over 3 months, occurred in 51% of intervention patients versus 71% in usual care (relative risk 0.74). Oncologists in the intervention arm more often reduced dose intensity at cycle 1, and 6-month and 1-year survival did not differ. A companion trial (GAIN, JAMA Oncology 2021) found a similar toxicity reduction.\n\nThe result made geriatric assessment-guided management a guideline standard (ASCO 2023) for older adults receiving systemic therapy.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S0140-6736(21)01789-X"},{"label":"ClinicalTrials.gov NCT02054741","url":"https://clinicaltrials.gov/study/NCT02054741"}],"tags":[],"related":["idea-moon-geriatric-assessment-default","idea-acc-geriatric-assessment-by-default","idea-tr1-geriatric-dose-finding-cohorts","idea-acc-upfront-reduced-dose-trials-frail"],"cancers":[],"sections":["supportive-care"],"technologies":["geriatric-assessment"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-aging-comorbidity","b-toxicity-qol","b-dose-optimisation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"doi":"10.1016/S0140-6736(21)01789-X","pmid":"34741815","authors":"Mohile SG, Mohamed MR, Xu H, et al.","paperType":"rct","findings":["Grade 3-5 toxic effects 51% vs 71% (relative risk 0.74, 95% CI 0.64-0.86)","Cycle 1 dose reduction 49% vs 35% in the intervention arm","No difference in 6-month overall survival (71% vs 74%) or 1-year survival","Falls and polypharmacy-related events were also reduced with geriatric management"],"whatItMeans":"Older patients are more likely to be harmed by standard-dose chemotherapy, and a structured assessment of function, cognition, nutrition and social support lets oncologists adjust treatment safely. Starting lower does not appear to shorten life. Most older patients still do not get such an assessment.","caveats":["Cluster randomisation at practice level with modest numbers per practice","Toxicity was the primary endpoint; quality-of-life and functional outcomes were secondary","Intervention effect depends on oncologists acting on recommendations; adherence varied","Excludes curative-intent settings, where dose reductions are riskier"],"changedPractice":true,"participants":718},{"id":"paper-garnet-dostarlimab-oaknin-jama-oncol-2020","kind":"paper","name":"GARNET: dostarlimab in mismatch repair-deficient recurrent or advanced endometrial cancer","aka":[],"tldr":"The PD-1 antibody dostarlimab shrank tumours in about four in ten women with mismatch repair-deficient endometrial cancer that had progressed after platinum chemotherapy, with most responses still ongoing after a year.","summary":"Interim analysis of the phase 1 GARNET trial's cohort of 104 patients with mismatch repair-deficient recurrent or advanced endometrial cancer treated with dostarlimab after platinum-based therapy.\n\nObjective response was 42.3 percent with complete response in 12.7 percent, and 93 percent of responses were ongoing at data cut-off; immune-related toxicity was manageable.","asOf":"2026-09-17","links":[{"label":"JAMA Oncol 2020","url":"https://doi.org/10.1001/jamaoncol.2020.4515"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33001143/"}],"tags":[],"related":[],"cancers":["endometrial-mmr-deficient"],"sections":[],"technologies":[],"targets":[],"drugs":["dostarlimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["garnet"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2020,"doi":"10.1001/jamaoncol.2020.4515","pmid":"33001143","authors":"Oaknin A, Tinker AV, Gilbert L, et al.","paperType":"observational","findings":["Objective response 42.3 percent; complete response 12.7 percent.","Median duration of response not reached; 93 percent of responses ongoing."],"whatItMeans":"Dostarlimab was approved for previously treated mismatch repair-deficient endometrial cancer on these data, before moving into first-line combination in RUBY.","caveats":["Single-arm, interim data.","Response in mismatch repair-proficient disease was much lower (about 13 percent) in a parallel cohort."],"changedPractice":true,"participants":104},{"id":"paper-hensley-gemcitabine-docetaxel-leiomyosarcoma-jco-2002","kind":"paper","name":"Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase 2 trial","aka":[],"tldr":"The combination of gemcitabine and docetaxel produced responses in more than half of patients with leiomyosarcoma, most of them uterine and many previously treated with doxorubicin, establishing a widely used second regimen for the disease.","summary":"Phase 2 study of 34 patients with unresectable leiomyosarcoma (29 uterine) treated with fixed-dose-rate gemcitabine followed by docetaxel every three weeks with growth factor support.\n\nObjective response was 53 percent including three complete responses, with responses in patients previously treated with doxorubicin; median time to progression was 5.6 months and myelosuppression was the main toxicity.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2002","url":"https://doi.org/10.1200/JCO.2002.11.050"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12065559/"}],"tags":[],"related":[],"cancers":["leiomyosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["docetaxel","gemcitabine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2002,"doi":"10.1200/JCO.2002.11.050","pmid":"12065559","authors":"Hensley ML, Maki R, Venkatraman E, et al.","paperType":"observational","findings":["Objective response 53 percent (18 of 34).","Responses in patients with prior doxorubicin exposure."],"whatItMeans":"Gemcitabine-docetaxel is a standard first- or second-line option for leiomyosarcoma, especially uterine, and remains in use alongside doxorubicin-based regimens.","caveats":["Single-arm study; randomised trials (GeDDiS) later found gemcitabine-docetaxel no better than doxorubicin first line."],"changedPractice":true,"participants":34},{"id":"paper-geometry-mono-1-capmatinib-nejm-2020","kind":"paper","name":"GEOMETRY mono-1: capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer","aka":[],"tldr":"The MET inhibitor capmatinib shrank tumours in two thirds of untreated and four in ten previously treated patients with MET exon 14-skipping lung cancer, leading to the first approval for this driver, while MET-amplified tumours responded only at very high copy number.","summary":"Phase 2 multicohort study of 364 patients with advanced non-small-cell lung cancer with MET exon 14 skipping or MET amplification treated with capmatinib.\n\nIn exon 14-skipping disease, objective response was 68 percent in treatment-naive and 41 percent in previously treated patients, with median durations of 12.6 and 9.7 months; in MET-amplified disease, response was 40 percent only with gene copy number of 10 or more. Peripheral oedema and nausea were common.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa2002787"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32877583/"}],"tags":[],"related":[],"cancers":["met-altered-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["capmatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["geometry-mono-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2002787","pmid":"32877583","authors":"Wolf J, Seto T, Han JY, et al.","paperType":"observational","findings":["Exon 14 skipping: objective response 68 percent (treatment-naive) and 41 percent (previously treated).","MET amplification: response 40 percent at gene copy number 10 or more, low below that."],"whatItMeans":"MET exon 14 skipping is a standard target in lung cancer, tested by RNA-based methods, with capmatinib or tepotinib as first-line or later options.","caveats":["Single-arm; peripheral oedema is frequent and can be dose limiting.","MET amplification without exon 14 skipping is a weaker target."],"changedPractice":true,"participants":364},{"id":"paper-gerlinger-intratumour-heterogeneity-nejm-2012","kind":"paper","name":"Gerlinger: a single biopsy misses most of the mutations in a kidney tumour","aka":[],"tldr":"Sequencing multiple regions of four kidney cancers and their metastases showed that around two-thirds of mutations were not shared across the whole tumour, that good- and poor-prognosis gene signatures coexisted in the same tumour, and that different regions had independently hit the same genes.","summary":"Swanton's group performed exome sequencing, chromosome aberration analysis and ploidy profiling on multiple spatially separated samples from primary clear-cell renal carcinomas and associated metastases in four patients, reconstructing phylogenetic trees for each tumour.\n\nBranched rather than linear evolution was the rule: 63-69% of all somatic mutations in the index case were not detectable in every region. Prognostic gene expression signatures classified different regions of the same tumour as favourable or unfavourable. Convergent evolution was seen, with distinct inactivating mutations in SETD2, KDM5C and PTEN arising in different regions, indicating strong selection on those pathways.\n\nThe paper made intratumour heterogeneity a central problem for biomarkers, drug resistance and trial design, and led directly to the TRACERx programme.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":["paper-tracerx-100-nejm-2017","idea-bio1-ctdna-clone-report"],"cancers":["rcc"],"sections":["diagnostics"],"technologies":["wes-wgs","liquid-biopsy"],"targets":[],"drugs":[],"companies":[],"institutions":["cruk","francis-crick"],"pathways":["clonal-evolution"],"terms":["resistance","vaf"],"trials":[],"people":["charles-swanton"],"bottlenecks":["b-tumor-heterogeneity","b-resistance","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1113205","pmid":"22397650","authors":"Gerlinger M, Rowan AJ, Horswell S, et al.","paperType":"translational","findings":["63-69% of somatic mutations in the index tumour were not present in every region sampled","A single biopsy captured only a minority of the tumour's mutational landscape","Good- and poor-prognosis expression signatures were found in different regions of the same tumour","Convergent evolution: distinct loss-of-function mutations in SETD2, KDM5C and PTEN in separate regions of the same tumour"],"whatItMeans":"A single biopsy is an incomplete picture of a patient's cancer. Truncal mutations shared by all cells (in kidney cancer, VHL) are the most reliable drug targets, whereas mutations in only some branches predict resistance. This is why liquid biopsy and multi-region sampling matter.","caveats":["Four patients; the extent of heterogeneity varies across cancer types","Clear-cell renal carcinoma may be unusually heterogeneous","Exome sequencing depth of the time limited detection of low-frequency subclones","Clinical consequences (whether targeting truncal alterations improves outcomes) were not tested"],"changedPractice":false,"participants":4},{"id":"paper-getug-13-fizazi-lancet-oncol-2014","kind":"paper","name":"GETUG 13: personalised chemotherapy based on tumour marker decline in poor-prognosis germ cell tumours","aka":[],"tldr":"In poor-risk testicular cancer, men whose tumour markers fell slowly after the first cycle of BEP did better when switched to an intensified dose-dense regimen, the first trial to individualise chemotherapy by early marker response.","summary":"Phase 3 trial of 263 men with poor-prognosis non-seminomatous germ cell tumours; those with unfavourable tumour marker decline after one cycle of BEP were randomised to continue BEP or switch to a dose-dense regimen (paclitaxel-BEP-oxaliplatin alternating with cisplatin-ifosfamide-bleomycin).\n\nThree-year progression-free survival was 59 percent with dose-dense therapy against 48 percent with BEP (hazard ratio 0.66), with more haematological toxicity but no increase in toxic deaths; overall survival was not significantly different.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2014","url":"https://doi.org/10.1016/S1470-2045(14)70490-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25456363/"}],"tags":[],"related":[],"cancers":["non-seminoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2014,"doi":"10.1016/S1470-2045(14)70490-5","pmid":"25456363","authors":"Fizazi K, Pagliaro L, Laplanche A, et al.","paperType":"rct","findings":["Three-year progression-free survival 59 percent vs 48 percent; hazard ratio 0.66.","Favourable marker decline identified men doing well on standard BEP (70 percent progression-free survival)."],"whatItMeans":"Marker decline after the first BEP cycle is now assessed in poor-risk disease, and intensification is offered in expert centres to slow decliners.","caveats":["No significant overall survival difference; toxicity of the intensified regimen requires specialist care."],"changedPractice":true,"participants":263},{"id":"paper-glow-zolbetuximab-nat-med-2023","kind":"paper","name":"GLOW: zolbetuximab plus CAPOX in claudin 18.2-positive, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma","aka":[],"tldr":"Adding the claudin 18.2 antibody zolbetuximab to CAPOX chemotherapy lengthened survival in claudin 18.2-positive advanced gastric cancer, confirming the SPOTLIGHT result with a different chemotherapy backbone.","summary":"Phase 3 placebo-controlled trial of 507 patients with untreated claudin 18.2-positive (75 percent or more of tumour cells), HER2-negative locally advanced or metastatic gastric or junctional adenocarcinoma randomised to zolbetuximab or placebo with capecitabine and oxaliplatin.\n\nMedian progression-free survival was 8.21 versus 6.80 months (hazard ratio 0.687) and median overall survival 14.39 versus 12.16 months (hazard ratio 0.771); nausea and vomiting were the characteristic added toxicities.","asOf":"2026-09-17","links":[{"label":"Nat Med 2023","url":"https://doi.org/10.1038/s41591-023-02465-7"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37524953/"}],"tags":[],"related":[],"cancers":["gastric-cldn18-2-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["zolbetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2023,"doi":"10.1038/s41591-023-02465-7","pmid":"37524953","authors":"Shah MA, Shitara K, Ajani JA, et al.","paperType":"rct","findings":["Median overall survival 14.39 vs 12.16 months; hazard ratio 0.771.","Median progression-free survival 8.21 vs 6.80 months."],"whatItMeans":"Zolbetuximab with either FOLFOX or CAPOX is a first-line standard for claudin 18.2-positive, HER2-negative gastric cancer, making claudin 18.2 testing routine.","caveats":["About 38 percent of screened patients were claudin 18.2-positive.","Nausea and vomiting in the first cycles lead to some discontinuation."],"changedPractice":true,"participants":507},{"id":"paper-rose-cisplatin-chemoradiation-cervical-nejm-1999","kind":"paper","name":"GOG 120: concurrent cisplatin-based chemotherapy with radiotherapy for locally advanced cervical cancer","aka":[],"tldr":"Giving cisplatin during pelvic radiotherapy nearly halved the risk of death compared with radiotherapy with hydroxyurea in locally advanced cervical cancer, establishing weekly cisplatin chemoradiation as the worldwide standard.","summary":"Phase 3 trial of 526 women with stage IIB to IVA cervical cancer randomised to radiotherapy with weekly cisplatin, with cisplatin plus fluorouracil and hydroxyurea, or with hydroxyurea alone.\n\nBoth cisplatin arms improved progression-free and overall survival compared with hydroxyurea (relative risk of death 0.61 and 0.58), and weekly cisplatin was the least toxic, becoming the standard regimen.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 1999","url":"https://doi.org/10.1056/NEJM199904153401502"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/10202165/"}],"tags":[],"related":[],"cancers":["locally-advanced-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1999,"doi":"10.1056/NEJM199904153401502","pmid":"10202165","authors":"Rose PG, Bundy BN, Watkins EB, et al.","paperType":"rct","findings":["Relative risk of death 0.61 with weekly cisplatin vs hydroxyurea.","Four-year progression-free survival about 65 percent with cisplatin vs 47 percent with hydroxyurea."],"whatItMeans":"Weekly cisplatin with external beam radiotherapy and brachytherapy remains the backbone of curative treatment for locally advanced cervical cancer; INTERLACE and KEYNOTE-A18 build on it.","caveats":["The comparator (hydroxyurea) is not a no-chemotherapy control.","Brachytherapy technique has since advanced."],"changedPractice":true,"participants":526},{"id":"paper-gog-240-bevacizumab-cervical-nejm-2014","kind":"paper","name":"GOG 240: bevacizumab added to chemotherapy for advanced cervical cancer","aka":[],"tldr":"Adding the anti-angiogenic antibody bevacizumab to chemotherapy lengthened survival by almost four months in recurrent or metastatic cervical cancer, the first targeted drug to improve survival in a gynaecological cancer.","summary":"Phase 3 factorial trial of 452 patients with recurrent, persistent or metastatic cervical cancer randomised to cisplatin-paclitaxel or topotecan-paclitaxel, with or without bevacizumab.\n\nMedian overall survival was 17.0 versus 13.3 months with bevacizumab (hazard ratio 0.71) and response 48 versus 36 percent; topotecan-paclitaxel was not superior to cisplatin-paclitaxel. Fistula occurred in about 6 percent of bevacizumab patients, mostly after prior radiotherapy.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2014","url":"https://doi.org/10.1056/NEJMoa1309748"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24552320/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/NEJMoa1309748","pmid":"24552320","authors":"Tewari KS, Sill MW, Long HJ, et al.","paperType":"rct","findings":["Median overall survival 17.0 vs 13.3 months; hazard ratio 0.71.","Objective response 48 percent vs 36 percent."],"whatItMeans":"Platinum-paclitaxel with bevacizumab became the first-line standard for advanced cervical cancer and remains the backbone to which pembrolizumab is added.","caveats":["Gastrointestinal and genitourinary fistulas in irradiated patients.","Hypertension and thromboembolism increased."],"changedPractice":true,"participants":452},{"id":"paper-gog-281-trametinib-lgsoc-gershenson-lancet-2022","kind":"paper","name":"GOG 281/LOGS: trametinib versus standard of care in recurrent low-grade serous ovarian cancer","aka":[],"tldr":"The MEK inhibitor trametinib more than doubled the time to progression compared with chemotherapy or hormone therapy in recurrent low-grade serous ovarian cancer, the first positive randomised trial in this slow-growing, chemotherapy-resistant disease.","summary":"Phase 2/3 trial of 260 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum randomised to trametinib or investigator's choice of letrozole, tamoxifen, weekly paclitaxel, pegylated liposomal doxorubicin or topotecan.\n\nMedian progression-free survival was 13.0 versus 7.2 months (hazard ratio 0.48) and response 26 versus 6 percent; skin rash, anaemia and hypertension were common with trametinib.","asOf":"2026-09-17","links":[{"label":"Lancet 2022","url":"https://doi.org/10.1016/S0140-6736(21)02175-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35123694/"}],"tags":[],"related":[],"cancers":["low-grade-serous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2022,"doi":"10.1016/S0140-6736(21)02175-9","pmid":"35123694","authors":"Gershenson DM, Miller A, Brady WE, et al.","paperType":"rct","findings":["Median progression-free survival 13.0 vs 7.2 months; hazard ratio 0.48.","Objective response 26 percent vs 6 percent."],"whatItMeans":"MEK inhibition is a standard option for recurrent low-grade serous ovarian cancer, and the trial validated the MAPK pathway as the disease's therapeutic target, now extended by avutometinib-defactinib.","caveats":["Open-label; overall survival not significantly different with crossover.","Toxicity led to dose reductions in many patients."],"changedPractice":true,"participants":260},{"id":"paper-gog-0261-carcinosarcoma-powell-jco-2022","kind":"paper","name":"GOG-0261: paclitaxel-carboplatin versus paclitaxel-ifosfamide in uterine carcinosarcoma","aka":[],"tldr":"For uterine carcinosarcoma, the standard breast and ovarian regimen carboplatin-paclitaxel was as effective as the older, more toxic paclitaxel-ifosfamide combination, simplifying treatment of this rare aggressive cancer.","summary":"Phase 3 non-inferiority trial of 536 patients with stage I to IV, persistent or recurrent uterine carcinosarcoma (with a small ovarian carcinosarcoma cohort) randomised to paclitaxel-carboplatin or paclitaxel-ifosfamide.\n\nMedian overall survival was 37 versus 29 months (hazard ratio 0.87, non-inferior) and progression-free survival 16 versus 12 months, with more haematological toxicity but less confusion and genitourinary toxicity with carboplatin.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2022","url":"https://doi.org/10.1200/JCO.21.02050"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35007153/"}],"tags":[],"related":[],"cancers":["uterine-carcinosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["carboplatin","ifosfamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2022,"doi":"10.1200/JCO.21.02050","pmid":"35007153","authors":"Powell MA, Filiaci VL, Hensley ML, et al.","paperType":"rct","findings":["Median overall survival 37 vs 29 months; hazard ratio 0.87 (non-inferior).","Median progression-free survival 16 vs 12 months."],"whatItMeans":"Carboplatin-paclitaxel is the chemotherapy standard for uterine carcinosarcoma in all stages, now combined with dostarlimab in advanced disease following RUBY, which included carcinosarcoma.","caveats":["Non-inferiority design; the trend favouring carboplatin was not tested for superiority.","Adjuvant radiotherapy was not standardised."],"changedPractice":true,"participants":536},{"id":"paper-grid-regorafenib-gist-lancet-2013","kind":"paper","name":"GRID: regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib","aka":[],"tldr":"Regorafenib delayed progression by almost four months compared with placebo in gastrointestinal stromal tumours resistant to both imatinib and sunitinib, giving patients a third line of targeted therapy.","summary":"Phase 3 placebo-controlled trial of 199 patients with metastatic or unresectable GIST after failure of imatinib and sunitinib randomised 2:1 to regorafenib 160 mg daily (three weeks on, one off) or placebo with crossover at progression.\n\nMedian progression-free survival was 4.8 versus 0.9 months (hazard ratio 0.27) with disease control in 53 versus 9 percent; hypertension, hand-foot skin reaction and diarrhoea were the main toxicities.","asOf":"2026-09-17","links":[{"label":"Lancet 2013","url":"https://doi.org/10.1016/S0140-6736(12)61857-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23177515/"}],"tags":[],"related":[],"cancers":["gist-imatinib-resistant"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib","regorafenib","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["grid"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2013,"doi":"10.1016/S0140-6736(12)61857-1","pmid":"23177515","authors":"Demetri GD, Reichardt P, Kang YK, et al.","paperType":"rct","findings":["Median progression-free survival 4.8 vs 0.9 months; hazard ratio 0.27.","Disease control rate 52.6 percent vs 9.1 percent."],"whatItMeans":"Regorafenib is the standard third-line treatment for GIST after imatinib and sunitinib.","caveats":["No overall survival benefit because of crossover.","Dose reductions needed in most patients."],"changedPractice":true,"participants":199},{"id":"paper-grivennikov-immunity-inflammation-cancer-cell-2010","kind":"paper","name":"Grivennikov, Greten and Karin 2010: immunity, inflammation and cancer","aka":[],"tldr":"The review that laid out how inflammation contributes at every stage of cancer, from the DNA damage that starts it to the signals that help it grow and spread, and named the molecular switches, such as NF-kB and STAT3, that connect immune cells to tumour cells.","summary":"Grivennikov, Greten and Karin reviewed the roles of inflammation in tumour initiation, promotion, progression and metastasis. Chronic inflammation from infection, autoimmunity or environmental irritants produces reactive oxygen species and cytokines that damage DNA and stimulate proliferation; tumour-promoting inflammation acts through transcription factors NF-kB and STAT3 and cytokines such as IL-6, TNF and IL-1; and inflammation also supports angiogenesis and metastasis while suppressing anti-tumour immunity. They noted that a substantial share of cancers, on some estimates up to a fifth, is linked to chronic infection or inflammation.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/j.cell.2010.01.025"}],"tags":[],"related":["paper-coussens-werb-inflammation-cancer-nature-2002"],"cancers":[],"sections":[],"technologies":["aspirin-cancer-prevention"],"targets":["il6"],"drugs":[],"companies":[],"institutions":["uct-frankfurt","ucsd-moores"],"pathways":["inflammation-nfkb","jak-stat"],"terms":["inflammation","tumor-promoting-inflammation"],"trials":[],"people":["florian-greten"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cell","year":2010,"doi":"10.1016/j.cell.2010.01.025","authors":"Grivennikov SI, Greten FR, Karin M.","paperType":"review","findings":["Inflammation contributes to initiation through DNA damage and to promotion through NF-kB and STAT3 signalling driven by cytokines such as IL-6 and TNF.","Tumour-associated inflammation also supports angiogenesis and metastasis and dampens adaptive anti-tumour immunity.","Chronic infection and inflammation are estimated to underlie up to about a fifth of cancers."],"whatItMeans":"This paper is the molecular sequel to the 2002 inflammation and cancer review and the basis for IL-6, JAK-STAT and NF-kB directed strategies in cancer as well as for aspirin and other anti-inflammatory prevention trials.","caveats":["A review synthesising mostly mouse genetic evidence.","Anti-inflammatory approaches have shown clearer benefit in prevention than in treating established cancers."],"changedPractice":false},{"id":"paper-hallmarks-new-dimensions-cancer-discov-2022","kind":"paper","name":"Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells","aka":[],"tldr":"The third hallmarks paper proposed two new hallmarks (unlocking phenotypic plasticity, senescent cells) and two new enabling characteristics (non-mutational epigenetic reprogramming, polymorphic microbiomes), bringing the framework to fourteen elements.","summary":"Twenty-two years after the original, Douglas Hanahan reviewed developments that the 2000 and 2011 frameworks did not accommodate. He proposed unlocking phenotypic plasticity (dedifferentiation, blocked differentiation and transdifferentiation, as in neuroendocrine transformation of prostate and lung cancers) as a hallmark, and senescent cells as a distinct cell type contributing to tumour progression.\n\nHe added non-mutational epigenetic reprogramming and polymorphic microbiomes as enabling characteristics: mechanisms by which cells acquire hallmark capabilities without new mutations, and ways in which microbial communities in gut and tumour modulate cancer risk, progression and therapy response.\n\nThe paper reflects how much lineage plasticity, epigenetics and the microbiome now feature in drug development, including for resistance to targeted therapy and immunotherapy.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1158/2159-8290.CD-21-1059"}],"tags":[],"related":["paper-hallmarks-of-cancer-cell-2000","unlocking-phenotypic-plasticity","nonmutational-epigenetic-reprogramming","polymorphic-microbiomes","senescent-cells"],"cancers":[],"sections":["drug-discovery","epigenetics"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","senescence","microbiome-tumour","cancer-stem-cells-plasticity"],"terms":["hallmarks-of-cancer"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-knowledge-diffusion"],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2022,"doi":"10.1158/2159-8290.CD-21-1059","pmid":"35022204","authors":"Hanahan D","paperType":"review","findings":["New hallmark: unlocking phenotypic plasticity (dedifferentiation, blocked differentiation, transdifferentiation)","New hallmark: senescent cells, whose secretory phenotype can promote proliferation, invasion and immune suppression","New enabling characteristic: non-mutational epigenetic reprogramming, including microenvironment-driven states","New enabling characteristic: polymorphic microbiomes affecting carcinogenesis and therapy response","Reaffirmed the 2011 set of eight hallmarks and two enabling characteristics"],"whatItMeans":"Cancer is now understood to change its identity and behaviour without new mutations, to be shaped by bacteria inside and around it, and to be helped along by ageing cells. This explains why some tumours escape targeted drugs by changing cell type and why gut bacteria affect immunotherapy response.","caveats":["Single-author perspective; some proposed additions remain contested as hallmarks rather than mechanisms","Evidence for microbiome causality in human tumours is uneven and confounded","Senolytic therapy in cancer is early and unproven","The framework has grown to 14 elements, reducing the parsimony that made the original influential"],"changedPractice":false},{"id":"paper-harmoni-2-lancet-2025","kind":"paper","name":"HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer","aka":[],"tldr":"In the first randomised trial to beat pembrolizumab directly, a single antibody that blocks both PD-1 and VEGF nearly doubled the time to progression in PD-L1-positive lung cancer, though survival data were still immature.","summary":"Double-blind phase 3 trial conducted in China of 398 patients with untreated, PD-L1-positive (TPS 1% or more) advanced NSCLC without EGFR or ALK alterations, randomised to ivonescimab or pembrolizumab monotherapy. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 11.1 vs 5.8 months (HR 0.51), with benefit in squamous and non-squamous histology and in PD-L1 1-49% and 50% or more. Overall survival was immature at publication and a later interim analysis did not reach statistical significance. It is the first time any agent has beaten pembrolizumab head-to-head in lung cancer and it revived interest in PD-(L)1 x VEGF bispecifics, with several Western companies licensing similar molecules.","asOf":"2026-09-08","links":[{"label":"PubMed search: HARMONi-2 ivonescimab Lancet","url":"https://pubmed.ncbi.nlm.nih.gov/?term=HARMONi-2+ivonescimab+pembrolizumab+Lancet"},{"label":"ClinicalTrials.gov NCT05499390","url":"https://clinicaltrials.gov/study/NCT05499390"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["bispecific-antibody","checkpoint-inhibitor","antiangiogenic"],"targets":["pd1","vegf"],"drugs":["ivonescimab","pembrolizumab"],"companies":["akeso","summit-therapeutics","merck"],"institutions":[],"pathways":[],"terms":["pfs","os","first-line"],"trials":[],"people":["zhou-caicun"],"bottlenecks":["b-immunotherapy-response","b-trial-diversity","b-regulatory-fragmentation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2025,"authors":"Zhou C, Chen J, Wu L, et al.","paperType":"rct","findings":["Median PFS 11.1 vs 5.8 months; HR 0.51 (95% CI 0.38-0.69).","Objective response 50.0% vs 38.5%.","Benefit seen in PD-L1 TPS 1-49% (HR 0.54) and 50% or more (HR 0.46), and in squamous (HR 0.48) and non-squamous (HR 0.54) tumours.","Grade 3 or higher treatment-related adverse events 29.4% vs 15.6%, largely VEGF-related (proteinuria, hypertension) with no excess of severe bleeding in squamous tumours.","Overall survival immature at primary analysis; a subsequent interim OS analysis showed a hazard ratio below 1 that was not statistically significant."],"whatItMeans":"For the first time a new drug has beaten pembrolizumab, the global first-line standard, in a randomised lung cancer trial, and it did so by combining checkpoint blockade with anti-angiogenesis in one molecule. For patients outside China nothing changes yet: the drug is not approved in the West, the trial was single-country, and survival benefit has not been shown. If confirmed in the global HARMONi-3 and HARMONi-7 trials, PD-1 x VEGF bispecifics could replace PD-1 antibodies as the immunotherapy backbone.","caveats":["Single-country (China) trial; generalisability to other populations is untested.","Progression-free survival only; overall survival has not reached significance, and pembrolizumab's own benefit is defined by OS.","Comparator was pembrolizumab monotherapy, whereas many PD-L1 1-49% patients would receive chemo-immunotherapy.","VEGF-class toxicities and the cost of a novel bispecific are additional considerations."],"changedPractice":false,"participants":398},{"id":"paper-plotkin-bevacizumab-nf2-nejm-2009","kind":"paper","name":"Hearing improvement after bevacizumab in patients with neurofibromatosis type 2","aka":[],"tldr":"In a small series of people with NF2 and progressive vestibular schwannomas, the anti-VEGF antibody bevacizumab shrank the tumours in most and, remarkably, improved hearing in more than half, opening the first drug treatment for these tumours.","summary":"Retrospective series of 10 patients with neurofibromatosis type 2 and progressive vestibular schwannomas treated with bevacizumab after showing VEGF expression in tumour specimens.\n\nTumour shrinkage occurred in nine of ten patients (volumetric response of 20 percent or more in six), and hearing improved in four of seven evaluable patients, with responses maintained over months of treatment.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2009","url":"https://doi.org/10.1056/NEJMoa0902579"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19587327/"}],"tags":[],"related":[],"cancers":["vestibular-schwannoma"],"sections":[],"technologies":[],"targets":[],"drugs":["bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2009,"doi":"10.1056/NEJMoa0902579","pmid":"19587327","authors":"Plotkin SR, Stemmer-Rachamimov AO, Barker FG, et al.","paperType":"observational","findings":["Volumetric tumour response in six of ten patients.","Hearing improvement in four of seven evaluable patients."],"whatItMeans":"Bevacizumab is used off label for NF2-related schwannomatosis with growing tumours or declining hearing, supported by later phase 2 trials, and the study opened the search for medical therapy of schwannoma.","caveats":["Ten patients, retrospective, no control.","Responses are not permanent and treatment must continue; hypertension and proteinuria limit long-term use."],"changedPractice":true,"participants":10},{"id":"paper-her2climb-brain-lin-jco-2020","kind":"paper","name":"HER2CLIMB brain metastases analysis: intracranial efficacy and survival with tucatinib","aka":[],"tldr":"Among the HER2CLIMB patients with brain metastases, tucatinib doubled the intracranial response rate, cut the risk of intracranial progression or death by about two thirds and lengthened survival.","summary":"Exploratory analysis of the 291 HER2CLIMB patients with brain metastases at baseline, including 174 with active lesions.\n\nRisk of intracranial progression or death was reduced by 68 percent with tucatinib, median central nervous system progression-free survival was 9.9 versus 4.2 months, intracranial response was 47.3 versus 20.0 percent, and median overall survival was 18.1 versus 12.0 months.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2020","url":"https://doi.org/10.1200/JCO.20.00775"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32468955/"}],"tags":[],"related":[],"cancers":["her2-positive-breast-brain-metastases"],"sections":[],"technologies":[],"targets":[],"drugs":["capecitabine","trastuzumab","tucatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["her2climb"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"doi":"10.1200/JCO.20.00775","pmid":"32468955","authors":"Lin NU, Borges V, Anders C, et al.","paperType":"rct","findings":["Intracranial objective response 47.3 percent vs 20.0 percent.","Median central nervous system progression-free survival 9.9 vs 4.2 months; median overall survival 18.1 vs 12.0 months."],"whatItMeans":"This analysis is the evidence base for treating active HER2-positive brain metastases with a systemic regimen, sometimes deferring radiotherapy, and for tucatinib's brain-specific labelling.","caveats":["Exploratory subgroup analysis, though prespecified.","Local therapy was permitted at isolated brain progression, which complicates interpretation."],"changedPractice":true,"participants":291},{"id":"paper-her2climb-nejm-2020","kind":"paper","name":"HER2CLIMB: tucatinib with trastuzumab and capecitabine for HER2-positive metastatic breast cancer, including brain metastases","aka":[],"tldr":"Adding the brain-penetrant HER2 pill tucatinib to trastuzumab and capecitabine lengthened survival in heavily pretreated HER2-positive metastatic breast cancer, and uniquely the trial included patients with active brain metastases, who also benefited.","summary":"Phase 3 placebo-controlled trial of 612 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab and T-DM1, randomised 2:1 to tucatinib or placebo with trastuzumab and capecitabine; nearly half had brain metastases, including untreated or progressing lesions.\n\nOverall survival at two years was 44.9 percent with tucatinib against 26.6 percent with placebo (hazard ratio 0.66); progression-free survival among patients with brain metastases at one year was 24.9 versus 0 percent.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa1914609"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31825569/"}],"tags":[],"related":[],"cancers":["her2-positive-breast-brain-metastases"],"sections":[],"technologies":[],"targets":[],"drugs":["capecitabine","trastuzumab","tucatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["her2climb"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa1914609","pmid":"31825569","authors":"Murthy RK, Loi S, Okines A, et al.","paperType":"rct","findings":["Two-year overall survival 44.9 percent vs 26.6 percent; hazard ratio for death 0.66.","One-year progression-free survival in patients with brain metastases 24.9 percent vs 0 percent."],"whatItMeans":"Tucatinib-based therapy is the standard for HER2-positive disease with active brain metastases and a standard later-line option overall; it was the first trial to enrol progressing brain metastases and show a systemic drug helps them.","caveats":["Diarrhoea and liver enzyme rises were more frequent with tucatinib.","Trial predates trastuzumab deruxtecan as second-line standard."],"changedPractice":true,"participants":612},{"id":"paper-heracles-lancet-oncol-2016","kind":"paper","name":"HERACLES: trastuzumab and lapatinib in HER2-amplified, KRAS wild-type metastatic colorectal cancer","aka":[],"tldr":"This small Italian trial was the first to show that HER2-amplified colorectal cancer responds to dual HER2 blockade, establishing HER2 as a genuine drug target in a disease where it had been ignored.","summary":"Proof-of-concept phase 2 trial that screened 914 KRAS exon 2 wild-type colorectal cancers to find 48 with HER2 amplification and treated 27 heavily pretreated patients with trastuzumab and lapatinib.\n\nObjective response was 30 percent including one complete response, with disease control in 59 percent and a median progression-free survival of 21 weeks; the trial also defined the HERACLES diagnostic criteria for HER2 positivity in colorectal cancer.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2016","url":"https://doi.org/10.1016/S1470-2045(16)00150-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27108243/"}],"tags":[],"related":[],"cancers":["her2-amplified-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["lapatinib","trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["heracles"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2016,"doi":"10.1016/S1470-2045(16)00150-9","pmid":"27108243","authors":"Sartore-Bianchi A, Trusolino L, Martino C, et al.","paperType":"observational","findings":["Objective response 30 percent (8 of 27), disease control 59 percent.","HER2 amplification found in about 5 percent of KRAS wild-type tumours."],"whatItMeans":"HERACLES opened HER2 as a target in colorectal cancer and set the immunohistochemistry and in situ hybridisation criteria later studies used; tucatinib and trastuzumab deruxtecan built on this result.","caveats":["Very small and non-randomised.","Lapatinib-based regimens have been superseded."],"changedPractice":true,"participants":27},{"id":"paper-himalaya-nejm-evidence-2022","kind":"paper","name":"HIMALAYA: tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","aka":[],"tldr":"A single priming dose of the CTLA-4 antibody tremelimumab followed by durvalumab lengthened survival compared with sorafenib in advanced liver cancer without the bleeding risk of bevacizumab, giving a second first-line immunotherapy standard.","summary":"Phase 3 trial of 1,171 patients with unresectable hepatocellular carcinoma and no prior systemic therapy randomised to STRIDE (single tremelimumab plus regular durvalumab), durvalumab alone or sorafenib.\n\nMedian overall survival was 16.4 months with STRIDE against 13.8 months with sorafenib (hazard ratio 0.78), with three-year survival of 30.7 versus 20.2 percent and durvalumab monotherapy non-inferior to sorafenib; grade 3 to 4 treatment-related adverse events were 25.8 versus 36.9 percent.","asOf":"2026-09-17","links":[{"label":"NEJM Evid 2022","url":"https://doi.org/10.1056/EVIDoa2100070"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38319892/"}],"tags":[],"related":[],"cancers":["hcc-advanced","hcc-intermediate"],"sections":[],"technologies":[],"targets":[],"drugs":["durvalumab","tremelimumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["himalaya"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm-evidence"],"dependsOn":[],"notes":[],"journal":"NEJM Evidence","year":2022,"doi":"10.1056/EVIDoa2100070","pmid":"38319892","authors":"Abou-Alfa GK, Lau G, Kudo M, et al.","paperType":"rct","findings":["Median overall survival 16.4 vs 13.8 months; hazard ratio 0.78.","Three-year overall survival 30.7 percent vs 20.2 percent."],"whatItMeans":"Durvalumab-tremelimumab is a first-line standard for advanced hepatocellular carcinoma, particularly for patients with varices or bleeding risk in whom atezolizumab-bevacizumab is unsuitable.","caveats":["Progression-free survival was not improved, reflecting a subset of long-term responders.","Excluded main portal vein thrombosis."],"changedPractice":true,"participants":1171},{"id":"paper-hodi-ipilimumab-melanoma-nejm-2010","kind":"paper","name":"Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma","aka":[],"tldr":"Blocking the immune brake CTLA-4 was the first treatment ever to prolong life in metastatic melanoma, with about one in five patients alive at two years and a new class of autoimmune side effects.","summary":"This phase 3 trial randomised 676 patients with previously treated, HLA-A*0201-positive metastatic melanoma in a 3:1:1 ratio to ipilimumab plus a gp100 peptide vaccine, ipilimumab alone, or gp100 alone. The primary endpoint was overall survival. Median OS was 10.0 months with ipilimumab plus gp100 and 10.1 months with ipilimumab alone versus 6.4 months with gp100 (hazard ratios 0.68 and 0.66), with survival curves showing a durable tail. Grade 3-4 immune-related adverse events occurred in 10-15% of ipilimumab-treated patients, and 14 deaths were related to study drugs, 7 from immune-related events. It led to FDA approval in March 2011 and validated James Allison's checkpoint-blockade hypothesis in humans.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1003466"},{"label":"ClinicalTrials.gov NCT00094653","url":"https://clinicaltrials.gov/study/NCT00094653"}],"tags":[],"related":["paper-topalian-anti-pd1-nejm-2012","paper-checkmate-067-ten-year-nejm-2025"],"cancers":["melanoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["ctla4"],"drugs":["ipilimumab"],"companies":["bms"],"institutions":["dana-farber"],"pathways":[],"terms":["irae","os"],"trials":[],"people":["f-stephen-hodi","james-allison","padmanee-sharma"],"bottlenecks":["b-immunotherapy-response","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa1003466","authors":"Hodi FS, O'Day SJ, McDermott DF, et al.","paperType":"rct","findings":["676 previously treated metastatic melanoma patients; ipilimumab + gp100, ipilimumab alone, or gp100 alone (3:1:1).","Median OS 10.0 and 10.1 months with ipilimumab arms vs 6.4 months with gp100; hazard ratios 0.68 and 0.66.","Response rates were low (about 11% for ipilimumab alone) yet survival improved, showing a disconnect between shrinkage and benefit.","Grade 3-4 immune-related adverse events 10-15% with ipilimumab; 7 deaths from immune-related events.","A plateau in the survival curve suggested long-term survivors, later confirmed at about 20% alive at 3 years in pooled analyses."],"whatItMeans":"This paper launched the immunotherapy era. It was the first randomised evidence that taking a brake off the immune system could extend life in a solid cancer, and it introduced clinicians to immune-related adverse events and to responses that arrive late or after apparent progression. Ipilimumab alone has since been superseded by PD-1 antibodies and combinations, but every checkpoint programme traces back to this result.","caveats":["Comparator was a peptide vaccine, not an active therapy, and was itself of uncertain effect.","Restricted to HLA-A*0201-positive patients because of the vaccine.","Response rate was low; benefit concentrated in a minority with durable responses.","Toxicity was substantial and management was still being learned."],"changedPractice":true,"participants":676},{"id":"paper-hollstein-p53-mutations-science-1991","kind":"paper","name":"Hollstein 1991: p53 mutations in human cancers","aka":[],"tldr":"The survey that showed p53 is the most commonly altered gene in human cancer and that the pattern of its mutations differs by cancer type and by cause, such as tobacco smoke in lung cancer and a dietary toxin in liver cancer.","summary":"Hollstein, Sidransky, Vogelstein and Harris compiled the p53 mutations reported across human tumours and showed that they occurred in a wide range of cancers, clustered in the evolutionarily conserved regions of the gene, and mostly changed single amino acids rather than truncating the protein. The spectrum of mutations varied by tumour type and exposure: G to T changes typical of tobacco carcinogens in lung cancer and a specific codon 249 change in liver cancers from regions with aflatoxin exposure. The paper established p53 mutation as a molecular record of carcinogen exposure.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.1905840"}],"tags":[],"related":[],"cancers":["nsclc","hcc","colorectal"],"sections":[],"technologies":[],"targets":["tp53"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":[],"terms":["tp53-mutated","tumour-suppressor-gene","mutational-signature"],"trials":[],"people":["bert-vogelstein"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":1991,"doi":"10.1126/science.1905840","authors":"Hollstein M, Sidransky D, Vogelstein B, Harris CC.","paperType":"review","findings":["p53 mutations were found across a wide range of human cancers, making it the most frequently mutated gene known.","Mutations clustered in four conserved regions of the gene and were mostly missense changes.","Mutation spectra differed by cancer and exposure, including tobacco-associated changes in lung cancer and a codon 249 hotspot in aflatoxin-related liver cancer."],"whatItMeans":"This paper is why TP53 status is reported in almost every tumour genome and why mutational signatures can point to causes. Its idea that mutation patterns record exposures grew into the mutational signature field, and TP53 mutation remains a marker of poor prognosis and a drug target still being pursued.","caveats":["A compilation of early sequencing studies with uneven coverage across cancers.","The functional consequences of different p53 mutations were still largely unknown."],"changedPractice":false},{"id":"paper-gershenson-hormonal-maintenance-lgsoc-jco-2017","kind":"paper","name":"Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum","aka":[],"tldr":"In this retrospective study, women who took an aromatase inhibitor or other hormonal therapy after first-line surgery and chemotherapy for low-grade serous ovarian cancer had a median progression-free survival of over five years compared with about two years with observation.","summary":"Retrospective analysis of 203 women with stage II to IV low-grade serous carcinoma treated with primary surgery and platinum-based chemotherapy, comparing those who received hormonal maintenance therapy (mostly letrozole) with those observed.\n\nMedian progression-free survival was 64.9 months with hormonal maintenance against 26.4 months with observation, with the benefit maintained in women without residual disease and in a multivariable analysis.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2017","url":"https://doi.org/10.1200/JCO.2016.71.0632"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28221866/"}],"tags":[],"related":[],"cancers":["low-grade-serous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2017,"doi":"10.1200/JCO.2016.71.0632","pmid":"28221866","authors":"Gershenson DM, Bodurka DC, Coleman RL, et al.","paperType":"observational","findings":["Median progression-free survival 64.9 vs 26.4 months.","Benefit maintained in patients with no gross residual disease."],"whatItMeans":"Letrozole maintenance after first-line therapy is now common practice and guideline-supported for low-grade serous ovarian cancer, and the randomised NRG-GY019 trial is testing letrozole alone.","caveats":["Retrospective single-institution study with selection bias.","No overall survival difference."],"changedPractice":true,"participants":203},{"id":"paper-sankaranarayanan-hpv-screening-nejm-2009","kind":"paper","name":"HPV screening for cervical cancer in rural India (Osmanabad)","aka":[],"tldr":"In 131,746 rural Indian women, a single round of HPV testing roughly halved deaths from cervical cancer within eight years, while Pap smears and visual inspection did not.","summary":"Cluster-randomised trial in 52 villages of Osmanabad district, Maharashtra, comparing one round of HPV DNA testing, cytology, visual inspection with acetic acid and usual care in women aged 30 to 59. In the HPV arm there were 39 advanced cancers versus 82 in controls (hazard ratio 0.47; 95% CI 0.32-0.69) and 34 deaths versus 64 (hazard ratio 0.52; 95% CI 0.33-0.83); the cytology and visual inspection arms showed no significant reduction. Adverse events occurred in 0.1% of screened women.","asOf":"2026-09-10","links":[{"label":"NEJM 2009","url":"https://doi.org/10.1056/NEJMoa0808516"}],"tags":[],"related":[],"cancers":["cervical"],"sections":[],"technologies":["hpv-testing"],"targets":[],"drugs":[],"companies":[],"institutions":["iarc","tata-memorial"],"pathways":[],"terms":[],"trials":["osmanabad-hpv-screening"],"people":["sankaranarayanan-rengaswamy","shastri-surendra"],"bottlenecks":["b-early-detection","b-prevention-adoption"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2009,"doi":"10.1056/NEJMoa0808516","authors":"Sankaranarayanan R, Nene BM, Shastri SS, et al.","paperType":"rct","findings":["Cervical cancer deaths: 34 with HPV testing versus 64 with usual care; hazard ratio 0.52.","Advanced cervical cancers: 39 versus 82; hazard ratio 0.47.","Neither cytology nor visual inspection with acetic acid significantly reduced advanced cancers or deaths in this trial.","Total cervical cancers detected were similar (127 versus 118), so the gain came from earlier stage and treatment."],"whatItMeans":"HPV DNA testing is the screening test that saves lives in low-resource settings, even when done once. The result underpins WHO's HPV-first screening guidance and India's operational guidelines, and gives the rationale for self-sampled HPV tests as the route to cervical cancer elimination.","caveats":["One round of screening with eight years of follow-up; long-term programme effects were not measured.","The visual inspection arm's null result differs from the later Mumbai trial, which used repeated rounds and health workers with intensive training.","Treatment access after a positive test was provided by the trial, which programmes must replicate."],"changedPractice":true,"participants":131746},{"id":"paper-hr-nbl1-busulfan-melphalan-ladenstein-lancet-oncol-2017","kind":"paper","name":"HR-NBL1/SIOPEN: busulfan-melphalan versus carboplatin-etoposide-melphalan high-dose chemotherapy for high-risk neuroblastoma","aka":[],"tldr":"Busulfan and melphalan as the high-dose conditioning before stem cell rescue gave better event-free survival and less severe toxicity than the carboplatin-etoposide-melphalan regimen in high-risk neuroblastoma, becoming Europe's standard.","summary":"Phase 3 trial within the European HR-NBL1 study randomising 598 children with high-risk neuroblastoma after rapid COJEC induction to busulfan-melphalan or carboplatin-etoposide-melphalan (CEM) high-dose chemotherapy with autologous stem cell rescue.\n\nThree-year event-free survival was 50 versus 38 percent (hazard ratio about 0.7), overall survival 60 versus 48 percent, and severe toxicity and toxic deaths were fewer with busulfan-melphalan.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2017","url":"https://doi.org/10.1016/S1470-2045(17)30070-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28259608/"}],"tags":[],"related":[],"cancers":["neuroblastoma-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["busulfan","carboplatin","etoposide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["hr-nbl1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2017,"doi":"10.1016/S1470-2045(17)30070-0","pmid":"28259608","authors":"Ladenstein R, Pötschger U, Pearson ADJ, et al.","paperType":"rct","findings":["Three-year event-free survival 50 percent vs 38 percent.","Severe acute toxicity 4 percent vs 10 percent."],"whatItMeans":"Busulfan-melphalan is the standard single high-dose regimen for high-risk neuroblastoma in Europe and many other regions; North America uses tandem transplant.","caveats":["Randomisation occurred after induction, so early failures are excluded.","Veno-occlusive disease is the characteristic busulfan toxicity."],"changedPractice":true,"participants":598},{"id":"paper-ang-hpv-oropharyngeal-nejm-2010","kind":"paper","name":"Human papillomavirus and survival of patients with oropharyngeal cancer (RTOG 0129)","aka":[],"tldr":"Analysing a large chemoradiation trial showed that HPV-positive oropharyngeal cancers have a far better prognosis than HPV-negative ones, with three-year survival of 82 versus 57 percent, and that smoking history further modifies risk.","summary":"Retrospective analysis of 323 patients with stage III to IV oropharyngeal cancer treated with cisplatin chemoradiation in RTOG 0129, stratified by tumour HPV status determined by in situ hybridisation and p16 immunohistochemistry.\n\nHPV-positive tumours (63.8 percent) had three-year overall survival of 82.4 versus 57.1 percent (hazard ratio for death 0.42 after adjustment), and a recursive partitioning model combining HPV status, pack-years of smoking, T stage and N stage defined low, intermediate and high-risk groups.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2010","url":"https://doi.org/10.1056/NEJMoa0912217"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20530316/"}],"tags":[],"related":[],"cancers":["hpv-positive-oropharyngeal-cancer","oropharyngeal-cancer","hpv-negative-head-and-neck-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa0912217","pmid":"20530316","authors":"Ang KK, Harris J, Wheeler R, et al.","paperType":"observational","findings":["Three-year overall survival 82.4 percent HPV-positive vs 57.1 percent HPV-negative.","Smoking of more than 10 pack-years shifted HPV-positive patients into intermediate risk."],"whatItMeans":"HPV-positive oropharyngeal cancer is now staged and studied separately, and this risk model underlies de-escalation trials and the eighth-edition staging system.","caveats":["Retrospective analysis of a single trial population treated with chemoradiation."],"changedPractice":true,"participants":323},{"id":"paper-hurwitz-bevacizumab-crc-nejm-2004","kind":"paper","name":"Hurwitz 2004: bevacizumab with chemotherapy for metastatic colorectal cancer, the first anti-angiogenic drug to extend life","aka":[],"tldr":"Adding the VEGF antibody bevacizumab to irinotecan-based chemotherapy prolonged survival in first-line metastatic colorectal cancer, the first time blocking a tumour's blood supply had been shown to help patients.","summary":"This phase 3 trial randomised 813 patients with untreated metastatic colorectal cancer to irinotecan, fluorouracil and leucovorin (IFL) plus bevacizumab or IFL plus placebo. Bevacizumab improved overall survival, progression-free survival and response rate. Grade 3 hypertension was more common with bevacizumab but manageable, and gastrointestinal perforation appeared as a rare but serious class effect. The trial led to the first approval of an anti-angiogenic drug and validated Judah Folkman's decades-old hypothesis that tumours depend on new blood vessels.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa032691"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["vegf"],"drugs":["bevacizumab","irinotecan","fluorouracil"],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["os","pfs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2004,"doi":"10.1056/NEJMoa032691","authors":"Hurwitz H, Fehrenbacher L, Novotny W, et al.","paperType":"rct","findings":["813 patients with untreated metastatic colorectal cancer; IFL plus bevacizumab or placebo.","Median overall survival 20.3 vs 15.6 months, hazard ratio 0.66.","Median progression-free survival 10.6 vs 6.2 months, hazard ratio 0.54; response rate 44.8% vs 34.8%.","Grade 3 hypertension 11.0% vs 2.3%; gastrointestinal perforation in 1.5% of bevacizumab patients."],"whatItMeans":"This trial opened anti-angiogenic therapy as a class, and bevacizumab went on to approvals in lung, kidney, ovarian, cervical and brain cancers. It also set the pattern of modest but real survival gains from adding a biologic to chemotherapy, and introduced hypertension, proteinuria and perforation as the signature side effects clinicians now monitor.","caveats":["IFL is no longer a standard backbone; FOLFOX and FOLFIRI replaced it.","Benefit in later trials was smaller and no predictive biomarker for bevacizumab has emerged.","Placebo-controlled but with an active chemotherapy backbone in both arms."],"changedPractice":true,"participants":813},{"id":"paper-body-fatness-iarc-nejm-2016","kind":"paper","name":"IARC verdict: excess body fat causes 13 cancers","aka":[],"tldr":"An IARC working group reviewed over 1,000 studies and concluded there is sufficient evidence that absence of excess body fat lowers the risk of 13 cancers, up from 5 in the 2002 evaluation.","summary":"The International Agency for Research on Cancer convened a working group in 2016 to re-evaluate body fatness and cancer for the IARC Handbooks of Cancer Prevention, reviewing more than 1,000 epidemiological studies, mostly cohort studies, plus mechanistic evidence on insulin, sex hormones and inflammation.\n\nSufficient evidence of a cancer-preventive effect of avoiding excess body fat was found for cancers of the oesophagus (adenocarcinoma), gastric cardia, colon and rectum, liver, gallbladder, pancreas, breast (postmenopausal), corpus uteri, ovary, kidney (renal cell), meningioma, thyroid and multiple myeloma. Relative risks rose with BMI, ranging from about 1.1 per 5 BMI units for postmenopausal breast cancer to around 7 for endometrial cancer at BMI 40 or above.\n\nThe paper reframed obesity as a leading modifiable cancer cause after tobacco.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMsr1606602"},{"label":"IARC Handbooks Volume 16","url":"https://publications.iarc.who.int/570"}],"tags":[],"related":["idea-prev-glp1-cancer-prevention-rct","idea-fund-prevention-moonshot"],"cancers":["colorectal","endometrial","esophageal","hcc","pancreatic","rcc","breast-hr-positive","multiple-myeloma","thyroid","ovarian","gastric"],"sections":["prevention","nutrition-lifestyle"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-funding-allocation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMsr1606602","pmid":"27557308","authors":"Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K (IARC Handbook Working Group)","paperType":"review","findings":["Thirteen cancers with sufficient evidence, up from five (colon, oesophagus, kidney, breast, endometrium) in 2002","Strongest associations: endometrial cancer (RR about 7.1 for BMI 40 or more) and oesophageal adenocarcinoma (RR 4.8)","Colorectal cancer RR 1.3 and postmenopausal breast cancer RR 1.1 for the highest BMI category studied","Evidence in children and young adults suggests early-life body fatness raises adult cancer risk"],"whatItMeans":"Maintaining a healthy weight is now established cancer prevention for over a dozen cancer types. For clinicians and policymakers, obesity belongs alongside tobacco and alcohol in prevention strategy. Whether intentional weight loss in adulthood reverses risk is still being studied, including in trials of GLP-1 drugs.","caveats":["Evidence is observational; residual confounding (diet, activity, socioeconomic status) cannot be excluded","BMI is a crude measure of body fat; central adiposity may matter more","Whether losing weight lowers risk is inferred, mainly from bariatric surgery cohorts","Relative risks for several cancers are modest even though population-attributable fractions are large"],"changedPractice":true},{"id":"paper-ibis-i-tamoxifen-lancet-oncol-2015","kind":"paper","name":"IBIS-I: five years of tamoxifen keeps preventing breast cancer for at least 20 years","aka":[],"tldr":"In women at increased risk, 5 years of tamoxifen reduced breast cancer by 29% over a median 16 years of follow-up, with the benefit continuing long after the pills stopped, but no reduction in breast cancer deaths.","summary":"IBIS-I randomised 7,154 women aged 35-70 at increased risk of breast cancer to tamoxifen 20 mg daily or placebo for 5 years. This long-term analysis had a median follow-up of 16 years.\n\nBreast cancer (invasive plus ductal carcinoma in situ) occurred in 251 tamoxifen-arm and 350 placebo-arm women (HR 0.71). The reduction was similar in the first 10 years and after 10 years, showing a carry-over effect. Oestrogen-receptor-positive invasive cancer fell by a third; ER-negative cancer was unaffected. There was no difference in breast cancer mortality. Endometrial cancer and thromboembolic events were increased mainly during active treatment.\n\nWith the earlier NSABP P-1 trial (49% reduction at 5 years), IBIS-I is the basis for guideline recommendations of tamoxifen for risk reduction.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S1470-2045(14)71171-4"},{"label":"NSABP P-1 (Fisher 1998)","url":"https://doi.org/10.1093/jnci/90.18.1371"}],"tags":[],"related":["idea-prev-low-dose-tamoxifen-uptake","idea-prev-chemoprevention-master-protocol"],"cancers":["breast-hr-positive"],"sections":["prevention","hormonal"],"technologies":["chemoprevention","endocrine-therapy"],"targets":["estrogen-receptor"],"drugs":["tamoxifen"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-hereditary-risk","b-toxicity-qol"],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"Lancet Oncology","year":2015,"doi":"10.1016/S1470-2045(14)71171-4","pmid":"25497694","authors":"Cuzick J, Sestak I, Cawthorn S, et al.","paperType":"rct","findings":["Breast cancer HR 0.71 (95% CI 0.60-0.83) over median 16 years; 251 vs 350 cases","ER-positive invasive breast cancer HR 0.66; no effect on ER-negative disease","Benefit continued beyond 10 years after randomisation (HR 0.69 for years 10 and later)","No significant difference in breast cancer deaths (31 vs 26) or all-cause mortality","Endometrial cancer was increased during the 5 treatment years but not afterwards"],"whatItMeans":"For women at raised risk, a 5-year course of tamoxifen offers long-lasting protection against the commonest kind of breast cancer. Uptake is low because of side effects and fear of rare serious harms; low-dose tamoxifen (TAM-01) is now being tested to improve the balance. It has not been shown to save lives.","caveats":["No mortality benefit despite fewer cancers, partly because ER-positive cancers are highly treatable","Only about 10% of eligible women in most countries accept preventive tamoxifen","Increased endometrial cancer and venous thromboembolism during treatment, concentrated in postmenopausal women","Risk assessment relied on family history criteria of the 1990s rather than modern risk models"],"changedPractice":true,"participants":7154},{"id":"paper-clark-syt-ssx-synovial-sarcoma-nat-genet-1994","kind":"paper","name":"Identification of SYT and SSX, the genes fused by the t(X;18) translocation in synovial sarcoma","aka":[],"tldr":"This study cloned the SYT-SSX (SS18-SSX) gene fusion produced by the chromosome translocation found in essentially every synovial sarcoma, giving the tumour a defining molecular marker and the basis for later targeted and immune therapies.","summary":"Molecular cloning of the t(X;18)(p11.2;q11.2) translocation breakpoint in synovial sarcoma, identifying the SYT gene on chromosome 18 fused to the SSX genes on the X chromosome and characterising the resulting fusion transcripts.","asOf":"2026-09-17","links":[{"label":"Nat Genet 1994","url":"https://doi.org/10.1038/ng0894-502"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/7951320/"}],"tags":[],"related":[],"cancers":["synovial-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":1994,"doi":"10.1038/ng0894-502","pmid":"7951320","authors":"Clark J, Rocques PJ, Crew AJ, et al.","paperType":"basic","findings":["SYT-SSX fusion identified as the product of t(X;18) in synovial sarcoma."],"whatItMeans":"SS18-SSX fusion testing confirms the diagnosis of synovial sarcoma, and the fusion's disruption of the BAF chromatin remodelling complex underlies experimental therapies such as BRD9 degraders; the tumour's MAGE-A4 and NY-ESO-1 expression enabled T-cell receptor therapy.","caveats":["Discovery paper; clinical translation came decades later."],"changedPractice":true},{"id":"paper-amary-idh-cartilaginous-tumours-j-pathol-2011","kind":"paper","name":"IDH1 and IDH2 mutations are frequent in central chondrosarcoma and central and periosteal chondromas","aka":[],"tldr":"Mutations in IDH1 and IDH2, previously known from brain tumours and leukaemia, were found in more than half of central chondrosarcomas and their benign precursors, defining the molecular basis of most cartilage tumours.","summary":"Mutation analysis of over 1,200 mesenchymal tumours identifying IDH1 or IDH2 mutations in 56 percent of central and periosteal cartilaginous tumours, including 71 percent of Ollier disease and Maffucci syndrome cases, but not in peripheral chondrosarcoma, osteochondroma or other sarcomas.","asOf":"2026-09-17","links":[{"label":"J Pathol 2011","url":"https://doi.org/10.1002/path.2913"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21598255/"}],"tags":[],"related":[],"cancers":["chondrosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Journal of Pathology","year":2011,"doi":"10.1002/path.2913","pmid":"21598255","authors":"Amary MF, Bacsi K, Maggiani F, et al.","paperType":"translational","findings":["IDH1 or IDH2 mutations in 56 percent of central and periosteal cartilaginous tumours.","Absent from peripheral chondrosarcoma and other mesenchymal tumours."],"whatItMeans":"IDH mutation testing helps distinguish chondrosarcoma from chondroblastic osteosarcoma and other mimics, and IDH inhibitors are being tested in advanced chondrosarcoma.","caveats":["Ivosidenib trials in chondrosarcoma have shown disease stabilisation rather than shrinkage so far."],"changedPractice":true},{"id":"paper-ielsg37-pmbcl-martelli-jco-2024","kind":"paper","name":"IELSG37: omission of radiotherapy in primary mediastinal B-cell lymphoma after a negative PET scan","aka":[],"tldr":"Patients with primary mediastinal B-cell lymphoma whose PET scan was negative after immunochemotherapy did just as well without consolidation radiotherapy as with it, so radiotherapy can safely be omitted for them.","summary":"Phase 3 non-inferiority trial of 545 patients with primary mediastinal B-cell lymphoma treated with rituximab-containing immunochemotherapy; the 268 with a complete metabolic response on PET were randomised to observation or consolidation mediastinal radiotherapy.\n\nThirty-month progression-free survival was 96.2 percent with observation and 98.5 percent with radiotherapy, meeting non-inferiority, with overall survival of 99 percent in both arms.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2024","url":"https://doi.org/10.1200/JCO-24-01373"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39159403/"}],"tags":[],"related":[],"cancers":["primary-mediastinal-b-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ielsg37"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2024,"doi":"10.1200/JCO-24-01373","pmid":"39159403","authors":"Martelli M, Ceriani L, Ciccone G, et al.","paperType":"rct","findings":["30-month progression-free survival 96.2 percent (observation) vs 98.5 percent (radiotherapy); non-inferior.","Overall survival 99 percent in both arms."],"whatItMeans":"End-of-treatment PET now decides radiotherapy in primary mediastinal B-cell lymphoma: a negative scan means no radiotherapy, whichever chemotherapy regimen was used.","caveats":["Patients with residual PET uptake were not randomised and mostly received radiotherapy.","Long-term second cancer data are pending."],"changedPractice":true,"participants":545},{"id":"paper-royer-plasma-cell-leukaemia-ifm-jco-2016","kind":"paper","name":"IFM 2006 prospective trial: bortezomib-based induction and transplantation for primary plasma cell leukaemia","aka":[],"tldr":"The first prospective trial dedicated to plasma cell leukaemia showed that a bortezomib-based four-drug induction followed by stem cell transplantation could produce remissions in most patients, though relapse remained the rule.","summary":"Phase 2 study of 40 patients with primary plasma cell leukaemia treated with bortezomib, doxorubicin, cyclophosphamide and dexamethasone induction followed by autologous transplant and, for those with a donor, reduced-intensity allogeneic transplant, or a second autologous transplant and maintenance.\n\nResponse after induction was 69 percent, median progression-free survival 15.1 months and median overall survival 36.3 months, a clear improvement on historical series with median survival under a year.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2016","url":"https://doi.org/10.1200/JCO.2015.63.1929"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27114594/"}],"tags":[],"related":[],"cancers":["plasma-cell-leukaemia"],"sections":[],"technologies":[],"targets":[],"drugs":["bortezomib","cyclophosphamide","dexamethasone","doxorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2016,"doi":"10.1200/JCO.2015.63.1929","pmid":"27114594","authors":"Royer B, Minvielle S, Diouf M, et al.","paperType":"observational","findings":["Overall response 69 percent after induction.","Median progression-free survival 15.1 months; median overall survival 36.3 months."],"whatItMeans":"Bortezomib-based induction with early transplant consolidation became the accepted approach for fit patients with this rare aggressive disease; daratumumab-containing quadruplets are now added by extrapolation.","caveats":["Small single-arm study.","Allogeneic transplant did not clearly improve outcomes compared with tandem autologous transplant."],"changedPractice":true,"participants":40},{"id":"paper-ifm-2009-attal-nejm-2017","kind":"paper","name":"IFM 2009: lenalidomide, bortezomib and dexamethasone with or without upfront transplantation for myeloma","aka":[],"tldr":"Adding an early autologous stem cell transplant to modern three-drug therapy delayed relapse in newly diagnosed myeloma, though overall survival was similar because patients in the drug-only arm could have a transplant later.","summary":"Phase 3 trial of 700 adults up to 65 with newly diagnosed multiple myeloma randomised to lenalidomide, bortezomib and dexamethasone (RVD) alone (eight cycles) or RVD with high-dose melphalan and autologous transplant, both followed by a year of lenalidomide maintenance.\n\nMedian progression-free survival was 50 months with transplant against 36 months without; complete response 59 versus 48 percent. Four-year overall survival was 81 versus 82 percent, with most drug-only patients receiving transplant at relapse.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1611750"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28379796/"}],"tags":[],"related":[],"cancers":["myeloma-transplant-eligible"],"sections":[],"technologies":[],"targets":[],"drugs":["bortezomib","dexamethasone","lenalidomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ifm-2009"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1611750","pmid":"28379796","authors":"Attal M, Lauwers-Cances V, Hulin C, et al.","paperType":"rct","findings":["Median progression-free survival 50 vs 36 months (hazard ratio 0.65).","Complete response 59 percent vs 48 percent; no overall survival difference at four years."],"whatItMeans":"Upfront transplant remains standard for fit patients because it lengthens the first remission, but deferring it to first relapse is a reasonable choice for some, particularly with deeper modern induction.","caveats":["Lenalidomide maintenance was limited to one year, shorter than current practice.","Quadruplet induction with daratumumab was not used."],"changedPractice":true,"participants":700},{"id":"paper-igcccg-update-gillessen-jco-2021","kind":"paper","name":"IGCCCG Update Consortium: predicting outcomes in men with metastatic non-seminomatous germ cell tumours","aka":[],"tldr":"Updating the 1997 classification with nearly 10,000 modern patients showed that survival has improved in every risk group, especially poor risk, and added age, lung metastases and LDH as continuous factors to refine individual prediction.","summary":"Analysis of 9,728 men with metastatic non-seminomatous germ cell tumours treated with cisplatin-based chemotherapy between 1990 and 2013 at 30 institutions, validating the IGCCCG groups and developing a refined model incorporating age, presence of lung metastases and LDH as a continuous variable.\n\nFive-year progression-free survival was 89, 75 and 54 percent and overall survival 96, 89 and 67 percent for good, intermediate and poor prognosis groups.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2021","url":"https://doi.org/10.1200/JCO.20.03296"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33822655/"}],"tags":[],"related":[],"cancers":["non-seminoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2021,"doi":"10.1200/JCO.20.03296","pmid":"33822655","authors":"Gillessen S, Sauvé N, Collette L, et al.","paperType":"observational","findings":["Five-year overall survival 96, 89 and 67 percent for good, intermediate and poor prognosis.","Age, lung metastases and continuous LDH added prognostic information."],"whatItMeans":"Treatment intensity decisions still rest on the three IGCCCG groups, and the online calculator from this work gives men a more accurate individual estimate of cure.","caveats":["Retrospective registry data from expert centres."],"changedPractice":true,"participants":9728},{"id":"paper-hodi-imatinib-kit-melanoma-jco-2013","kind":"paper","name":"Imatinib for melanomas harbouring mutationally activated or amplified KIT arising on mucosal, acral and chronically sun-damaged skin","aka":[],"tldr":"Imatinib shrank tumours in about a third of patients with melanoma carrying KIT mutations, but only in those with mutations in specific exons, defining a small targetable subgroup among mucosal and acral melanomas.","summary":"Phase 2 study of 25 patients with advanced melanoma with KIT mutations or amplification arising on mucosal, acral or chronically sun-damaged skin treated with imatinib.\n\nOverall response was 29 percent, with durable responses confined to tumours with KIT mutations in exons 11 and 13 (particularly L576P and K642E), and none in tumours with KIT amplification alone; median time to progression was 3.7 months overall.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2013","url":"https://doi.org/10.1200/JCO.2012.47.7836"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23775962/"}],"tags":[],"related":[],"cancers":["mucosal-melanoma","acral-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2013,"doi":"10.1200/JCO.2012.47.7836","pmid":"23775962","authors":"Hodi FS, Corless CL, Giobbie-Hurder A, et al.","paperType":"observational","findings":["Objective response 29 percent overall; responses limited to exon 11 and 13 mutations.","No responses with KIT amplification without mutation."],"whatItMeans":"KIT testing is worthwhile in mucosal and acral melanoma, and imatinib is a guideline option for exon 11 or 13 mutations after or alongside immunotherapy.","caveats":["Small study; KIT mutations occur in under 15 percent of mucosal and acral melanomas."],"changedPractice":true,"participants":25},{"id":"paper-imatinib-dfsp-eortc-swog-rutkowski-jco-2010","kind":"paper","name":"Imatinib in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase 2 trials (EORTC 62027 and SWOG S0345)","aka":[],"tldr":"Pooling two trials, imatinib shrank tumours in about half of patients with locally advanced or metastatic dermatofibrosarcoma protuberans, confirming that blocking the PDGF receptor works in this fusion-driven sarcoma.","summary":"Pooled analysis of 24 patients with locally advanced or metastatic dermatofibrosarcoma protuberans treated with imatinib in the EORTC 62027 (800 mg) and SWOG S0345 (400 mg) phase 2 trials, both closed early for slow accrual.\n\nObjective response was 46 percent, with median time to progression of 1.7 years, and responses were similar at both doses; tumours with fibrosarcomatous transformation also responded.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2010","url":"https://doi.org/10.1200/JCO.2009.25.7899"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20194851/"}],"tags":[],"related":[],"cancers":["dermatofibrosarcoma-protuberans"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2010,"doi":"10.1200/JCO.2009.25.7899","pmid":"20194851","authors":"Rutkowski P, Van Glabbeke M, Rankin CJ, et al.","paperType":"observational","findings":["Objective response 46 percent.","Median time to progression 1.7 years; no dose-response difference between 400 and 800 mg."],"whatItMeans":"Imatinib is the standard systemic treatment for unresectable, recurrent or metastatic dermatofibrosarcoma protuberans and is used neoadjuvantly to shrink large tumours before surgery.","caveats":["Small pooled cohort from two prematurely closed trials."],"changedPractice":true,"participants":24},{"id":"paper-imbrave050-lancet-2023","kind":"paper","name":"IMbrave050: adjuvant atezolizumab plus bevacizumab versus active surveillance after resection or ablation of high-risk hepatocellular carcinoma","aka":[],"tldr":"A year of atezolizumab plus bevacizumab after surgery or ablation for high-risk liver cancer initially reduced recurrences, but the benefit disappeared with longer follow-up, so there is still no proven adjuvant therapy.","summary":"Phase 3 trial of 668 patients with hepatocellular carcinoma at high risk of recurrence after resection or ablation randomised to 12 months of atezolizumab plus bevacizumab or active surveillance.\n\nAt the first interim analysis recurrence-free survival favoured treatment (hazard ratio 0.72), but the updated analysis showed the curves converging (hazard ratio 0.90) with no overall survival benefit; bleeding and immune-related events occurred in the treatment arm.","asOf":"2026-09-17","links":[{"label":"Lancet 2023","url":"https://doi.org/10.1016/S0140-6736(23)01796-8"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37871608/"}],"tags":[],"related":[],"cancers":["hcc-early"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["imbrave050"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"doi":"10.1016/S0140-6736(23)01796-8","pmid":"37871608","authors":"Qin S, Chen M, Cheng AL, et al.","paperType":"rct","findings":["Interim recurrence-free survival hazard ratio 0.72; updated hazard ratio 0.90 (not significant).","No overall survival benefit."],"whatItMeans":"Adjuvant immunotherapy is not standard after curative treatment of hepatocellular carcinoma; surveillance, antiviral therapy and risk factor control remain the approach.","caveats":["Early positive result was widely reported before the later negative update."],"changedPractice":true,"participants":668},{"id":"paper-imbrave150-nejm-2020","kind":"paper","name":"IMbrave150: atezolizumab plus bevacizumab replaces sorafenib as first treatment for advanced liver cancer","aka":[],"tldr":"Combining the immunotherapy atezolizumab with the anti-blood-vessel antibody bevacizumab helped patients with advanced hepatocellular carcinoma live longer than sorafenib, ending a decade in which nothing had beaten that drug.","summary":"Open-label phase 3 trial of 501 patients with unresectable hepatocellular carcinoma and preserved liver function (Child-Pugh A) who had not received systemic therapy, randomised 2:1 to atezolizumab plus bevacizumab or sorafenib. Co-primary endpoints were OS and PFS.\n\n12-month OS was 67.2% vs 54.6% (HR 0.58) and median PFS 6.8 vs 4.3 months (HR 0.59). The updated analysis showed median OS 19.2 vs 13.4 months (HR 0.66). It made atezolizumab plus bevacizumab the first-line standard, showed that immunotherapy combinations can work in liver cancer despite the failure of single-agent checkpoint inhibitors, and set the template for durvalumab plus tremelimumab (HIMALAYA).","asOf":"2026-09-08","links":[{"label":"NEJM 2020","url":"https://doi.org/10.1056/NEJMoa1915745"},{"label":"ClinicalTrials.gov NCT03434379","url":"https://clinicaltrials.gov/study/NCT03434379"}],"tags":[],"related":[],"cancers":["hcc"],"sections":[],"technologies":["checkpoint-inhibitor","antiangiogenic","monoclonal-antibody"],"targets":["pdl1","vegf"],"drugs":["atezolizumab"],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["os","pfs","first-line","standard-of-care"],"trials":[],"people":["kim-tae-you","lim-ho-yeong"],"bottlenecks":["b-immunotherapy-response","b-global-access","b-combination-space"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa1915745","authors":"Finn RS, Qin S, Ikeda M, et al.","paperType":"rct","findings":["12-month overall survival 67.2% vs 54.6%; HR 0.58 (95% CI 0.42-0.79).","Median PFS 6.8 vs 4.3 months; HR 0.59.","Objective response 27.3% vs 11.9% (RECIST 1.1).","Updated analysis (2022): median OS 19.2 vs 13.4 months, HR 0.66; median PFS 6.9 vs 4.3 months.","Grade 3-4 adverse events similar (57% vs 55%); upper gastrointestinal bleeding with bevacizumab required endoscopic screening for varices within six months before enrolment.","Patient-reported quality of life deteriorated later with the combination (11.2 vs 3.6 months)."],"whatItMeans":"Patients with advanced liver cancer and good liver function should be offered atezolizumab plus bevacizumab (or durvalumab plus tremelimumab) rather than sorafenib as first treatment; median survival is now around 19 months and about a quarter of patients respond. Endoscopy to treat varices before starting bevacizumab is essential because of bleeding risk. Patients with poorer liver function (Child-Pugh B) or autoimmune disease or transplants were not studied.","caveats":["Excluded Child-Pugh B, untreated varices, and prior transplant, so applies to a selected population.","Open-label; sorafenib is now a weak comparator.","Non-viral (metabolic) liver cancer appeared to benefit less in exploratory analyses across several immunotherapy trials.","Bleeding and hypertension from bevacizumab, and cost, remain barriers in high-incidence low-income regions."],"changedPractice":true,"participants":501},{"id":"paper-imerge-imetelstat-mds-lancet-2024","kind":"paper","name":"IMerge: imetelstat, a telomerase inhibitor, for transfusion-dependent lower-risk MDS after erythropoietin has failed","aka":[],"tldr":"In IMerge, imetelstat, the first telomerase inhibitor to reach approval, freed about 40% of heavily transfused MDS patients from transfusions for eight weeks and 28% for six months, versus 15% and 3% with placebo.","summary":"IMerge randomised 178 patients with lower-risk, non-del(5q) MDS who were red-cell transfusion dependent and had relapsed after or were refractory to, or ineligible for, erythropoiesis-stimulating agents to intravenous imetelstat every four weeks or placebo (2:1). The primary endpoint was eight-week red-cell transfusion independence. This was achieved by 39.8% versus 15.0%; 24-week independence was 28.0% versus 3.3%, and responses lasted around a year with reductions in the SF3B1 mutant allele burden suggesting disease modification. Grade 3-4 thrombocytopenia and neutropenia were frequent but short-lived. Imetelstat was approved in 2024, the first drug in its class.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=IMerge%20imetelstat%20lower-risk%20MDS%20Platzbecker%20Lancet%202024"},{"label":"ClinicalTrials.gov NCT02598661","url":"https://clinicaltrials.gov/study/NCT02598661"}],"tags":[],"related":["paper-commands-luspatercept-mds-lancet-2023"],"cancers":["mds"],"sections":[],"technologies":[],"targets":[],"drugs":["imetelstat","luspatercept"],"companies":[],"institutions":[],"pathways":[],"terms":["orr"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-toxicity-qol"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"authors":"Platzbecker U, Santini V, Fenaux P, et al.","paperType":"rct","findings":["178 ESA-relapsed/refractory, transfusion-dependent, non-del(5q) lower-risk MDS patients; imetelstat vs placebo (2:1).","8-week transfusion independence 39.8% vs 15.0%; 24-week independence 28.0% vs 3.3%.","Median duration of transfusion independence about one year in responders.","Reductions in variant allele frequency of SF3B1 and other mutations in responders, suggesting disease-modifying activity.","Grade 3-4 thrombocytopenia and neutropenia common (roughly two-thirds), usually resolving within 4 weeks."],"whatItMeans":"IMerge validated telomerase as a drug target in cancer, decades after its discovery, and gave a second-line option for MDS patients whose anaemia no longer responds to erythropoietin or luspatercept. The hint of clonal reduction is what makes the drug interesting beyond transfusion counts. Cytopenias require close monitoring in the first cycles.","caveats":["Surrogate endpoint (transfusion independence) rather than survival or progression.","High rates of grade 3-4 cytopenias in a population already at bleeding and infection risk.","Only 8-week independence was the primary endpoint; the more meaningful 24-week rate was secondary.","Disease-modifying claims rest on exploratory molecular analyses."],"changedPractice":true,"participants":178},{"id":"paper-imvigor011-nejm-2025","kind":"paper","name":"IMvigor011: using a blood test for leftover cancer to decide who gets immunotherapy after bladder surgery","aka":[],"tldr":"Patients whose blood turned positive for tumour DNA after cystectomy lived longer with atezolizumab than placebo; patients who stayed ctDNA-negative did well without any treatment. It is the first ctDNA-guided adjuvant trial to improve survival.","summary":"IMvigor011 enrolled patients with muscle-invasive bladder cancer after radical cystectomy into ctDNA surveillance with a tumour-informed assay (Signatera). Those who became ctDNA-positive within a year were randomised 2:1 to atezolizumab or placebo; those who remained negative were followed without treatment.\n\nIn the ctDNA-positive randomised population, atezolizumab improved disease-free survival (HR 0.64) and overall survival (HR 0.59) versus placebo. Patients who never became ctDNA-positive had very low recurrence rates, supporting the safety of withholding adjuvant therapy from them. The design was built on the exploratory IMvigor010 ctDNA analysis (Powles, Nature 2021), which had shown benefit confined to ctDNA-positive patients.\n\nRegulatory approval in 2026 made this the first indication defined by a ctDNA result.","asOf":"2026-09-08","links":[{"label":"ClinicalTrials.gov NCT04660344","url":"https://clinicaltrials.gov/study/NCT04660344"},{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=IMvigor011%20atezolizumab%20ctDNA%20Powles"}],"tags":[],"related":["ctdna-mrd-to-adjuvant","idea-ctdna-switch-generalised","idea-bio2-mrd-coverage-with-evidence"],"cancers":["urothelial"],"sections":["diagnostics","immunotherapy"],"technologies":["mrd-testing","liquid-biopsy","checkpoint-inhibitor"],"targets":["pdl1"],"drugs":["atezolizumab","signatera"],"companies":[],"institutions":[],"pathways":[],"terms":["mrd","ctdna","neoadjuvant-adjuvant"],"trials":["imvigor011"],"people":[],"bottlenecks":["b-dormancy-mrd","b-trial-design","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"authors":"Powles T, Chang Y-H, Yamamoto Y, et al.","paperType":"rct","findings":["Disease-free survival in ctDNA-positive patients: HR 0.64 for atezolizumab vs placebo","Overall survival: HR 0.59, a rare survival gain in the adjuvant setting","Patients who remained ctDNA-negative on surveillance had excellent outcomes without treatment","Roughly two-thirds of surveilled patients avoided adjuvant immunotherapy altogether"],"whatItMeans":"After bladder removal, a blood test can now tell who needs immunotherapy and who can safely be spared it. This is the model for MRD-guided adjuvant therapy across cancers: treat the blood-positive, watch the blood-negative.","caveats":["Applies to a tumour-informed assay with defined sampling schedule; other assays and intervals are not interchangeable","Placebo rather than standard adjuvant nivolumab (CheckMate 274) as comparator, so it does not settle which drug or strategy is best","Some ctDNA-negative patients still relapsed; surveillance intervals and duration remain to be optimised","Cost and logistics of serial testing over 12 months are substantial"],"changedPractice":true},{"id":"paper-mateos-20-2-20-smouldering-bcj-2020","kind":"paper","name":"IMWG 20/2/20 risk stratification model for smouldering multiple myeloma","aka":[],"tldr":"A simple score using three numbers, marrow plasma cells over 20 percent, M-protein over 2 grams per decilitre and a free light-chain ratio over 20, sorts smouldering myeloma into risk groups and is used to decide who might be treated early.","summary":"Retrospective study of 1,996 patients with smouldering myeloma from international centres developing a risk model based on marrow plasma cell percentage, M-protein level and involved to uninvolved free light-chain ratio, with cytogenetics as an optional fourth variable.\n\nTwo-year progression risk ranged from about 6 percent with no risk factors to about 44 percent with all three, and the model was validated in an independent cohort.","asOf":"2026-09-17","links":[{"label":"Blood Cancer J 2020","url":"https://doi.org/10.1038/s41408-020-00366-3"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33067414/"}],"tags":[],"related":[],"cancers":["smouldering-myeloma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood-cancer-journal"],"dependsOn":[],"notes":[],"journal":"Blood cancer journal","year":2020,"doi":"10.1038/s41408-020-00366-3","pmid":"33067414","authors":"Mateos MV, Kumar S, Dimopoulos MA, et al.","paperType":"observational","findings":["Two-year progression risk 6 percent, 18 percent and 44 percent for low, intermediate and high risk.","Adding high-risk cytogenetics improved discrimination."],"whatItMeans":"The 20/2/20 model defines high-risk smouldering myeloma in current guidelines and trial eligibility, including in AQUILA-informed practice.","caveats":["Retrospective and based on values at diagnosis; evolving markers over time also matter."],"changedPractice":true,"participants":1996},{"id":"paper-imwg-plasma-cell-leukaemia-definition-bcj-2021","kind":"paper","name":"IMWG consensus definition of primary plasma cell leukaemia at 5 percent circulating plasma cells","aka":[],"tldr":"The International Myeloma Working Group lowered the threshold for diagnosing plasma cell leukaemia from 20 percent to 5 percent circulating plasma cells, because patients at 5 percent already have the same dismal outlook.","summary":"Consensus statement from the International Myeloma Working Group reviewing evidence that 5 percent or more circulating plasma cells on a blood film carries the same poor survival as the historical 20 percent threshold, and redefining primary plasma cell leukaemia accordingly, with recommendations for work-up.","asOf":"2026-09-17","links":[{"label":"Blood Cancer J 2021","url":"https://doi.org/10.1038/s41408-021-00587-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34857730/"}],"tags":[],"related":[],"cancers":["plasma-cell-leukaemia"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood-cancer-journal"],"dependsOn":[],"notes":[],"journal":"Blood cancer journal","year":2021,"doi":"10.1038/s41408-021-00587-0","pmid":"34857730","authors":"Fernández de Larrea C, Kyle R, Rosiñol L, et al.","paperType":"guideline","findings":[],"whatItMeans":"More patients now receive the diagnosis and the intensive, transplant-based approach that goes with it; trial eligibility uses the new definition.","caveats":["Based on retrospective series; treatment recommendations remain largely extrapolated from myeloma."],"changedPractice":true},{"id":"paper-imwg-criteria-rajkumar-lancet-oncol-2014","kind":"paper","name":"IMWG updated criteria for the diagnosis of multiple myeloma (2014)","aka":[],"tldr":"The 2014 International Myeloma Working Group criteria allow myeloma to be diagnosed and treated before organ damage occurs when biomarkers such as 60 percent marrow plasma cells or a very high light-chain ratio predict imminent progression.","summary":"Updated diagnostic criteria adding three myeloma-defining biomarkers (clonal marrow plasma cells 60 percent or more, involved to uninvolved free light chain ratio 100 or more, more than one focal lesion on MRI) to the classic CRAB features, and revising the definitions of smouldering myeloma and related plasma cell disorders.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2014","url":"https://doi.org/10.1016/S1470-2045(14)70442-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25439696/"}],"tags":[],"related":[],"cancers":["smouldering-myeloma","plasma-cell-leukaemia"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2014,"doi":"10.1016/S1470-2045(14)70442-5","pmid":"25439696","authors":"Rajkumar SV, Dimopoulos MA, Palumbo A, et al.","paperType":"guideline","findings":[],"whatItMeans":"Whether a patient is labelled smouldering or active myeloma, and therefore whether treatment starts, depends on these criteria.","caveats":["Biomarker thresholds were based on retrospective cohorts and continue to be refined."],"changedPractice":true},{"id":"paper-gotoda-endoscopic-resection-criteria-gastric-cancer-2000","kind":"paper","name":"Incidence of lymph node metastasis from early gastric cancer: estimation from 5,265 patients at two large centres","aka":[],"tldr":"By analysing over 5,000 surgical cases, this study identified early gastric cancers with essentially zero risk of lymph node spread, defining the expanded criteria that allow endoscopic removal instead of gastrectomy.","summary":"Retrospective analysis of 5,265 patients who underwent gastrectomy with lymph node dissection for early gastric cancer at two Japanese centres, examining the incidence of nodal metastasis by depth, size, histology, ulceration and lymphovascular invasion.\n\nNo nodal metastases were found in differentiated intramucosal cancers without ulceration regardless of size, in ulcerated differentiated intramucosal cancers up to 3 cm, or in differentiated cancers with minute submucosal invasion up to 3 cm without lymphovascular invasion.","asOf":"2026-09-17","links":[{"label":"Gastric Cancer 2000","url":"https://doi.org/10.1007/PL00011720"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/11984739/"}],"tags":[],"related":[],"cancers":["early-gastric-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["gastric-cancer"],"dependsOn":[],"notes":[],"journal":"Gastric cancer","year":2000,"doi":"10.1007/PL00011720","pmid":"11984739","authors":"Gotoda T, Yanagisawa A, Sasako M, et al.","paperType":"observational","findings":["Zero nodal metastasis in differentiated intramucosal cancers without ulceration of any size.","Zero nodal metastasis in differentiated cancers with submucosal invasion under 500 micrometres up to 3 cm without lymphovascular invasion."],"whatItMeans":"The expanded criteria for endoscopic submucosal dissection in Japanese and international guidelines derive from this analysis.","caveats":["Retrospective surgical series; undifferentiated-type criteria were validated later in JCOG1009/1010."],"changedPractice":true,"participants":5265},{"id":"paper-sinicrope-early-onset-crc-nejm-2022","kind":"paper","name":"Increasing incidence of early-onset colorectal cancer (review)","aka":[],"tldr":"This review explains the rise of colorectal cancer in adults under 50, what is known about its causes and distinct features, and how screening ages and clinical management have responded.","summary":"Review of the epidemiology of colorectal cancer diagnosed before age 50, including birth-cohort effects, proposed risk factors (obesity, diet, microbiome, antibiotics), clinical and molecular features (left-sided and rectal predominance, later stage at diagnosis, similar mutational profiles in sporadic cases), germline findings, and implications for screening and treatment.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMra2200869"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35443109/"}],"tags":[],"related":[],"cancers":["early-onset-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMra2200869","pmid":"35443109","authors":"Sinicrope FA.","paperType":"review","findings":[],"whatItMeans":"The early-onset colorectal cancer page's emphasis on investigating rectal bleeding at any age, universal germline testing and avoiding treatment escalation on age alone follows this framing.","caveats":["Causes remain hypotheses; no single exposure explains the trend."],"changedPractice":false},{"id":"paper-indigo-nejm-2023","kind":"paper","name":"INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma","aka":[],"tldr":"An oral drug that blocks the mutant IDH enzyme more than doubled the time before slow-growing IDH-mutant brain tumours progressed, letting patients postpone radiotherapy and chemotherapy for years.","summary":"Double-blind, placebo-controlled phase 3 trial of 331 patients with residual or recurrent grade 2 IDH1- or IDH2-mutant oligodendroglioma or astrocytoma who had undergone surgery alone and were candidates for watch-and-wait, randomised to vorasidenib (a brain-penetrant dual IDH1/2 inhibitor) or placebo. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 27.7 vs 11.1 months (HR 0.39) and the time to next intervention (radiotherapy or chemotherapy) was markedly delayed (HR 0.26). It was the first targeted therapy approved for glioma (FDA 2024) and the first drug to change the natural history of low-grade glioma, a disease of young adults where treatment toxicity accumulates over decades.","asOf":"2026-09-08","links":[{"label":"NEJM 2023","url":"https://doi.org/10.1056/NEJMoa2304194"},{"label":"ClinicalTrials.gov NCT04164901","url":"https://clinicaltrials.gov/study/NCT04164901"}],"tags":[],"related":[],"cancers":["glioblastoma"],"sections":[],"technologies":["kinase-inhibitors","mri"],"targets":["idh"],"drugs":["vorasidenib"],"companies":["servier"],"institutions":["mskcc"],"pathways":[],"terms":["pfs","oncogene-addiction"],"trials":[],"people":[],"bottlenecks":["b-brain-delivery","b-toxicity-qol","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2304194","authors":"Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al.","paperType":"rct","findings":["Median PFS 27.7 vs 11.1 months; HR 0.39 (95% CI 0.27-0.56).","Time to next intervention: HR 0.26 (95% CI 0.15-0.43); at 24 months, 83.4% vs 27.0% had not needed further treatment.","Tumour growth rate was reversed in many patients, with volumetric shrinkage on vorasidenib versus continued growth on placebo.","Grade 3 or higher adverse events 22.8% vs 13.5%, mainly raised liver enzymes (ALT increase in about 10%).","Crossover from placebo to vorasidenib was allowed at progression; overall survival is not yet evaluable."],"whatItMeans":"Young adults with a grade 2 IDH-mutant glioma who have had surgery can now take a daily tablet that slows or reverses tumour growth and defers radiotherapy and chemotherapy, both of which carry long-term cognitive costs, by years. It confirms that the IDH mutation is a driver that can be targeted, not just a marker. Whether it improves survival or cognition over the long term, and whether it helps in higher-grade or previously treated tumours, is unknown.","caveats":["PFS and time to next intervention are surrogates; overall survival data will take many years given the indolent disease.","Only patients who had not received radiotherapy or chemotherapy were eligible; the drug's role after those treatments is undefined.","Liver toxicity requires regular monitoring.","Indefinite treatment of young patients is costly, and stopping rules are not established."],"changedPractice":true,"participants":331},{"id":"paper-pietrantonio-msi-gastric-meta-analysis-jco-2019","kind":"paper","name":"Individual patient data meta-analysis of microsatellite instability as a biomarker in gastric cancer (MAGIC, CLASSIC, ARTIST, ITACA-S)","aka":[],"tldr":"Pooling four trials showed that microsatellite-unstable gastric cancers have a much better prognosis after surgery and gain nothing from perioperative or adjuvant chemotherapy, which may even harm them.","summary":"Individual patient data meta-analysis of 1,556 patients from four randomised trials of resectable gastric cancer (MAGIC, CLASSIC, ARTIST, ITACA-S), of whom 7.8 percent had microsatellite instability-high tumours.\n\nFive-year disease-free survival was 71.8 versus 52.3 percent and overall survival 77.5 versus 59.3 percent for microsatellite-unstable versus stable tumours; chemotherapy improved survival in stable tumours (hazard ratio 0.65) but not in unstable ones (hazard ratio 1.03), with a suggestion of harm.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.19.01124"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31513484/"}],"tags":[],"related":[],"cancers":["gastric-msi-high"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.19.01124","pmid":"31513484","authors":"Pietrantonio F, Miceli R, Raimondi A, et al.","paperType":"meta-analysis","findings":["Five-year overall survival 77.5 percent (unstable) vs 59.3 percent (stable) with surgery alone.","Chemotherapy hazard ratio 1.03 in microsatellite-unstable tumours vs 0.65 in stable."],"whatItMeans":"Microsatellite instability testing is recommended before perioperative chemotherapy for gastric cancer, and immunotherapy-based trials are the preferred approach for unstable tumours.","caveats":["Small number of microsatellite-unstable patients (121); confidence intervals were wide."],"changedPractice":true,"participants":1556},{"id":"paper-innovatv-301-tisotumab-nejm-2024","kind":"paper","name":"innovaTV 301: tisotumab vedotin versus chemotherapy as second- or third-line therapy for recurrent cervical cancer","aka":[],"tldr":"The tissue factor-directed antibody-drug conjugate tisotumab vedotin lengthened survival compared with chemotherapy in cervical cancer that had progressed after first-line treatment, at the cost of eye and nerve side effects.","summary":"Phase 3 trial of 502 patients with recurrent or metastatic cervical cancer after one or two prior systemic regimens randomised to tisotumab vedotin or investigator's choice chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan or pemetrexed).\n\nMedian overall survival was 11.5 versus 9.5 months (hazard ratio 0.70), progression-free survival 4.2 versus 2.9 months and objective response 17.8 versus 5.2 percent; ocular events, peripheral neuropathy and bleeding were the characteristic toxicities.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2024","url":"https://doi.org/10.1056/NEJMoa2313811"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38959480/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["tisotumab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["innovatv-301"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2313811","pmid":"38959480","authors":"Vergote I, González-Martín A, Fujiwara K, et al.","paperType":"rct","findings":["Median overall survival 11.5 vs 9.5 months; hazard ratio 0.70.","Objective response 17.8 percent vs 5.2 percent."],"whatItMeans":"Tisotumab vedotin is the standard second-line treatment for recurrent cervical cancer after chemo-immunotherapy, with a mandatory eye-care protocol.","caveats":["Modest absolute gains.","Conjunctivitis and keratitis require prophylactic eye drops and regular examinations."],"changedPractice":true,"participants":502},{"id":"paper-ino-vate-inotuzumab-all-nejm-2016","kind":"paper","name":"INO-VATE: inotuzumab ozogamicin, a CD22 antibody-drug conjugate, versus chemotherapy for relapsed adult B-cell ALL","aka":[],"tldr":"A CD22 antibody-drug conjugate produced complete remission in 81% of adults with relapsed ALL compared with 29% on chemotherapy, at the cost of liver toxicity in about one in ten.","summary":"INO-VATE randomised 326 adults with relapsed or refractory CD22-positive B-cell ALL to inotuzumab ozogamicin or standard intensive salvage chemotherapy. The two primary endpoints were complete remission (analysed in the first 218 patients) and overall survival. Complete remission was 80.7% versus 29.4%, with MRD-negativity among responders 78.4% versus 28.1%, and median PFS 5.0 versus 1.8 months. Median OS was 7.7 versus 6.7 months (hazard ratio 0.77), which did not meet the prespecified boundary, although two-year survival was 23% versus 10%. Hepatic veno-occlusive disease occurred in 11% of inotuzumab patients, especially after subsequent transplant with dual-alkylator conditioning.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1509277"},{"label":"ClinicalTrials.gov NCT01564784","url":"https://clinicaltrials.gov/study/NCT01564784"}],"tags":[],"related":["inotuzumab-then-transplant-caution"],"cancers":["all-leukemia"],"sections":[],"technologies":["adc","allogeneic-hsct"],"targets":["cd22"],"drugs":["inotuzumab-ozogamicin","blinatumomab"],"companies":["pfizer"],"institutions":["md-anderson"],"pathways":[],"terms":["mrd","os"],"trials":[],"people":["hagop-kantarjian"],"bottlenecks":["b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1509277","authors":"Kantarjian HM, DeAngelo DJ, Stelljes M, et al.","paperType":"rct","findings":["326 adults with relapsed/refractory B-ALL; inotuzumab ozogamicin vs salvage chemotherapy.","Complete remission 80.7% vs 29.4%; MRD-negativity among responders 78.4% vs 28.1%.","Median PFS 5.0 vs 1.8 months; more patients bridged to transplant (41% vs 11%).","Median OS 7.7 vs 6.7 months (HR 0.77); 2-year OS 23% vs 10%.","Veno-occlusive disease 11% vs 1%, highest after transplant with dual-alkylator conditioning."],"whatItMeans":"INO-VATE made inotuzumab a standard salvage therapy for adult ALL and a common route to transplant, and, with the TOWER trial of blinatumomab, moved adult ALL from chemotherapy-only salvage to immunotherapy. Both drugs have since been pulled into front-line regimens. The liver toxicity signal shaped how transplant conditioning is chosen after inotuzumab.","caveats":["OS benefit was modest and did not meet the trial's statistical threshold at the primary analysis.","Veno-occlusive disease is a serious, sometimes fatal, toxicity that constrains dosing before transplant.","Open-label with heterogeneous chemotherapy comparators.","Requires CD22 expression; antigen loss is a resistance mechanism."],"changedPractice":true,"participants":326},{"id":"paper-tcga-ovarian-nature-2011","kind":"paper","name":"Integrated genomic analyses of ovarian carcinoma (The Cancer Genome Atlas)","aka":[],"tldr":"Sequencing nearly 500 high-grade serous ovarian cancers showed that almost all carry TP53 mutations and about half have defects in homologous recombination DNA repair, the biology that PARP inhibitors exploit.","summary":"Integrated genomic analysis by The Cancer Genome Atlas of 489 high-grade serous ovarian adenocarcinomas, finding TP53 mutations in 96 percent, germline or somatic BRCA1/2 mutations in about 20 percent, homologous recombination defects in about half, widespread copy-number changes, and four transcriptional subtypes.","asOf":"2026-09-17","links":[{"label":"Nature 2011","url":"https://doi.org/10.1038/nature10166"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21720365/"}],"tags":[],"related":[],"cancers":["high-grade-serous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2011,"doi":"10.1038/nature10166","pmid":"21720365","authors":"Cancer Genome Atlas Research Network.","paperType":"translational","findings":["TP53 mutated in 96 percent of high-grade serous ovarian cancers.","Homologous recombination pathway defects in about 50 percent, including BRCA1/2 in about 20 percent."],"whatItMeans":"The homologous recombination deficiency concept, and the case for testing all high-grade serous cancers for BRCA and related defects, come from this dataset.","caveats":["Research-grade profiling of primary tumours; clinical homologous recombination deficiency assays came later."],"changedPractice":true,"participants":489},{"id":"paper-tcga-endometrial-nature-2013","kind":"paper","name":"Integrated genomic characterisation of endometrial carcinoma (The Cancer Genome Atlas)","aka":[],"tldr":"Sequencing of 373 endometrial cancers revealed four molecular groups, POLE ultramutated, microsatellite unstable, copy-number low and copy-number high, that cut across the traditional endometrioid and serous types and predict outcome.","summary":"Integrated genomic, transcriptomic and proteomic analysis of 373 endometrial carcinomas by The Cancer Genome Atlas defining four groups: POLE ultramutated (with excellent outcome), microsatellite instability hypermutated, copy-number low (endometrioid) and copy-number high (serous-like, TP53-mutated, worst outcome); about a quarter of high-grade endometrioid tumours resembled serous carcinoma molecularly.","asOf":"2026-09-17","links":[{"label":"Nature 2013","url":"https://doi.org/10.1038/nature12113"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23636398/"}],"tags":[],"related":[],"cancers":["endometrial-pole-ultramutated","endometrial-p53-abnormal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2013,"doi":"10.1038/nature12113","pmid":"23636398","authors":"Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al.","paperType":"translational","findings":["Four molecular subgroups with distinct progression-free survival.","25 percent of high-grade endometrioid tumours had serous-like copy-number-high profiles."],"whatItMeans":"This is the origin of the molecular classification now used for every endometrial cancer, translated into a practical test by ProMisE.","caveats":["Research-grade sequencing; clinical surrogates were needed for routine use."],"changedPractice":true,"participants":373},{"id":"paper-mackay-paediatric-hgg-cancer-cell-2017","kind":"paper","name":"Integrated molecular meta-analysis of 1,000 paediatric high-grade and diffuse intrinsic pontine gliomas","aka":[],"tldr":"Pooling molecular data from a thousand childhood high-grade gliomas showed they are a collection of distinct diseases defined by mutations such as histone H3 K27M and G34R, IDH, and BRAF, with different ages, locations and survival, rather than a single tumour type.","summary":"Meta-analysis of published and unpublished molecular data on 1,000 paediatric high-grade gliomas and diffuse intrinsic pontine gliomas, integrating mutations, copy number, methylation and expression to define subgroups by histone H3 and IDH status and by other drivers, with clinical correlates and survival.\n\nSubgroups differed markedly in age, anatomical location and outcome, and the analysis identified targetable alterations (BRAF, NTRK, ALK, ROS1, PDGFRA) in a subset of tumours.","asOf":"2026-09-17","links":[{"label":"Cancer Cell 2017","url":"https://doi.org/10.1016/j.ccell.2017.08.017"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28966033/"}],"tags":[],"related":[],"cancers":["paediatric-high-grade-glioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-cell"],"dependsOn":[],"notes":[],"journal":"Cancer Cell","year":2017,"doi":"10.1016/j.ccell.2017.08.017","pmid":"28966033","authors":"Mackay A, Burford A, Carvalho D, et al.","paperType":"translational","findings":["Histone H3 K27M and G34R/V, IDH1 and wild-type subgroups with distinct age, location and survival distributions.","Targetable kinase alterations identified in a minority, especially in infants."],"whatItMeans":"The 2021 WHO paediatric-type diffuse high-grade glioma categories, and the practice of profiling every childhood glioma for a targetable fusion or mutation, rest on this landscape.","caveats":["Heterogeneous retrospective data with variable treatment information."],"changedPractice":true,"participants":1000},{"id":"paper-interfant-06-pieters-jco-2019","kind":"paper","name":"Interfant-06: outcome of infants under one year with acute lymphoblastic leukaemia","aka":[],"tldr":"This international trial of infant leukaemia found no benefit from adding myeloid-style chemotherapy courses, and confirmed that KMT2A-rearranged infants remain a high-risk group with survival under 50 percent, setting the baseline that blinatumomab has since improved.","summary":"International trial of 651 infants with ALL treated on the Interfant backbone, with 240 medium- and high-risk KMT2A-rearranged infants randomised to standard lymphoid-style consolidation or myeloid-style (ADE and MAE) courses; allogeneic transplant was indicated for high-risk patients.\n\nSix-year event-free survival was 46.1 percent overall; there was no difference between consolidation arms (39.3 versus 37.2 percent), and KMT2A-rearranged infants had 36 percent event-free survival against 74 percent for germline KMT2A.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.19.00261"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31283407/"}],"tags":[],"related":[],"cancers":["all-infant"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["interfant-06"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.19.00261","pmid":"31283407","authors":"Pieters R, De Lorenzo P, Ancliffe P, et al.","paperType":"rct","findings":["Six-year event-free survival 46.1 percent overall; 36 percent for KMT2A-rearranged infants.","No benefit from myeloid-style consolidation (39.3 percent vs 37.2 percent)."],"whatItMeans":"Interfant-06 is the backbone and control benchmark for infant ALL; the successor Interfant-21 adds blinatumomab after this trial showed chemotherapy intensification had reached its limit.","caveats":["Toxicity-related deaths remained substantial in infants."],"changedPractice":true,"participants":651},{"id":"paper-interfant-99-lancet-2007","kind":"paper","name":"Interfant-99: a treatment protocol for infants under one year with acute lymphoblastic leukaemia","aka":[],"tldr":"The first international infant leukaemia trial established a hybrid chemotherapy backbone and showed that a late intensification course did not help, while identifying age under six months, KMT2A rearrangement and poor steroid response as the key risk factors.","summary":"International observational study and randomised trial of 482 infants with ALL treated with a hybrid protocol including elements of ALL and AML therapy, with randomisation to a late intensification course or not.\n\nFour-year event-free survival was 47 percent overall with no benefit from late intensification; KMT2A rearrangement, age under six months, high white count and poor prednisone response defined high-risk infants with event-free survival around 20 percent.","asOf":"2026-09-17","links":[{"label":"Lancet 2007","url":"https://doi.org/10.1016/S0140-6736(07)61126-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/17658395/"}],"tags":[],"related":[],"cancers":["all-infant"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2007,"doi":"10.1016/S0140-6736(07)61126-X","pmid":"17658395","authors":"Pieters R, Schrappe M, De Lorenzo P, et al.","paperType":"rct","findings":["Four-year event-free survival 47 percent overall.","No benefit from late intensification (hazard ratio 1.07)."],"whatItMeans":"Interfant-99 defined the risk groups and backbone used in Interfant-06 and Interfant-21.","caveats":["Outcomes remained poor for high-risk infants, motivating later immunotherapy."],"changedPractice":true,"participants":482},{"id":"paper-interlace-lancet-2024","kind":"paper","name":"INTERLACE: induction chemotherapy before chemoradiotherapy for locally advanced cervical cancer","aka":[],"tldr":"Six weekly cycles of carboplatin and paclitaxel given immediately before standard chemoradiation improved survival in locally advanced cervical cancer by about eight percentage points at five years, using cheap widely available drugs.","summary":"Phase 3 trial of 500 women with locally advanced cervical cancer (stage IB1 node-positive to IVA) randomised to six weeks of induction carboplatin-paclitaxel followed by cisplatin chemoradiotherapy, or chemoradiotherapy alone.\n\nFive-year progression-free survival was 72 versus 64 percent (hazard ratio 0.65) and overall survival 80 versus 72 percent (hazard ratio 0.60), with more haematological toxicity during induction but no compromise of chemoradiation delivery.","asOf":"2026-09-17","links":[{"label":"Lancet 2024","url":"https://doi.org/10.1016/S0140-6736(24)01438-7"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39419054/"}],"tags":[],"related":[],"cancers":["locally-advanced-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["interlace"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"doi":"10.1016/S0140-6736(24)01438-7","pmid":"39419054","authors":"McCormack M, Eminowicz G, Gallardo D, et al.","paperType":"rct","findings":["Five-year progression-free survival 72 percent vs 64 percent; hazard ratio 0.65.","Five-year overall survival 80 percent vs 72 percent; hazard ratio 0.60."],"whatItMeans":"Short induction chemotherapy is a standard option before chemoradiation, particularly where pembrolizumab is unaffordable, and can be delivered in most health systems.","caveats":["Most patients had stage IIB disease; fewer node-positive and stage III patients.","Whether induction adds to chemoradiation plus pembrolizumab is untested."],"changedPractice":true,"participants":500},{"id":"paper-icc-2022-arber-blood-2022","kind":"paper","name":"International Consensus Classification of myeloid neoplasms and acute leukaemias (2022)","aka":[],"tldr":"A parallel classification to the WHO 2022 edition from an international expert group, which among other changes creates an MDS/AML category for 10 to 19 percent blasts and gives TP53-mutated disease its own entities.","summary":"Classification of myeloid neoplasms and acute leukaemias integrating morphology, clinical features and genomics, produced by the International Consensus Classification group, with new categories for MDS/AML, TP53-mutated myeloid neoplasms and genetically defined AML subtypes at lower blast thresholds.","asOf":"2026-09-17","links":[{"label":"Blood 2022","url":"https://doi.org/10.1182/blood.2022015850"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35767897/"}],"tags":[],"related":[],"cancers":["mds-higher-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2022,"doi":"10.1182/blood.2022015850","pmid":"35767897","authors":"Arber DA, Orazi A, Hasserjian RP, et al.","paperType":"guideline","findings":[],"whatItMeans":"Trial eligibility and risk stratification in AML and MDS often refer to this classification alongside the WHO edition; the two overlap heavily but not completely.","caveats":["Coexists with the WHO fifth edition, so the same marrow may carry two names."],"changedPractice":true},{"id":"paper-dawood-inflammatory-breast-consensus-ann-oncol-2011","kind":"paper","name":"International expert panel consensus on the diagnosis and treatment of inflammatory breast cancer","aka":[],"tldr":"This consensus statement standardised how inflammatory breast cancer is diagnosed, with rapid onset of breast redness and swelling involving at least a third of the breast, and set out its trimodality treatment.","summary":"Consensus from an international expert panel defining the clinical diagnostic criteria for inflammatory breast cancer, recommended staging, the requirement for biopsy confirmation, and treatment with neoadjuvant systemic therapy followed by modified radical mastectomy and post-mastectomy radiotherapy, with HER2-directed therapy where appropriate.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2011","url":"https://doi.org/10.1093/annonc/mdq345"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20603440/"}],"tags":[],"related":[],"cancers":["inflammatory-breast-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2011,"doi":"10.1093/annonc/mdq345","pmid":"20603440","authors":"Dawood S, Merajver SD, Viens P, et al.","paperType":"guideline","findings":[],"whatItMeans":"The definition used in trials and clinics, and the insistence on systemic therapy first and mastectomy rather than breast conservation, come from this document.","caveats":["Diagnosis remains clinical and subjective; molecular definitions are still lacking."],"changedPractice":true},{"id":"paper-igcccg-classification-jco-1997","kind":"paper","name":"International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers","aka":[],"tldr":"Pooling over 5,000 patients, the IGCCCG classification sorted metastatic testicular cancer into good, intermediate and poor prognosis groups using tumour markers, primary site and non-lung metastases, and still decides how many cycles of chemotherapy a man receives.","summary":"Analysis of 5,202 patients with metastatic non-seminomatous and 660 with seminomatous germ cell tumours treated with cisplatin-based chemotherapy, identifying tumour marker levels (AFP, hCG, LDH), mediastinal primary site and non-pulmonary visceral metastases as independent prognostic factors and defining good (56 percent, 92 percent five-year survival), intermediate (28 percent, 80 percent) and poor (16 percent, 48 percent) prognosis groups for non-seminoma.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 1997","url":"https://doi.org/10.1200/JCO.1997.15.2.594"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/9053482/"}],"tags":[],"related":[],"cancers":["non-seminoma","seminoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":1997,"doi":"10.1200/JCO.1997.15.2.594","pmid":"9053482","authors":"Unknown","paperType":"methods","findings":["Good, intermediate and poor prognosis non-seminoma: five-year survival 92, 80 and 48 percent.","Seminoma: good (86 percent) and intermediate (72 percent) groups by non-pulmonary visceral metastases."],"whatItMeans":"Three cycles of BEP for good risk and four for intermediate and poor risk follow directly from this classification, which was updated in 2021 with modern survival figures.","caveats":["Survival figures predate modern supportive care; the 2021 update reports better outcomes in all groups."],"changedPractice":true,"participants":5202},{"id":"paper-cavalli-medulloblastoma-subtypes-cancer-cell-2017","kind":"paper","name":"Intertumoural heterogeneity within medulloblastoma subgroups","aka":[],"tldr":"Combining gene expression and methylation data from 763 medulloblastomas split the four subgroups into twelve subtypes with distinct genetics and survival, refining who is at high and low risk within each group.","summary":"Integrative clustering of 763 primary medulloblastomas using DNA methylation and gene expression identifying twelve subtypes: two WNT, four SHH, three group 3 and three group 4, each with distinct copy-number alterations, mutations, age distribution and survival.","asOf":"2026-09-17","links":[{"label":"Cancer Cell 2017","url":"https://doi.org/10.1016/j.ccell.2017.05.005"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28609654/"}],"tags":[],"related":[],"cancers":["medulloblastoma-group-3-4","medulloblastoma-shh","medulloblastoma-wnt"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-cell"],"dependsOn":[],"notes":[],"journal":"Cancer Cell","year":2017,"doi":"10.1016/j.ccell.2017.05.005","pmid":"28609654","authors":"Cavalli FMG, Remke M, Rampasek L, et al.","paperType":"translational","findings":["Twelve subtypes with distinct survival; for example SHH-alpha (TP53-mutant, children) had poor outcome and group 3-gamma (MYC-amplified) the worst."],"whatItMeans":"Subtype-level classification, particularly separating infant and TP53-mutant SHH tumours and MYC-amplified group 3 tumours, guides current risk stratification and trial design.","caveats":["Subtype assignment requires methylation profiling."],"changedPractice":true,"participants":763},{"id":"paper-intrigue-ripretinib-vs-sunitinib-jco-2022","kind":"paper","name":"INTRIGUE: ripretinib versus sunitinib in advanced gastrointestinal stromal tumour after imatinib","aka":[],"tldr":"Ripretinib was not better than sunitinib as second-line treatment for gastrointestinal stromal tumour overall, but it was better tolerated and worked better in tumours with KIT exon 11 plus exon 17/18 secondary mutations, while sunitinib was better for exon 13/14 mutations.","summary":"Phase 3 open-label trial of 453 patients with advanced GIST after imatinib randomised to ripretinib or sunitinib.\n\nMedian progression-free survival was 8.3 versus 7.0 months in the intention-to-treat population (hazard ratio 0.91, not superior); ripretinib had fewer grade 3 to 4 adverse events (41 versus 66 percent) and better quality of life. Circulating tumour DNA analysis showed ripretinib superior in exon 11 plus 17/18 mutations and sunitinib superior in exon 11 plus 13/14 mutations.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2022","url":"https://doi.org/10.1200/JCO.22.00294"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35947817/"}],"tags":[],"related":[],"cancers":["gist-imatinib-resistant"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib","ripretinib","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2022,"doi":"10.1200/JCO.22.00294","pmid":"35947817","authors":"Bauer S, Jones RL, Blay JY, et al.","paperType":"rct","findings":["Median progression-free survival 8.3 vs 7.0 months; hazard ratio 0.91 (not superior).","Exon 17/18 secondary mutations: ripretinib 14.2 vs 1.5 months; exon 13/14: sunitinib 15.0 vs 4.0 months."],"whatItMeans":"Sunitinib remains the standard second-line treatment, with ripretinib as a better-tolerated alternative, and mutation-guided choice by circulating tumour DNA is being tested prospectively in INSIGHT.","caveats":["Failed its primary superiority endpoint.","Mutation subgroup analysis was exploratory."],"changedPractice":true,"participants":453},{"id":"paper-invictus-ripretinib-lancet-oncol-2020","kind":"paper","name":"INVICTUS: ripretinib in advanced gastrointestinal stromal tumours after three or more prior kinase inhibitors","aka":[],"tldr":"The switch-control KIT inhibitor ripretinib lengthened progression-free survival from one to six months and improved survival compared with placebo in gastrointestinal stromal tumours that had failed imatinib, sunitinib and regorafenib.","summary":"Phase 3 placebo-controlled trial of 129 patients with advanced GIST after at least three prior kinase inhibitors randomised 2:1 to ripretinib 150 mg daily or placebo with crossover.\n\nMedian progression-free survival was 6.3 versus 1.0 months (hazard ratio 0.15) and median overall survival 15.1 versus 6.6 months (hazard ratio 0.36); alopecia, myalgia and hand-foot syndrome were common and mostly low grade.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2020","url":"https://doi.org/10.1016/S1470-2045(20)30168-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32511981/"}],"tags":[],"related":[],"cancers":["gist-imatinib-resistant"],"sections":[],"technologies":[],"targets":[],"drugs":["ripretinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["invictus"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2020,"doi":"10.1016/S1470-2045(20)30168-6","pmid":"32511981","authors":"Blay JY, Serrano C, Heinrich MC, et al.","paperType":"rct","findings":["Median progression-free survival 6.3 vs 1.0 months; hazard ratio 0.15.","Median overall survival 15.1 vs 6.6 months; hazard ratio 0.36."],"whatItMeans":"Ripretinib is the approved fourth-line treatment for GIST and is being tested earlier in mutation-selected patients (INSIGHT).","caveats":["Objective response was only 9 percent; benefit is disease stabilisation.","Small trial in a heavily pretreated population."],"changedPractice":true,"participants":129},{"id":"paper-ipss-m-bernard-nejm-evidence-2022","kind":"paper","name":"IPSS-M: the molecular international prognostic scoring system for myelodysplastic syndromes","aka":[],"tldr":"By adding mutations in 31 genes to blood counts and chromosomes, the IPSS-M sorts myelodysplastic syndromes into six risk groups and reclassifies about half of patients compared with the older score.","summary":"Development and validation of a prognostic model in 2,957 patients with MDS, combining clinical variables, cytogenetics and mutations in 31 genes into a continuous score with six risk categories; validated in an independent cohort of 754 patients.\n\nTP53 multi-hit, FLT3 and MLL partial tandem duplications carried the most adverse weight; SF3B1 was favourable. Compared with IPSS-R, 46 percent of patients were reclassified, most often upwards.","asOf":"2026-09-17","links":[{"label":"NEJM Evid 2022","url":"https://doi.org/10.1056/EVIDoa2200008"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38319256/"}],"tags":[],"related":[],"cancers":["mds-higher-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm-evidence"],"dependsOn":[],"notes":[],"journal":"NEJM Evidence","year":2022,"doi":"10.1056/EVIDoa2200008","pmid":"38319256","authors":"Bernard E, Tuechler H, Greenberg PL, et al.","paperType":"methods","findings":["Six risk categories with median survival from over 10 years to about one year.","46 percent of patients reclassified compared with IPSS-R, 74 percent of those to a higher risk group."],"whatItMeans":"Sequencing at diagnosis now changes the risk group, and therefore the transplant discussion, for a large fraction of patients. Trials and guidelines are adopting the IPSS-M in place of the IPSS-R.","caveats":["Requires a broad myeloid sequencing panel that is not universally available.","Derived mostly from untreated patients at diagnosis."],"changedPractice":true,"participants":2957},{"id":"paper-iris-imatinib-nejm-2003","kind":"paper","name":"IRIS: imatinib versus interferon plus cytarabine as first treatment for chronic myeloid leukaemia","aka":[],"tldr":"Imatinib beat the previous standard by a wide margin in newly diagnosed CML, and the long-term follow-up showed most patients alive at ten years.","summary":"IRIS randomised 1106 patients with newly diagnosed chronic-phase CML to imatinib 400 mg daily or interferon alfa plus low-dose cytarabine. The primary endpoint was progression-free survival; secondary endpoints included haematological and cytogenetic response. At 18 months the complete cytogenetic response rate was 76.2% with imatinib versus 14.5%, and freedom from progression to accelerated phase or blast crisis was 96.7% versus 91.5%. Crossover from the interferon arm was extensive. The 10-year follow-up (Hochhaus et al., NEJM 2017) reported estimated overall survival of 83.3% on imatinib, with few new serious adverse events after the first year.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa022457"},{"label":"10-year follow-up (Hochhaus 2017)","url":"https://doi.org/10.1056/NEJMoa1609324"},{"label":"ClinicalTrials.gov NCT00006343","url":"https://clinicaltrials.gov/study/NCT00006343"}],"tags":[],"related":["paper-druker-imatinib-phase1-nejm-2001"],"cancers":["cml"],"sections":[],"technologies":[],"targets":["bcr-abl"],"drugs":["imatinib","dasatinib","nilotinib","asciminib"],"companies":["novartis"],"institutions":[],"pathways":[],"terms":["pfs","os"],"trials":[],"people":[],"bottlenecks":["b-drug-pricing","b-global-access"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2003,"doi":"10.1056/NEJMoa022457","authors":"O'Brien SG, Guilhot F, Larson RA, et al.","paperType":"rct","findings":["1106 patients randomised; imatinib 400 mg/day vs interferon alfa + low-dose cytarabine.","Complete cytogenetic response at 18 months: 76.2% vs 14.5%; major cytogenetic response 87.1% vs 34.7%.","Freedom from progression to accelerated phase or blast crisis at 18 months: 96.7% vs 91.5%.","Imatinib was far better tolerated; most interferon patients eventually crossed over.","10-year follow-up: estimated overall survival 83.3% on imatinib, close to age-matched population survival."],"whatItMeans":"IRIS made imatinib the first-line standard for CML worldwide and established the tyrosine kinase inhibitor as a chronic, life-long oral therapy. For most patients CML became a manageable condition with near-normal life expectancy. Later generations of TKIs (dasatinib, nilotinib, asciminib) produce faster, deeper responses but have not shown a survival advantage over imatinib.","caveats":["Heavy crossover meant overall survival could not be compared cleanly between arms.","The primary endpoint was progression, not survival; molecular response monitoring was introduced later.","Long-term data come from the imatinib arm alone.","Treatment-free remission, now a goal for deep responders, was not part of the original design."],"changedPractice":true,"participants":1106},{"id":"paper-isg-sts-1001-gronchi-lancet-oncol-2017","kind":"paper","name":"ISG-STS 1001: histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in high-risk soft tissue sarcoma","aka":[],"tldr":"Trying to match neoadjuvant chemotherapy to sarcoma subtype backfired: standard epirubicin-ifosfamide gave better disease-free and overall survival than the tailored regimens, and in doing so provided evidence that neoadjuvant anthracycline-ifosfamide itself helps high-risk patients.","summary":"Phase 3 trial of 287 patients with high-risk localised soft tissue sarcoma of the limbs or trunk wall in five histological subtypes randomised to three cycles of neoadjuvant epirubicin-ifosfamide or a histotype-tailored regimen (gemcitabine-docetaxel, trabectedin, high-dose ifosfamide, etoposide-ifosfamide or gemcitabine-dacarbazine).\n\nThe trial stopped early for futility: 46-month disease-free survival was 62 percent with standard chemotherapy against 38 percent with tailored regimens, and overall survival 89 versus 64 percent, with the difference driven by undifferentiated pleomorphic sarcoma and other subtypes.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2017","url":"https://doi.org/10.1016/S1470-2045(17)30334-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28499583/"}],"tags":[],"related":[],"cancers":["extremity-soft-tissue-sarcoma","undifferentiated-pleomorphic-sarcoma","synovial-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["isg-sts-1001"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2017,"doi":"10.1016/S1470-2045(17)30334-0","pmid":"28499583","authors":"Gronchi A, Ferrari S, Quagliuolo V, et al.","paperType":"rct","findings":["46-month disease-free survival 62 percent (standard) vs 38 percent (tailored).","Overall survival 89 percent vs 64 percent."],"whatItMeans":"Three cycles of neoadjuvant anthracycline-ifosfamide is a reasonable standard for fit patients with high-risk limb or trunk sarcoma, particularly undifferentiated pleomorphic sarcoma.","caveats":["Absence of a surgery-alone arm means the benefit of chemotherapy is inferred rather than proven.","Tailored regimens performed worse partly because some had little single-agent activity."],"changedPractice":true,"participants":287},{"id":"paper-iwai-pdl1-tumour-escape-pnas-2002","kind":"paper","name":"Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack","aka":[],"tldr":"A decade after Honjo's group cloned PD-1 (1992), this study showed that tumour cells expressing PD-L1 resist killing by cytotoxic T cells in mice, and that anti-PD-L1 antibody or PD-1 deficiency restores tumour rejection, the foundation of PD-1/PD-L1 therapy.","summary":"Tasuku Honjo's group discovered PD-1 in 1992 (Ishida et al., EMBO J) as a gene induced during programmed cell death in T-cell lines, and later showed PD-1-deficient mice develop autoimmunity, identifying it as an inhibitory receptor. PD-L1 (B7-H1) was identified as its ligand by Freeman, Honjo and colleagues in 2000.\n\nIn this paper, P815 mastocytoma cells transfected with PD-L1 were less susceptible to lysis by cytotoxic T lymphocytes in vitro and grew more aggressively in vivo; anti-PD-L1 antibody reversed this. Myeloma cells naturally expressing PD-L1 grew in wild-type mice but were rejected in PD-1-deficient mice. In parallel, Dong and Chen (Nature Medicine 2002) showed that PD-L1 expressed on human tumours induced T-cell apoptosis.\n\nThese data motivated the development of nivolumab (Ono/Medarex) and other PD-1 and PD-L1 antibodies, now the most widely used cancer drugs in the world. Honjo shared the 2018 Nobel Prize with James Allison.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1073/pnas.192461099"},{"label":"Discovery of PD-1 (Ishida 1992)","url":"https://doi.org/10.1002/j.1460-2075.1992.tb05481.x"}],"tags":[],"related":["paper-leach-allison-ctla4-blockade-science-1996"],"cancers":[],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor"],"targets":["pd1","pdl1"],"drugs":["nivolumab","pembrolizumab","atezolizumab"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","antigen-presentation-immunoediting"],"terms":[],"trials":[],"people":["drew-pardoll","james-allison"],"bottlenecks":["b-immunotherapy-response","b-biomarker-validation"],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"PNAS","year":2002,"doi":"10.1073/pnas.192461099","pmid":"12218188","authors":"Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N","paperType":"basic","findings":["PD-L1 expression on tumour cells reduced cytotoxic T-cell killing in vitro and enhanced tumour growth in mice","Anti-PD-L1 antibody suppressed growth of PD-L1-expressing tumours","Naturally PD-L1-positive myeloma cells were rejected in PD-1-deficient mice but not in wild-type mice","Together with Ishida 1992 and Freeman 2000, defined the PD-1/PD-L1 axis as a tumour immune-escape mechanism"],"whatItMeans":"Tumours hide from T cells by displaying PD-L1; blocking that interaction lets the immune system attack. This is the mechanism of pembrolizumab, nivolumab, atezolizumab and their relatives, which now treat more than 20 cancer types.","caveats":["Mouse tumour models overexpressing PD-L1 exaggerate a mechanism that is only one of many in human tumours","PD-L1 expression on tumour cells is an imperfect biomarker of response in patients","Most patients do not respond to PD-1 blockade, and mechanisms of primary resistance remain incompletely understood","Clinical translation took another decade and depended on industry (Ono, Medarex, BMS, Merck) investment"],"changedPractice":false},{"id":"paper-jaiswal-chip-nejm-2014","kind":"paper","name":"Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70","aka":[],"tldr":"Blood DNA from 17,182 people showed that clones carrying leukaemia-associated mutations (mostly DNMT3A, TET2, ASXL1) are present in about 10% of people over 70, raising the risk of blood cancer 11-fold and, unexpectedly, of heart attack and stroke.","summary":"Exome sequences generated for diabetes genetics studies were mined for somatic mutations in genes recurrently mutated in blood cancers. Clonal haematopoiesis of indeterminate potential (CHIP) was rare under 40 but present in 9.5% of people aged 70-79 and 18.4% over 90.\n\nCarriers had an 11-fold higher risk of subsequent haematological cancer, though the absolute rate was modest (about 0.5-1% per year). Strikingly, CHIP was associated with higher all-cause mortality (HR 1.4), driven by cardiovascular disease: coronary heart disease HR 2.0 and ischaemic stroke HR 2.6. A companion paper (Genovese, NEJM 2014) reported the same phenomenon in a Swedish cohort.\n\nCHIP is now recognised as a common age-related premalignant state, a driver of cardiovascular inflammation, a source of false positives in ctDNA tests, and a target for prevention.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1408617"},{"label":"Genovese 2014 companion paper","url":"https://doi.org/10.1056/NEJMoa1409405"}],"tags":[],"related":["paper-martincorena-somatic-mutations-normal-skin-science-2015","idea-chip-risk-modifiers"],"cancers":["aml"],"sections":["early-detection","prevention"],"technologies":["wes-wgs","liquid-biopsy"],"targets":[],"drugs":[],"companies":[],"institutions":["broad-institute","dana-farber"],"pathways":["clonal-haematopoiesis","clonal-evolution"],"terms":["vaf","ctdna"],"trials":[],"people":["benjamin-ebert"],"bottlenecks":["b-early-detection","b-biomarker-validation","b-aging-comorbidity"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/NEJMoa1408617","pmid":"25426837","authors":"Jaiswal S, Fontanillas P, Flannick J, et al.","paperType":"observational","findings":["CHIP prevalence 9.5% at ages 70-79 and 18.4% over 90, versus under 1% below 40","Haematological cancer risk HR 11.1 (95% CI 3.9-32.6); absolute risk about 0.5-1% per year","All-cause mortality HR 1.4; coronary heart disease HR 2.0; ischaemic stroke HR 2.6","Most common mutated genes: DNMT3A, TET2, ASXL1"],"whatItMeans":"Many older people carry blood clones one or two steps from leukaemia, and those clones also drive heart disease through inflammation. CHIP is why blood-based cancer tests must filter out mutations from blood cells, and it opens a route to preventing both leukaemia and cardiovascular events in carriers.","caveats":["Cross-sectional discovery with limited follow-up; the leukaemia progression rate was estimated from a small number of events","Exome sequencing at modest depth detects only clones above about 2% variant allele fraction","Cohorts were ascertained for metabolic disease, which may inflate cardiovascular associations","No intervention has yet been shown to reduce CHIP-related risk"],"changedPractice":false,"participants":17182},{"id":"paper-japanese-gastric-cancer-treatment-guidelines-2021-gastric-cancer-2023","kind":"paper","name":"Japanese gastric cancer treatment guidelines 2021 (6th edition)","aka":[],"tldr":"The Japanese Gastric Cancer Association guideline sets the criteria for endoscopic resection, the extent of gastrectomy and lymph node dissection, adjuvant chemotherapy by stage and systemic therapy for advanced disease, and is the reference for early gastric cancer worldwide.","summary":"Sixth edition of the Japanese guideline covering absolute and expanded indications for endoscopic submucosal dissection, eCura assessment of curability, surgical procedures and D1+ or D2 lymphadenectomy, laparoscopic and robotic surgery, adjuvant S-1-based chemotherapy, perioperative therapy, and first- to third-line systemic therapy for unresectable disease.","asOf":"2026-09-17","links":[{"label":"Gastric Cancer 2023","url":"https://doi.org/10.1007/s10120-022-01331-8"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36342574/"}],"tags":[],"related":[],"cancers":["early-gastric-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["gastric-cancer"],"dependsOn":[],"notes":[],"journal":"Gastric cancer","year":2023,"doi":"10.1007/s10120-022-01331-8","pmid":"36342574","authors":"Japanese Gastric Cancer Association.","paperType":"guideline","findings":[],"whatItMeans":"The early gastric cancer page's endoscopic criteria and surgical recommendations follow this guideline.","caveats":["Adjuvant and advanced-disease recommendations reflect Japanese practice (S-1) and differ from Western guidelines."],"changedPractice":true},{"id":"paper-javelin-bladder-100-nejm-2020","kind":"paper","name":"JAVELIN Bladder 100: avelumab maintenance after first-line platinum chemotherapy in advanced urothelial cancer","aka":[],"tldr":"Continuing with the immunotherapy avelumab after chemotherapy had controlled advanced bladder cancer lengthened survival by about seven months compared with watching and waiting.","summary":"Phase 3 trial of 700 patients with unresectable locally advanced or metastatic urothelial carcinoma whose disease had not progressed on four to six cycles of platinum-based chemotherapy, randomised to avelumab maintenance plus best supportive care or supportive care alone.\n\nMedian overall survival was 21.4 months with avelumab against 14.3 months with supportive care (hazard ratio 0.69). The benefit was seen regardless of PD-L1 status and established switch maintenance immunotherapy as the standard after first-line chemotherapy until enfortumab vedotin plus pembrolizumab displaced chemotherapy in the first line.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa2002788"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32945632/"}],"tags":[],"related":[],"cancers":["muscle-invasive-bladder-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["avelumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["javelin-bladder-100"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2002788","pmid":"32945632","authors":"Powles T, Park SH, Voog E, et al.","paperType":"rct","findings":["Median overall survival 21.4 vs 14.3 months; hazard ratio for death 0.69.","Benefit in the PD-L1-positive population (hazard ratio 0.56) and in the overall population."],"whatItMeans":"For patients who still receive platinum chemotherapy first, avelumab maintenance rather than observation is the standard next step. Where enfortumab vedotin plus pembrolizumab is available first line, this sequence is used less.","caveats":["Open-label design.","The comparator did not include immunotherapy at progression for all patients, which may exaggerate the gain compared with sequential use."],"changedPractice":true,"participants":700},{"id":"paper-jcog0912-katai-lancet-gastroenterol-hepatol-2020","kind":"paper","name":"JCOG0912: laparoscopy-assisted versus open distal gastrectomy for clinical stage IA or IB gastric cancer","aka":[],"tldr":"Japan's randomised trial confirmed that laparoscopy-assisted distal gastrectomy is not inferior to open surgery for relapse-free survival in stage I gastric cancer, cementing the minimally invasive approach.","summary":"Phase 3 non-inferiority trial of 921 patients with clinical stage IA or IB gastric cancer randomised to laparoscopy-assisted or open distal gastrectomy with D1+ or D2 lymphadenectomy at Japanese centres.\n\nFive-year relapse-free survival was 95.1 percent with laparoscopic and 94.0 percent with open surgery, meeting non-inferiority, with similar overall survival and no differences in long-term complications.","asOf":"2026-09-17","links":[{"label":"Lancet Gastroenterol Hepatol 2020","url":"https://doi.org/10.1016/S2468-1253(19)30332-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31757656/"}],"tags":[],"related":[],"cancers":["early-gastric-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["klass-01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Lancet Gastroenterology and Hepatology","year":2020,"doi":"10.1016/S2468-1253(19)30332-2","pmid":"31757656","authors":"Katai H, Mizusawa J, Katayama H, et al.","paperType":"rct","findings":["Five-year relapse-free survival 95.1 percent (laparoscopic) vs 94.0 percent (open); non-inferior."],"whatItMeans":"Together with KLASS-01, this trial makes laparoscopic distal gastrectomy the standard for early gastric cancer needing surgery.","caveats":["Applies to distal tumours; total gastrectomy and advanced disease were studied separately."],"changedPractice":true,"participants":921},{"id":"paper-jemal-cancer-statistics-2007-cacancer-2007","kind":"paper","name":"Jemal 2007: Cancer statistics, 2007","aka":[],"tldr":"The American Cancer Society's 2007 report projected about 1.44 million new US cancer cases and recorded a 13.6 percent fall in the overall cancer death rate between 1991 and 2004, even though the absolute number of deaths had only just begun to fall.","summary":"Jemal and colleagues projected 1,444,920 new cancer cases and 559,650 cancer deaths in the United States for 2007, using incidence data to 2003 and mortality data to 2004. Age-standardised incidence for all cancers combined had been stable in men since 1995 while still rising 0.3 percent a year in women, and the combined cancer death rate had fallen 13.6 percent between 1991 and 2004. The report also broke incidence, mortality and survival down by site, sex, race and ethnicity and geography.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/canjclin.57.1.43"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2023-cacancer-2023","paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2007,"doi":"10.3322/canjclin.57.1.43","authors":"Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ.","paperType":"observational","findings":["Projected 1,444,920 new cancer cases and 559,650 cancer deaths in the United States in 2007.","Overall cancer death rate down 13.6 percent between 1991 and 2004.","Incidence stable in men since 1995 and rising 0.3 percent a year in women."],"whatItMeans":"One of the first editions to quantify the sustained fall in US cancer death rates that later reports tracked as deaths averted.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-jemal-cancer-statistics-2008-cacancer-2008","kind":"paper","name":"Jemal 2008: Cancer statistics, 2008","aka":[],"tldr":"The American Cancer Society's 2008 report projected about 1.44 million new US cancer cases and estimated that falling death rates since the early 1990s had already avoided more than half a million cancer deaths.","summary":"Jemal and colleagues projected 1,437,180 new cancer cases and 565,650 cancer deaths in the United States for 2008. Incidence rates for all sites combined had stabilised in men from 1995 and in women from 1999, and death rates had fallen 18.4 percent in men since 1990 and 10.5 percent in women since 1991, which the authors translated into more than half a million deaths avoided. The report added education level to its breakdowns by site, sex, race and ethnicity and geography.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/ca.2007.0010"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2023-cacancer-2023","paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2008,"doi":"10.3322/ca.2007.0010","authors":"Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ.","paperType":"observational","findings":["Projected 1,437,180 new cancer cases and 565,650 cancer deaths in the United States in 2008.","Death rates down 18.4 percent in men from 1990 and 10.5 percent in women from 1991, to 2004.","More than half a million cancer deaths avoided over that period."],"whatItMeans":"The first edition to express progress as deaths avoided, the framing every later report has kept.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-jemal-cancer-statistics-2009-cacancer-2009","kind":"paper","name":"Jemal 2009: Cancer statistics, 2009","aka":[],"tldr":"The American Cancer Society's 2009 report projected about 1.48 million new US cancer cases and showed incidence now falling in both sexes, with lung, prostate, colorectal and breast cancers driving most of the decline in deaths.","summary":"Jemal and colleagues projected 1,479,350 new cancer cases and 562,340 cancer deaths in the United States for 2009. Overall incidence was falling in men (1.8 percent a year from 2001 to 2005) and women (0.6 percent a year from 1998 to 2005), largely through the big sites: lung, prostate and colorectal cancer in men, breast and colorectal cancer in women. Death rates had fallen 19.2 percent in men between 1990 and 2005 and 11.4 percent in women between 1991 and 2005; declines in lung, prostate and colorectal cancer accounted for nearly 80 percent of the fall in men, and breast and colorectal cancer for 60 percent in women.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.20006"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2023-cacancer-2023","paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2009,"doi":"10.3322/caac.20006","authors":"Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ.","paperType":"observational","findings":["Projected 1,479,350 new cancer cases and 562,340 cancer deaths in the United States in 2009.","Incidence falling in men by 1.8 percent a year (2001 to 2005) and in women by 0.6 percent a year (1998 to 2005).","Death rates down 19.2 percent in men and 11.4 percent in women; lung, prostate and colorectal cancer explained nearly 80 percent of the fall in men."],"whatItMeans":"Showed the fall in deaths was concentrated in a handful of common cancers where smoking decline, screening and better treatment had taken hold.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-jemal-cancer-statistics-2010-cacancer-2010","kind":"paper","name":"Jemal 2010: Cancer statistics, 2010","aka":[],"tldr":"The American Cancer Society's 2010 report projected about 1.53 million new US cancer cases and a 21 percent fall in the male cancer death rate since 1990, with declines seen in every racial and ethnic group.","summary":"Jemal, Siegel, Xu and Ward projected 1,529,560 new cancer cases and 569,490 cancer deaths in the United States for 2010. Incidence was falling in men by 1.3 percent a year (2000 to 2006) and in women by 0.5 percent a year (1998 to 2006), driven by lung, prostate and colorectal cancer in men and breast and colorectal cancer in women, and the decrease was seen in every racial and ethnic group except American Indian and Alaska Native women, whose rates were stable. Death rates in men fell 21.0 percent between 1990 and 2006, with lung, prostate and colorectal cancer accounting for nearly 80 percent of the decline.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.20073"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2023-cacancer-2023","paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2010,"doi":"10.3322/caac.20073","authors":"Jemal A, Siegel R, Xu J, Ward E.","paperType":"observational","findings":["Projected 1,529,560 new cancer cases and 569,490 cancer deaths in the United States in 2010.","Incidence falling in men by 1.3 percent a year and in women by 0.5 percent a year.","Male cancer death rate down 21.0 percent between 1990 and 2006."],"whatItMeans":"Confirmed that the decline in incidence and deaths was reaching most population groups, while flagging the groups it was not.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-jemal-global-cancer-statistics-2011-cacancer","kind":"paper","name":"Jemal 2011: Global cancer statistics (GLOBOCAN 2008)","aka":[],"tldr":"The world cancer count for 2008: about 12.7 million new cases, with more than half of cases and almost two thirds of deaths already occurring in the economically developing world, breast cancer the most common cancer in women and lung cancer in men.","summary":"Jemal, Bray and colleagues summarised the GLOBOCAN 2008 estimates for the American Cancer Society. They reported about 12.7 million new cancer cases and 7.6 million cancer deaths in 2008, of which 56% of cases and 64% of deaths occurred in the economically developing world. Breast cancer was the most frequently diagnosed cancer and leading cause of cancer death in women; lung cancer held both positions in men. The paper stressed that the burden was shifting to lower-income countries and that much of it was preventable through tobacco control, vaccination and early detection.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.20107"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-torre-global-cancer-statistics-2012-cacancer-2015"],"cancers":["breast-hr-positive","nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":["bray-freddie"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2011,"doi":"10.3322/caac.20107","authors":"Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D.","paperType":"observational","findings":["About 12.7 million new cancer cases and 7.6 million cancer deaths worldwide in 2008.","56% of cases and 64% of deaths in the economically developing world.","Breast cancer the leading cancer in women and lung cancer in men, for both incidence and death."],"whatItMeans":"For years the most cited paper in oncology, it fixed the picture of cancer as a growing problem of developing countries and is the baseline against which the 2012, 2018, 2020 and 2022 GLOBOCAN releases show the burden rising.","caveats":["Estimates for many countries were modelled from sparse registry data.","Superseded by later GLOBOCAN releases."],"changedPractice":false},{"id":"paper-juliet-tisagenlecleucel-dlbcl-nejm-2019","kind":"paper","name":"JULIET: tisagenlecleucel for adults with relapsed or refractory diffuse large B-cell lymphoma","aka":[],"tldr":"In adults with aggressive lymphoma after at least two prior treatments, tisagenlecleucel produced responses in 52% and complete responses in 40%, most of which lasted.","summary":"JULIET was an international single-arm phase 2 trial of tisagenlecleucel in adults with relapsed or refractory DLBCL after two or more lines of therapy who were ineligible for or had relapsed after autologous transplant. Of 165 enrolled, 111 were infused; 93 were evaluable for efficacy at the primary analysis. The best overall response rate was 52% with complete response in 40%; among responders the estimated relapse-free survival at 12 months was 65% and median duration of response was not reached. Grade 3-4 cytokine release syndrome occurred in 22% and grade 3-4 neurological events in 12%, with no deaths attributed to the product. Bridging chemotherapy was allowed. It supported approval of tisagenlecleucel in DLBCL in 2018, the second CD19 CAR-T for this disease.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1804980"},{"label":"ClinicalTrials.gov NCT02445248","url":"https://clinicaltrials.gov/study/NCT02445248"}],"tags":[],"related":["paper-zuma-1-axi-cel-nejm-2017"],"cancers":["dlbcl"],"sections":[],"technologies":["car-t"],"targets":["cd19"],"drugs":["tisagenlecleucel"],"companies":["novartis"],"institutions":["penn-abramson"],"pathways":[],"terms":["crs","icans","orr"],"trials":["belinda"],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1804980","authors":"Schuster SJ, Bishop MR, Tam CS, et al.","paperType":"translational","findings":["165 enrolled, 111 infused, 93 efficacy-evaluable adults with relapsed/refractory DLBCL; 27 sites in 10 countries.","Best overall response 52%; complete response 40%.","12-month relapse-free survival among responders 65%; median duration of response not reached.","Grade 3-4 CRS 22%; grade 3-4 neurological events 12%; no treatment-related deaths.","A third of enrolled patients never received the product, mostly because of disease progression or manufacturing issues."],"whatItMeans":"JULIET, with ZUMA-1, showed that CAR-T could rescue a substantial minority of adults with chemotherapy-refractory lymphoma and that complete responders often stay in remission. The lower toxicity of a 4-1BB construct and the option of bridging therapy made it usable in a broader population. The high drop-out between enrolment and infusion remains a lesson about turnaround time.","caveats":["Single-arm; efficacy reported on infused patients, flattering the intention-to-treat picture.","Lower response rates than in ZUMA-1, possibly reflecting product, patient selection or manufacturing time.","Long vein-to-vein time (median about 54 days) meant many patients progressed before infusion.","Later randomised second-line trial (BELINDA) was negative for this product."],"changedPractice":true,"participants":111},{"id":"paper-kalluri-weinberg-emt-basics-jci-2009","kind":"paper","name":"Kalluri and Weinberg 2009: the basics of epithelial-mesenchymal transition","aka":[],"tldr":"The standard primer on how cancer cells borrow a programme from embryonic development to loosen their attachments, become mobile and invade, and how the same programme also drives wound healing and organ scarring.","summary":"Kalluri and Weinberg organised the epithelial-mesenchymal transition (EMT) into three types: type 1 in embryonic development, type 2 in wound healing and fibrosis, and type 3 in cancer, where carcinoma cells at the invasive front lose E-cadherin and epithelial polarity, gain mesenchymal markers such as vimentin and N-cadherin, and acquire motility and invasiveness. They summarised the transcription factors that drive it (Snail, Slug, Twist, ZEB1 and ZEB2), the signals that trigger it (TGF-beta, Wnt, Notch and growth factor receptor pathways) and the reverse transition that lets disseminated cells re-form epithelial metastases.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1172/JCI39104"}],"tags":[],"related":["paper-thiery-emt-tumour-progression-nrc-2002","paper-mani-emt-stem-cell-properties-cell-2008"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["emt","tgf-beta","metastatic-cascade"],"terms":["metastasis","activating-invasion-metastasis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Investigation","year":2009,"doi":"10.1172/JCI39104","authors":"Kalluri R, Weinberg RA.","paperType":"review","findings":["EMT is classified into three types: developmental, fibrotic and cancer-associated (type 3).","Type 3 EMT gives carcinoma cells motility, invasiveness and resistance to apoptosis, and is driven by Snail, Slug, Twist and ZEB transcription factors downstream of TGF-beta and other signals.","The reverse process, mesenchymal-epithelial transition, is proposed to allow disseminated cells to form metastases."],"whatItMeans":"EMT is the most cited explanation for how carcinomas invade and spread and for part of their drug resistance. This primer is the entry point for the field, and its framework informs current work on partial EMT states, circulating tumour cells and therapies aimed at the transition.","caveats":["The extent to which full EMT occurs in human tumours in vivo, versus partial or hybrid states, is still debated.","A review; lineage-tracing evidence for EMT in metastasis came later and is mixed."],"changedPractice":false},{"id":"paper-karmma-3-ide-cel-nejm-2023","kind":"paper","name":"KarMMa-3: ide-cel CAR-T versus standard regimens in triple-class-exposed relapsed myeloma","aka":[],"tldr":"The first randomised CAR-T trial in myeloma tripled median progression-free survival (13.3 versus 4.4 months) compared with standard combinations after two to four prior lines.","summary":"KarMMa-3 randomised 386 patients with relapsed and refractory multiple myeloma after two to four prior lines, including an immunomodulatory drug, a proteasome inhibitor and daratumumab, to idecabtagene vicleucel (ide-cel) or one of five standard regimens. The primary endpoint was PFS. Median PFS was 13.3 versus 4.4 months (hazard ratio 0.49); overall response was 71% versus 42% and complete response 39% versus 5%. CRS occurred in 88% (grade 3 or higher in 5%) and neurotoxicity in 15%. Overall survival did not differ significantly, in part because more than half of standard-arm patients crossed over to ide-cel.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2213614"},{"label":"ClinicalTrials.gov NCT03651128","url":"https://clinicaltrials.gov/study/NCT03651128"}],"tags":[],"related":["paper-cartitude-4-cilta-cel-nejm-2023"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["car-t"],"targets":["bcma"],"drugs":["idecabtagene-vicleucel"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["pfs","orr","crs"],"trials":["karmma-3"],"people":[],"bottlenecks":["b-manufacturing-cell-therapy","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2213614","authors":"Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al.","paperType":"rct","findings":["386 patients after 2-4 prior lines, triple-class exposed; ide-cel vs 5 standard regimens (2:1).","Median PFS 13.3 vs 4.4 months; hazard ratio 0.49.","Overall response 71% vs 42%; complete response or better 39% vs 5%.","CRS 88% (grade 3 or higher 5%); investigator-identified neurotoxicity 15% (grade 3 or higher 3%).","No significant OS difference after adjusting for crossover; most standard-arm patients received ide-cel at progression."],"whatItMeans":"KarMMa-3 was the first randomised evidence that CAR-T beats conventional drugs in myeloma and led to ide-cel's approval after two prior lines. It confirmed that earlier use of CAR-T produces deeper and longer remissions than in the end-stage setting. Because responses are shorter than with cilta-cel and OS was not improved, it also sharpened debate about which BCMA CAR-T to use and when.","caveats":["Crossover blunted the OS comparison; a survival benefit could not be shown.","Standard-arm regimens varied and included some now regarded as suboptimal.","Median PFS with ide-cel remains modest compared with cilta-cel in CARTITUDE-4 (indirect comparison).","Manufacturing time and slot availability restrict real-world use."],"changedPractice":true,"participants":386},{"id":"paper-katherine-nejm-2019","kind":"paper","name":"KATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatment","aka":[],"tldr":"Women whose HER2-positive breast cancer was still present at surgery after chemotherapy and trastuzumab had half the risk of relapse if their post-surgery treatment was switched to the antibody-drug conjugate T-DM1 instead of continuing trastuzumab.","summary":"Open-label phase 3 trial of 1,486 patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axilla after neoadjuvant taxane- and trastuzumab-based therapy, randomised to 14 cycles of adjuvant trastuzumab emtansine (T-DM1) or trastuzumab. Primary endpoint was invasive disease-free survival.\n\nThree-year iDFS was 88.3% vs 77.0% (HR 0.50). Later follow-up confirmed an overall survival benefit. It established the response-adapted strategy: treat before surgery, then escalate only for those with residual disease.","asOf":"2026-09-08","links":[{"label":"NEJM 2019","url":"https://doi.org/10.1056/NEJMoa1814017"},{"label":"ClinicalTrials.gov NCT01772472","url":"https://clinicaltrials.gov/study/NCT01772472"}],"tags":[],"related":["idea-post-neoadjuvant-adc"],"cancers":["breast-her2-positive"],"sections":[],"technologies":["adc"],"targets":["her2"],"drugs":["trastuzumab-emtansine","trastuzumab"],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["pcr","rcb","neoadjuvant-adjuvant"],"trials":["destiny-breast03","destiny-breast11"],"people":["gunter-von-minckwitz","sibylle-loibl","shao-zhi-ming","charles-geyer"],"bottlenecks":["b-dormancy-mrd","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1814017","authors":"von Minckwitz G, Huang CS, Mano MS, et al.","paperType":"rct","findings":["Three-year invasive disease-free survival 88.3% with T-DM1 vs 77.0% with trastuzumab, an 11.3-point gain; HR 0.50 (95% CI 0.39-0.64).","Distant recurrence as first event 10.5% vs 15.9%.","Benefit was consistent across hormone-receptor status, extent of residual disease, and prior pertuzumab use.","Long-term follow-up confirmed a significant overall survival benefit (HR about 0.66).","More grade 3 or higher adverse events with T-DM1 (25.7% vs 15.4%), notably thrombocytopenia and neuropathy."],"whatItMeans":"HER2-positive breast cancer is now routinely treated before surgery so that the pathology result can guide what comes after: patients with no residual cancer continue trastuzumab (with or without pertuzumab), while those with residual disease switch to T-DM1. This model of using the tumour's response as a test has since been copied in triple-negative and other cancers.","caveats":["Open-label design.","A minority of patients had received pertuzumab before surgery, fewer than in current practice.","Whether adding tucatinib or switching to trastuzumab deruxtecan can further improve outcomes for residual disease is being tested (CompassHER2 RD, DESTINY-Breast05).","Brain metastases as a first site of relapse were not reduced."],"changedPractice":true,"participants":1486},{"id":"paper-keynote-001-pembrolizumab-nsclc-nejm-2015","kind":"paper","name":"KEYNOTE-001 (Garon 2015): pembrolizumab in non-small-cell lung cancer and the 50% PD-L1 cut-off","aka":[],"tldr":"The large early trial that showed pembrolizumab shrinks about a fifth of advanced lung cancers, with responses that last, and that identified a PD-L1 score of 50% or more as the group most likely to benefit.","summary":"KEYNOTE-001 treated 495 patients with advanced non-small-cell lung cancer, both previously treated and untreated, with pembrolizumab at several doses and schedules. The overall response rate was about 19% with a median duration of response around a year and no clear difference between doses. A training and validation approach on PD-L1 immunohistochemistry defined a tumour proportion score of at least 50% as the threshold at which response and survival were markedly better, a cut-off adopted by KEYNOTE-024 and now used in clinics worldwide.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1501824"},{"label":"ClinicalTrials.gov NCT01295827","url":"https://clinicaltrials.gov/study/NCT01295827"}],"tags":[],"related":["paper-keynote-024-nejm-2016","paper-keynote-010-lancet-2016"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["tps","pd-l1-testing","orr"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1501824","authors":"Garon EB, Rizvi NA, Hui R, et al.","paperType":"translational","findings":["495 patients with advanced NSCLC treated with pembrolizumab at 2 or 10 mg/kg every three weeks or 10 mg/kg every two weeks.","Objective response rate 19.4% overall; median duration of response 12.5 months.","PD-L1 tumour proportion score of at least 50%, seen in 23.2% of patients, was associated with a response rate of 45.2% and longer progression-free and overall survival.","Treatment-related grade 3 or higher adverse events in 9.5% of patients."],"whatItMeans":"This trial gave lung cancer its immunotherapy biomarker. The 50% PD-L1 cut-off decides today whether a patient with advanced lung cancer can start immunotherapy alone or needs chemotherapy added, and the five-year follow-up later showed long-term survivors among first-line responders.","caveats":["Single-arm study with several dose cohorts; the cut-off was derived and validated within the same trial.","PD-L1 testing depends on the assay and the sample and misses some responders."],"changedPractice":true,"participants":495},{"id":"paper-keynote-006-pembrolizumab-ipilimumab-melanoma-nejm-2015","kind":"paper","name":"KEYNOTE-006 (Robert 2015): pembrolizumab versus ipilimumab in advanced melanoma","aka":[],"tldr":"Head to head, the PD-1 antibody pembrolizumab held melanoma back longer, prolonged life and caused fewer severe side effects than ipilimumab, the CTLA-4 antibody that had been the first immunotherapy to extend survival.","summary":"KEYNOTE-006 randomised 834 patients with advanced melanoma, most untreated with immunotherapy, to pembrolizumab every two weeks, pembrolizumab every three weeks, or ipilimumab. Both pembrolizumab schedules improved progression-free and overall survival and roughly tripled the response rate compared with ipilimumab, with fewer grade 3 to 5 treatment-related adverse events. The trial made PD-1 blockade the first-line immunotherapy standard in melanoma and showed the three-weekly schedule was as effective as the two-weekly one.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1503093"},{"label":"ClinicalTrials.gov NCT01866319","url":"https://clinicaltrials.gov/study/NCT01866319"}],"tags":[],"related":["paper-hodi-ipilimumab-melanoma-nejm-2010"],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":["pd1","ctla4"],"drugs":["pembrolizumab","ipilimumab"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["pfs","os","orr"],"trials":["keynote-006"],"people":["caroline-robert"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1503093","authors":"Robert C, Schachter J, Long GV, et al.","paperType":"rct","findings":["834 patients with advanced melanoma; pembrolizumab every 2 weeks, every 3 weeks, or ipilimumab.","Six-month progression-free survival 47.3% and 46.4% vs 26.5%; hazard ratios 0.58.","Twelve-month overall survival 74.1% and 68.4% vs 58.2%; hazard ratios 0.63 and 0.69.","Response rates 33.7% and 32.9% vs 11.9%; grade 3 to 5 treatment-related adverse events 13.3% and 10.1% vs 19.9%."],"whatItMeans":"This trial settled which checkpoint to block first in melanoma and set the pattern for PD-1 antibodies displacing ipilimumab across cancers. Long-term follow-up later showed that many responders remained free of progression years after stopping treatment.","caveats":["Open-label design.","Ipilimumab was given at 3 mg/kg for four doses; the comparison does not cover combination therapy.","Most patients had received no prior systemic therapy, so results apply mainly to first-line use."],"changedPractice":true,"participants":834},{"id":"paper-keynote-010-lancet-2016","kind":"paper","name":"KEYNOTE-010 (Herbst 2016): pembrolizumab versus docetaxel in previously treated PD-L1-positive lung cancer","aka":[],"tldr":"After chemotherapy had failed, pembrolizumab prolonged life compared with docetaxel in lung cancers expressing any PD-L1, with the largest gain in tumours where at least half the cells were positive, and caused fewer severe side effects.","summary":"KEYNOTE-010 randomised 1,034 patients with previously treated advanced non-small-cell lung cancer and a PD-L1 tumour proportion score of at least 1% to pembrolizumab at 2 mg/kg or 10 mg/kg or to docetaxel. Both pembrolizumab doses improved overall survival in the whole population and by a larger margin in the group with a score of 50% or more, with fewer grade 3 to 5 treatment-related adverse events than docetaxel. It secured pembrolizumab's regular approval in previously treated lung cancer and established PD-L1 of 1% as the entry threshold for that use.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/S0140-6736(15)01281-7"},{"label":"ClinicalTrials.gov NCT01905657","url":"https://clinicaltrials.gov/study/NCT01905657"}],"tags":[],"related":["paper-keynote-001-pembrolizumab-nsclc-nejm-2015","paper-checkmate-057-nejm-2015"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["pembrolizumab","docetaxel"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["tps","os"],"trials":[],"people":["roy-herbst"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2016,"doi":"10.1016/S0140-6736(15)01281-7","authors":"Herbst RS, Baas P, Kim DW, et al.","paperType":"rct","findings":["1,034 patients with previously treated NSCLC and PD-L1 tumour proportion score of at least 1%; pembrolizumab 2 mg/kg, 10 mg/kg or docetaxel.","Median overall survival 10.4 and 12.7 months with pembrolizumab vs 8.5 months with docetaxel; hazard ratios 0.71 and 0.61.","In tumours with a score of 50% or more: median overall survival 14.9 and 17.3 vs 8.2 months; hazard ratios 0.54 and 0.50.","Grade 3 to 5 treatment-related adverse events 13% and 16% vs 35%."],"whatItMeans":"Alongside the CheckMate trials this study replaced docetaxel with PD-1 blockade as second-line treatment for most lung cancers, and its PD-L1 threshold of 1% became the basis of pembrolizumab's label in previously treated disease.","caveats":["Open-label design.","Patients with PD-L1-negative tumours were excluded, so the trial says nothing about them.","Second-line setting; first-line immunotherapy has since reduced its relevance."],"changedPractice":true,"participants":1034},{"id":"paper-keynote-024-nejm-2016","kind":"paper","name":"KEYNOTE-024: pembrolizumab alone beats chemotherapy in PD-L1-high lung cancer","aka":[],"tldr":"In patients whose lung tumours carried PD-L1 on at least half their cells, pembrolizumab alone held the cancer back longer than chemotherapy and caused fewer serious side effects, making immunotherapy the first treatment for this group.","summary":"KEYNOTE-024 randomised 305 patients with untreated advanced non-small-cell lung cancer, a PD-L1 tumour proportion score of 50% or more and no EGFR or ALK alteration to pembrolizumab or platinum-based chemotherapy. Pembrolizumab improved progression-free survival, the primary endpoint, and overall survival at the interim analysis, with a higher response rate and fewer grade 3 to 5 adverse events, and patients on chemotherapy could cross over at progression. Five-year follow-up later confirmed the survival advantage. The trial made PD-L1 testing routine at lung cancer diagnosis and established chemotherapy-free first-line immunotherapy for the PD-L1-high group.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1606774"},{"label":"ClinicalTrials.gov NCT02142738","url":"https://clinicaltrials.gov/study/NCT02142738"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["tps","pfs","os"],"trials":["keynote-024-189"],"people":["martin-reck"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1606774","authors":"Reck M, Rodríguez-Abreu D, Robinson AG, et al.","paperType":"rct","findings":["305 patients with PD-L1 tumour proportion score of 50% or more; pembrolizumab vs platinum doublet chemotherapy.","Median progression-free survival 10.3 vs 6.0 months, hazard ratio 0.50.","Overall survival hazard ratio 0.60 at the interim analysis; estimated six-month survival 80.2% vs 72.4%.","Response rate 44.8% vs 27.8%; grade 3 to 5 treatment-related adverse events 26.6% vs 53.3%."],"whatItMeans":"This trial is why PD-L1 is measured on every new advanced lung cancer and why a patient with a high score can start immunotherapy without chemotherapy. Together with KEYNOTE-189 for the rest of the population, it moved checkpoint inhibitors from second-line rescue to the first treatment most lung cancer patients receive.","caveats":["Applies only to the roughly 30% of patients with a PD-L1 score of 50% or more and no EGFR or ALK driver.","Crossover from chemotherapy to pembrolizumab affected the survival comparison.","PD-L1 testing varies by assay and is imperfect as a predictor within the eligible group."],"changedPractice":true,"participants":305},{"id":"paper-keynote-048-lancet-2019","kind":"paper","name":"KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer","aka":[],"tldr":"Pembrolizumab, either alone in PD-L1-positive tumours or combined with chemotherapy, helped patients with recurrent or metastatic head and neck squamous cell cancer live longer than the previous cetuximab-based standard.","summary":"Open-label phase 3 trial of 882 patients with untreated recurrent or metastatic head and neck squamous cell carcinoma randomised to pembrolizumab alone, pembrolizumab plus platinum and fluorouracil, or the EXTREME regimen (cetuximab plus platinum and fluorouracil). Primary endpoints were OS and PFS in PD-L1 CPS 20 or more, CPS 1 or more, and all patients.\n\nPembrolizumab alone improved OS in CPS 20 or more (14.9 vs 10.7 months, HR 0.61) and CPS 1 or more (12.3 vs 10.3 months, HR 0.78) and was non-inferior overall. Pembrolizumab plus chemotherapy improved OS in all patients (13.0 vs 10.7 months, HR 0.77). It replaced EXTREME as the first-line standard and made PD-L1 CPS testing routine in head and neck cancer.","asOf":"2026-09-08","links":[{"label":"PubMed search: KEYNOTE-048 Lancet 2019","url":"https://pubmed.ncbi.nlm.nih.gov/?term=KEYNOTE-048+pembrolizumab+head+and+neck+Burtness+Lancet+2019"},{"label":"ClinicalTrials.gov NCT02358031","url":"https://clinicaltrials.gov/study/NCT02358031"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","platinum","monoclonal-antibody"],"targets":["pd1","egfr"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":["icr-london","royal-marsden"],"pathways":[],"terms":["cps","os","pfs","first-line","orr"],"trials":[],"people":["kevin-harrington"],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2019,"authors":"Burtness B, Harrington KJ, Greil R, et al.","paperType":"rct","findings":["Pembrolizumab alone vs EXTREME, CPS 20 or more: median OS 14.9 vs 10.7 months, HR 0.61 (95% CI 0.45-0.83).","Pembrolizumab alone vs EXTREME, CPS 1 or more: median OS 12.3 vs 10.3 months, HR 0.78.","Pembrolizumab plus chemotherapy vs EXTREME, all patients: median OS 13.0 vs 10.7 months, HR 0.77 (95% CI 0.63-0.93).","Response rates were lower with pembrolizumab alone (17% vs 36% in CPS 20 or more) but responses lasted far longer (median 22.6 vs 4.5 months).","Grade 3 or higher all-cause adverse events 55% (pembrolizumab alone), 85% (pembrolizumab plus chemotherapy) and 83% (EXTREME)."],"whatItMeans":"Patients with head and neck squamous cell cancer that has recurred or spread should be treated first with pembrolizumab: alone if their tumour is strongly PD-L1 positive and they can wait for a slower response, or with chemotherapy if the tumour is bulky or PD-L1 low. Cetuximab-based chemotherapy is no longer the default. Long-term follow-up shows a small but real group of patients alive at four to five years, which was almost unheard of before.","caveats":["Open-label with a complex multi-comparison design; PFS was not improved in any comparison.","Pembrolizumab alone has a lower response rate and early progression can occur, so patients with rapidly symptomatic disease may need chemotherapy added.","CPS below 1 (about 15% of patients) derived no clear benefit from either pembrolizumab arm.","EXTREME is now an outdated comparator; the optimal strategy for HPV-positive versus HPV-negative disease was not defined."],"changedPractice":true,"participants":882},{"id":"paper-keynote-054-eggermont-nejm-2018","kind":"paper","name":"KEYNOTE-054 (EORTC 1325): adjuvant pembrolizumab versus placebo in resected stage III melanoma","aka":[],"tldr":"A year of pembrolizumab after surgery for stage III melanoma cut the risk of recurrence by 43 percent compared with placebo, the first placebo-controlled proof that adjuvant PD-1 blockade works.","summary":"Phase 3 placebo-controlled trial of 1,019 patients with completely resected stage III melanoma randomised to pembrolizumab or placebo for one year.\n\nTwelve-month recurrence-free survival was 75.4 versus 61.0 percent (hazard ratio 0.57), consistent across PD-L1 and BRAF subgroups; five-year recurrence-free survival was 55.4 versus 38.3 percent and distant metastasis-free survival was also improved, with grade 3 or higher immune-related events in 7.1 percent.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1802357"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29658430/"}],"tags":[],"related":[],"cancers":["stage-iii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1802357","pmid":"29658430","authors":"Eggermont AMM, Blank CU, Mandala M, et al.","paperType":"rct","findings":["Twelve-month recurrence-free survival 75.4 percent vs 61.0 percent; hazard ratio 0.57.","Five-year recurrence-free survival 55.4 percent vs 38.3 percent."],"whatItMeans":"Adjuvant pembrolizumab is a standard for resected stage III melanoma, with subsequent trials extending it to stage II and to the neoadjuvant setting.","caveats":["Overall survival benefit not demonstrated, as placebo patients could receive pembrolizumab at relapse."],"changedPractice":true,"participants":1019},{"id":"paper-keynote-057-lancet-oncol-2021","kind":"paper","name":"KEYNOTE-057: pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ","aka":[],"tldr":"In patients whose high-risk bladder cancer no longer responded to BCG and who could not or would not have their bladder removed, pembrolizumab cleared the disease in about four in ten, with a response lasting a year or more in roughly half of those.","summary":"Single-arm phase 2 study of 101 patients with BCG-unresponsive carcinoma in situ, with or without papillary tumours, treated with pembrolizumab every three weeks for up to two years.\n\nThe complete response rate at three months was 41 percent and the median duration of response was 16.2 months. On these data pembrolizumab became the first systemic drug approved for BCG-unresponsive non-muscle-invasive bladder cancer, as an alternative to immediate cystectomy.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(21)00147-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34051177/"}],"tags":[],"related":[],"cancers":["non-muscle-invasive-bladder-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-057"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00147-9","pmid":"34051177","authors":"Balar AV, Kamat AM, Kulkarni GS, et al.","paperType":"observational","findings":["Complete response at three months in 41 percent of patients with carcinoma in situ.","Median duration of complete response 16.2 months; 46 percent of responses lasted at least 12 months."],"whatItMeans":"Patients facing cystectomy for BCG-unresponsive disease have a bladder-sparing option, though most will eventually relapse and need close cystoscopic surveillance. The choice is a trade between keeping the bladder and the risk of progression while waiting.","caveats":["No randomised comparator; cystectomy remains the curative standard.","Progression to muscle-invasive disease occurred in a minority during follow-up."],"changedPractice":true,"participants":101},{"id":"paper-keynote-062-shitara-jama-oncol-2020","kind":"paper","name":"KEYNOTE-062: pembrolizumab or pembrolizumab plus chemotherapy versus chemotherapy in PD-L1-positive advanced gastric cancer","aka":[],"tldr":"In first-line PD-L1-positive gastric cancer, pembrolizumab alone was no worse than chemotherapy for survival but did not beat it, and adding it to chemotherapy did not help either; the exception was microsatellite-unstable tumours, which did dramatically better with pembrolizumab.","summary":"Phase 3 trial of 763 patients with untreated advanced gastric or junctional adenocarcinoma with PD-L1 combined positive score of 1 or more randomised to pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy.\n\nPembrolizumab was non-inferior to chemotherapy for overall survival (10.6 versus 11.1 months) and combination therapy was not superior; in the 50 patients with microsatellite instability-high tumours, median overall survival was not reached with pembrolizumab against 8.5 months with chemotherapy.","asOf":"2026-09-17","links":[{"label":"JAMA Oncol 2020","url":"https://doi.org/10.1001/jamaoncol.2020.3370"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32880601/"}],"tags":[],"related":[],"cancers":["gastric-msi-high"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-062"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2020,"doi":"10.1001/jamaoncol.2020.3370","pmid":"32880601","authors":"Shitara K, Van Cutsem E, Bang YJ, et al.","paperType":"rct","findings":["Pembrolizumab non-inferior to chemotherapy overall (10.6 vs 11.1 months).","Microsatellite instability-high: overall survival not reached vs 8.5 months with chemotherapy."],"whatItMeans":"Single-agent pembrolizumab is an option for microsatellite-unstable gastric cancer first line, whereas for the broader PD-L1-positive population chemo-immunotherapy from CheckMate 649 and KEYNOTE-859 became standard.","caveats":["Microsatellite-unstable subgroup was small and exploratory.","Early progression was more frequent with pembrolizumab alone."],"changedPractice":true,"participants":763},{"id":"paper-keynote-170-pembrolizumab-pmbcl-armand-jco-2019","kind":"paper","name":"KEYNOTE-170: pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma","aka":[],"tldr":"Pembrolizumab produced responses in about 45 percent of patients with primary mediastinal B-cell lymphoma that had relapsed after chemotherapy, a lymphoma whose frequent 9p24.1 amplification makes it unusually sensitive to PD-1 blockade.","summary":"Phase 2 study of 53 patients with relapsed or refractory primary mediastinal large B-cell lymphoma treated with pembrolizumab, supported by a phase 1b cohort of 21 patients.\n\nObjective response was 45 percent with complete responses in 13 percent, median duration of response not reached after a median follow-up of 12.5 months, and no deaths from treatment-related events; 9p24.1 alterations were near-universal.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.19.01389"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31609651/"}],"tags":[],"related":[],"cancers":["primary-mediastinal-b-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-170"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.19.01389","pmid":"31609651","authors":"Armand P, Rodig S, Melnichenko V, et al.","paperType":"observational","findings":["Objective response 45 percent; complete response 13 percent.","Median duration of response not reached at 12.5 months."],"whatItMeans":"Pembrolizumab is approved for relapsed primary mediastinal B-cell lymphoma and is the usual bridge to CAR-T or transplant in chemotherapy-refractory patients.","caveats":["Single-arm; small numbers.","Most responders eventually need consolidative therapy."],"changedPractice":true,"participants":53},{"id":"paper-keynote-177-nejm-2020","kind":"paper","name":"KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer","aka":[],"tldr":"For the roughly 5% of metastatic bowel cancers with defective DNA mismatch repair, pembrolizumab alone lengthened the time without progression compared with chemotherapy, with far fewer severe side effects, and 83% of responses lasted two years or more. It made first-line pembrolizumab the standard for this group.","summary":"Open-label phase 3 trial of 307 patients with untreated microsatellite-instability-high or mismatch-repair-deficient metastatic colorectal cancer randomised to pembrolizumab or investigator's choice chemotherapy (FOLFOX or FOLFIRI with or without bevacizumab or cetuximab). Primary endpoints were PFS and OS.\n\nMedian PFS was 16.5 vs 8.2 months (HR 0.60), with 43.8% vs 33.1% responding and 83% vs 35% of responses lasting two years or more. Overall survival was not significantly different (HR 0.74) because 60% of chemotherapy patients crossed over to immunotherapy. It made first-line pembrolizumab the standard for dMMR metastatic colorectal cancer and cemented mismatch repair testing for every colorectal cancer.","asOf":"2026-09-08","links":[{"label":"NEJM 2020","url":"https://doi.org/10.1056/NEJMoa2017699"},{"label":"ClinicalTrials.gov NCT02563002","url":"https://clinicaltrials.gov/study/NCT02563002"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor","histopathology-ihc"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["msi","pfs","os","first-line","tmb"],"trials":[],"people":["kim-tae-won","elena-elez","dung-le","yoshino-takayuki","luis-diaz"],"bottlenecks":["b-immunotherapy-response","b-trial-design","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2017699","authors":"Andre T, Shiu KK, Kim TW, et al.","paperType":"rct","findings":["Median PFS 16.5 vs 8.2 months; HR 0.60 (95% CI 0.45-0.80); 24-month PFS 48.3% vs 18.6%.","Objective response 43.8% vs 33.1%; complete response 11% vs 4%.","Grade 3 or higher treatment-related adverse events 22% vs 66%.","Overall survival (Lancet Oncology 2022): HR 0.74 (95% CI 0.53-1.03), not significant; median 77.5 vs 36.7 months; 60% of chemotherapy patients received subsequent anti-PD-1 therapy.","PFS curves crossed early: about 29% of pembrolizumab patients progressed by 4 months, suggesting a subgroup of primary resistance."],"whatItMeans":"Every colorectal cancer should be tested for mismatch repair deficiency, because patients whose metastatic tumour is dMMR should receive pembrolizumab rather than chemotherapy as first treatment, gaining a much better chance of durable remission with fewer side effects. About a third of dMMR tumours do not respond initially, so early scans are essential and chemotherapy remains available. The trial does not apply to the 95% of colorectal cancers that are mismatch-repair proficient.","caveats":["OS was not significantly improved, mostly because of crossover; the design makes an OS benefit unprovable.","Early crossing of the PFS curves indicates a group with rapid progression on immunotherapy who might be better served by combinations (nivolumab plus ipilimumab in CheckMate 8HW).","Open-label design and a heterogeneous chemotherapy control arm.","Immunohistochemistry and PCR for mismatch repair can disagree; misclassification of pMMR tumours as dMMR leads to ineffective treatment."],"changedPractice":true,"participants":307},{"id":"paper-keynote-189-nejm-2018","kind":"paper","name":"KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation","aka":[],"tldr":"Adding pembrolizumab to standard chemotherapy roughly halved the risk of death in newly diagnosed non-squamous lung cancer, whatever the PD-L1 level, making chemo-immunotherapy the default first treatment.","summary":"Double-blind phase 3 trial of 616 patients with untreated metastatic non-squamous NSCLC without EGFR or ALK alterations, randomised 2:1 to pembrolizumab or placebo plus pemetrexed and a platinum. Primary endpoints were overall survival and PFS.\n\n12-month overall survival was 69.2% vs 49.4% (HR 0.49) and median PFS 8.8 vs 4.9 months (HR 0.52), with benefit in every PD-L1 stratum including below 1%. Together with KEYNOTE-024 (pembrolizumab alone for PD-L1 of 50% or more) it made PD-1 blockade part of first-line treatment for almost all patients with advanced NSCLC. The five-year update showed OS 19.4% vs 11.3%.","asOf":"2026-09-08","links":[{"label":"NEJM 2018","url":"https://doi.org/10.1056/NEJMoa1801005"},{"label":"ClinicalTrials.gov NCT02578680","url":"https://clinicaltrials.gov/study/NCT02578680"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","platinum"],"targets":["pd1","pdl1"],"drugs":["pembrolizumab","carboplatin"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["first-line","os","pfs","cold-vs-hot","irae"],"trials":[],"people":["enriqueta-felip"],"bottlenecks":["b-immunotherapy-response","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1801005","authors":"Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al.","paperType":"rct","findings":["12-month overall survival 69.2% vs 49.4%; HR 0.49 (95% CI 0.38-0.64).","Median PFS 8.8 vs 4.9 months; HR 0.52.","OS benefit in all PD-L1 subgroups: TPS below 1% HR 0.59; 1-49% HR 0.55; 50% or more HR 0.42.","Objective response 47.6% vs 18.9%.","Five-year update (2023): OS 19.4% vs 11.3%; median 22.0 vs 10.6 months despite about 57% crossover to immunotherapy."],"whatItMeans":"Most patients with newly diagnosed advanced non-squamous lung cancer that lacks a targetable mutation should receive chemotherapy plus pembrolizumab; those with PD-L1 of 50% or more may reasonably receive pembrolizumab alone. About one in five patients is alive at five years, compared with roughly one in ten with chemotherapy alone. Patients with EGFR or ALK alterations were excluded and should have targeted therapy first.","caveats":["Excluded EGFR- and ALK-positive tumours; immunotherapy benefit in driver-mutated lung cancer is much smaller.","Whether patients with PD-L1 of 50% or more need chemotherapy added to pembrolizumab has never been directly randomised.","Immune-related adverse events, including pneumonitis and nephritis, were more frequent with pembrolizumab.","Crossover in the control arm means the true OS effect is probably larger than measured."],"changedPractice":true,"participants":616},{"id":"paper-keynote-355-nejm-2022","kind":"paper","name":"KEYNOTE-355: pembrolizumab plus chemotherapy for PD-L1-positive advanced triple-negative breast cancer","aka":[],"tldr":"Adding pembrolizumab to first-line chemotherapy lengthened survival by almost seven months in advanced triple-negative breast cancer whose tumours had a PD-L1 combined positive score of 10 or more.","summary":"Phase 3 placebo-controlled trial of 847 patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer randomised 2:1 to pembrolizumab or placebo with nab-paclitaxel, paclitaxel or gemcitabine-carboplatin.\n\nIn patients with a combined positive score of 10 or more, median overall survival was 23.0 versus 16.1 months (hazard ratio 0.73); no significant benefit was seen at lower PD-L1 scores.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2202809"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35857659/"}],"tags":[],"related":[],"cancers":["tnbc-metastatic"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-355"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2202809","pmid":"35857659","authors":"Cortes J, Rugo HS, Cescon DW, et al.","paperType":"rct","findings":["Median overall survival 23.0 vs 16.1 months in combined positive score 10 or more; hazard ratio 0.73.","Median progression-free survival 9.7 vs 5.6 months in the same group."],"whatItMeans":"PD-L1 testing with the combined positive score decides first-line treatment in metastatic triple-negative breast cancer; pembrolizumab-chemotherapy is the standard for scores of 10 or more.","caveats":["No benefit demonstrated below a combined positive score of 10.","The chemotherapy partner was chosen by the investigator."],"changedPractice":true,"participants":847},{"id":"paper-keynote-426-nejm-2019","kind":"paper","name":"KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma","aka":[],"tldr":"Combining pembrolizumab with the kinase inhibitor axitinib lengthened survival and delayed progression compared with sunitinib as first treatment for advanced clear cell kidney cancer, across all risk groups.","summary":"Phase 3 trial of 861 patients with previously untreated advanced clear cell renal cell carcinoma randomised to pembrolizumab plus axitinib or sunitinib.\n\nAt 12.8 months, overall survival at one year was 89.9 versus 78.3 percent (hazard ratio 0.53), median progression-free survival 15.1 versus 11.1 months and response 59.3 versus 35.7 percent; the final analysis confirmed a survival benefit (median 47.2 versus 40.8 months).","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2019","url":"https://doi.org/10.1056/NEJMoa1816714"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30779529/"}],"tags":[],"related":[],"cancers":["clear-cell-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["axitinib","pembrolizumab","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-426"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1816714","pmid":"30779529","authors":"Rini BI, Plimack ER, Stus V, et al.","paperType":"rct","findings":["One-year overall survival 89.9 percent vs 78.3 percent; hazard ratio 0.53 at first analysis.","Objective response 59.3 percent vs 35.7 percent."],"whatItMeans":"Immunotherapy plus a VEGF kinase inhibitor is a first-line standard for advanced clear cell kidney cancer in all risk groups; comparable regimens include nivolumab-cabozantinib and lenvatinib-pembrolizumab.","caveats":["Open-label; the survival hazard ratio attenuated with longer follow-up (about 0.84).","Liver enzyme elevation is a characteristic combination toxicity."],"changedPractice":true,"participants":861},{"id":"paper-keynote-483-lancet-2023","kind":"paper","name":"KEYNOTE-483 (CCTG IND.227): pembrolizumab plus chemotherapy versus chemotherapy in untreated pleural mesothelioma","aka":[],"tldr":"Adding pembrolizumab to platinum-pemetrexed chemotherapy lengthened survival in untreated pleural mesothelioma by about a year in non-epithelioid tumours and by a smaller margin overall, giving a chemo-immunotherapy option alongside nivolumab-ipilimumab.","summary":"Phase 3 open-label trial of 440 patients with unresectable advanced pleural mesothelioma in Canada, Italy and France randomised to pembrolizumab plus platinum-pemetrexed or chemotherapy alone.\n\nMedian overall survival was 17.3 versus 16.1 months (hazard ratio 0.79), with three-year survival 25 versus 17 percent and a larger effect in non-epithelioid disease; grade 3 to 4 adverse events were more frequent with pembrolizumab.","asOf":"2026-09-17","links":[{"label":"Lancet 2023","url":"https://doi.org/10.1016/S0140-6736(23)01613-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37931632/"}],"tags":[],"related":[],"cancers":["pleural-mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-483"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"doi":"10.1016/S0140-6736(23)01613-6","pmid":"37931632","authors":"Chu Q, Perrone F, Greillier L, et al.","paperType":"rct","findings":["Median overall survival 17.3 vs 16.1 months; hazard ratio 0.79.","Three-year overall survival 25 percent vs 17 percent."],"whatItMeans":"Pembrolizumab with chemotherapy is approved and offered first line, particularly in epithelioid disease where dual immunotherapy showed little benefit over chemotherapy.","caveats":["Modest median gain; benefit concentrated in a minority of long-term responders.","Open-label with academic sponsorship and relatively small size."],"changedPractice":true,"participants":440},{"id":"paper-keynote-522-nejm-2022","kind":"paper","name":"KEYNOTE-522: adding pembrolizumab before and after surgery in early triple-negative breast cancer","aka":[],"tldr":"Adding the immunotherapy pembrolizumab to chemotherapy before surgery, then continuing it afterwards, cut the risk of relapse or death by about a third in stage II-III triple-negative breast cancer and later improved survival.","summary":"Phase 3, double-blind trial randomising 1,174 patients with untreated stage II-III triple-negative breast cancer (2:1) to neoadjuvant pembrolizumab or placebo plus carboplatin-paclitaxel then anthracycline-cyclophosphamide, followed by surgery and nine cycles of adjuvant pembrolizumab or placebo. Dual primary endpoints were pathological complete response (pCR) and event-free survival (EFS).\n\nThe 2020 report showed pCR 64.8% vs 51.2%. This 2022 report showed the EFS benefit: 36-month EFS 84.5% vs 76.8% (HR 0.63). A 2024 report added an overall survival benefit (5-year OS 86.6% vs 81.7%, HR 0.66). It established chemo-immunotherapy as the standard for stage II-III TNBC regardless of PD-L1 status.","asOf":"2026-09-08","links":[{"label":"NEJM 2022 (EFS)","url":"https://doi.org/10.1056/NEJMoa2112651"},{"label":"NEJM 2020 (pCR)","url":"https://doi.org/10.1056/NEJMoa1910549"},{"label":"ClinicalTrials.gov NCT03036488","url":"https://clinicaltrials.gov/study/NCT03036488"}],"tags":[],"related":["idea-post-neoadjuvant-adc","idea-ctdna-escalation-tnbc"],"cancers":["tnbc"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","platinum"],"targets":["pd1"],"drugs":["pembrolizumab","carboplatin","paclitaxel"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["pcr","efs","neoadjuvant-adjuvant","cps","irae","rcb"],"trials":["keynote-522"],"people":["javier-cortes","jonas-bergh","park-yeon-hee","carsten-denkert"],"bottlenecks":["b-immunotherapy-response","b-toxicity-qol","b-dormancy-mrd"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2112651","authors":"Schmid P, Cortes J, Dent R, et al.","paperType":"rct","findings":["pCR (ypT0/Tis ypN0) 64.8% with pembrolizumab vs 51.2% with placebo, a 13.6-point absolute gain (2020 interim report).","36-month event-free survival 84.5% vs 76.8%; HR for event or death 0.63 (95% CI 0.48-0.82).","Benefit was seen regardless of PD-L1 expression (CPS), unlike in the metastatic setting.","Patients with residual disease still did worse than those with pCR, but pembrolizumab improved EFS in both groups.","5-year overall survival 86.6% vs 81.7%, HR 0.66 (2024 update)."],"whatItMeans":"For stage II-III triple-negative breast cancer, chemotherapy plus pembrolizumab before surgery and pembrolizumab alone afterwards is now the standard approach worldwide, and the survival gain is real, not just a surrogate. It does not apply to stage I disease or to hormone-receptor-positive or HER2-positive cancers. The price is a year of immunotherapy with a meaningful chance of a permanent endocrine side effect such as hypothyroidism or adrenal insufficiency.","caveats":["The trial cannot say whether the adjuvant phase of pembrolizumab is needed for patients who reach pCR; de-escalation trials are testing this.","Immune-related adverse events (thyroid, adrenal, pituitary) are often permanent.","Carboplatin was part of the backbone in both arms, so the trial does not isolate the contribution of platinum.","The control arm did not include capecitabine for residual disease, which some regard as a weaker comparator."],"changedPractice":true,"participants":1174},{"id":"paper-keynote-564-nejm-2021","kind":"paper","name":"KEYNOTE-564: a year of pembrolizumab after kidney cancer surgery","aka":[],"tldr":"One year of pembrolizumab after surgery for high-risk kidney cancer reduced relapses by about a third and, in later follow-up, became the first adjuvant treatment to help kidney cancer patients live longer.","summary":"Double-blind, placebo-controlled phase 3 trial of 994 patients with clear-cell renal cell carcinoma at intermediate-high or high risk of recurrence after nephrectomy, or with resected metastatic disease (M1 NED), randomised to one year of pembrolizumab or placebo. Primary endpoint was disease-free survival.\n\n24-month DFS was 77.3% vs 68.1% (HR 0.68). The 2024 overall survival analysis showed HR 0.62 with 48-month OS 91.2% vs 86.0%. It was the first adjuvant therapy in kidney cancer to improve survival, after decades of negative trials with cytokines and VEGF inhibitors, and it stands alone: three other adjuvant checkpoint inhibitor trials (IMmotion010, CheckMate 914, PROSPER) were negative.","asOf":"2026-09-08","links":[{"label":"NEJM 2021","url":"https://doi.org/10.1056/NEJMoa2106391"},{"label":"NEJM 2024 (OS)","url":"https://doi.org/10.1056/NEJMoa2312695"},{"label":"ClinicalTrials.gov NCT03142334","url":"https://clinicaltrials.gov/study/NCT03142334"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":["dana-farber"],"pathways":[],"terms":["neoadjuvant-adjuvant","os","irae"],"trials":[],"people":["toni-choueiri","lee-jae-lyun"],"bottlenecks":["b-dormancy-mrd","b-negative-results","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2106391","authors":"Choueiri TK, Tomczak P, Park SH, et al.","paperType":"rct","findings":["24-month disease-free survival 77.3% vs 68.1%; HR 0.68 (95% CI 0.53-0.87).","Overall survival (NEJM 2024): HR 0.62 (95% CI 0.44-0.87); 48-month OS 91.2% vs 86.0%.","Largest DFS benefit in the small M1 NED group (HR 0.28) and in sarcomatoid tumours.","Grade 3 or higher adverse events 32.4% vs 17.7%; about 21% discontinued pembrolizumab for adverse events.","Endocrine immune-related events (hypothyroidism, adrenal insufficiency) were the most frequent lasting toxicities."],"whatItMeans":"Patients whose kidney cancer has been removed but who are at high risk of recurrence (large or high-grade tumours, node involvement, or resected metastases) can now be offered a year of pembrolizumab, which increases the chance of being alive and cancer-free several years later. Roughly nine patients need treatment to prevent one recurrence at two years, and some will have permanent side effects, so shared decision-making matters. Why pembrolizumab succeeded where similar drugs failed is not fully understood.","caveats":["The three other adjuvant checkpoint inhibitor trials in kidney cancer were negative, and the reasons (drug, population, chance) are debated.","Absolute DFS benefit of about 9 points; most patients treated would not have relapsed anyway.","The trial predated widespread use of immunotherapy at relapse in the control arm during the early years, which may exaggerate the OS effect relative to current practice.","Non-clear-cell histology was excluded."],"changedPractice":true,"participants":994},{"id":"paper-keynote-590-lancet-2021","kind":"paper","name":"KEYNOTE-590: pembrolizumab plus chemotherapy for first-line treatment of advanced oesophageal cancer","aka":[],"tldr":"Adding pembrolizumab to cisplatin-fluorouracil lengthened survival in advanced oesophageal cancer of both histologies, most clearly in squamous cell carcinoma and in tumours with high PD-L1, establishing chemo-immunotherapy as the first-line standard.","summary":"Phase 3 placebo-controlled trial of 749 patients with untreated advanced oesophageal or Siewert type 1 junctional cancer (73 percent squamous) randomised to pembrolizumab or placebo with cisplatin and fluorouracil.\n\nMedian overall survival was 12.4 versus 9.8 months overall (hazard ratio 0.73), 13.9 versus 8.8 months in squamous cell carcinoma with combined positive score of 10 or more (hazard ratio 0.57), and progression-free survival was improved in all groups.","asOf":"2026-09-17","links":[{"label":"Lancet 2021","url":"https://doi.org/10.1016/S0140-6736(21)01234-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34454674/"}],"tags":[],"related":[],"cancers":["oesophageal-squamous-cell-carcinoma","oesophageal-adenocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-590"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"doi":"10.1016/S0140-6736(21)01234-4","pmid":"34454674","authors":"Sun JM, Shen L, Shah MA, et al.","paperType":"rct","findings":["Median overall survival 12.4 vs 9.8 months overall; hazard ratio 0.73.","Squamous with combined positive score 10 or more: 13.9 vs 8.8 months; hazard ratio 0.57."],"whatItMeans":"Pembrolizumab plus chemotherapy is a first-line standard for advanced oesophageal cancer, with the strongest recommendation for PD-L1-expressing tumours.","caveats":["Benefit in adenocarcinoma and in low PD-L1 tumours was smaller.","Cisplatin-fluorouracil backbone is less used in some regions."],"changedPractice":true,"participants":749},{"id":"paper-keynote-629-pembrolizumab-cscc-grob-jco-2020","kind":"paper","name":"KEYNOTE-629: pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma","aka":[],"tldr":"Pembrolizumab shrank tumours in about a third of patients with recurrent or metastatic cutaneous squamous cell carcinoma, with most responses lasting beyond a year, leading to its approval as an alternative to cemiplimab.","summary":"Phase 2 study of 105 patients with recurrent or metastatic cutaneous squamous cell carcinoma, most previously treated, given pembrolizumab every three weeks.\n\nObjective response was 34.3 percent with complete response in 3.8 percent, median duration of response not reached, median progression-free survival 6.9 months, and toxicity typical of PD-1 blockade; a later cohort in locally advanced disease responded in about half.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2020","url":"https://doi.org/10.1200/JCO.19.03054"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32673170/"}],"tags":[],"related":[],"cancers":["advanced-cutaneous-scc"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-629"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"doi":"10.1200/JCO.19.03054","pmid":"32673170","authors":"Grob JJ, Gonzalez R, Basset-Seguin N, et al.","paperType":"observational","findings":["Objective response 34.3 percent; median duration of response not reached.","Median progression-free survival 6.9 months."],"whatItMeans":"Pembrolizumab is an approved first-line option for advanced cutaneous squamous cell carcinoma alongside cemiplimab.","caveats":["Single-arm; lower response rate than cemiplimab in cross-trial comparison, partly reflecting more prior treatment."],"changedPractice":true,"participants":105},{"id":"paper-keynote-689-nejm-2025","kind":"paper","name":"KEYNOTE-689: neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck cancer","aka":[],"tldr":"Giving pembrolizumab before surgery and continuing it afterwards alongside radiotherapy reduced recurrences in resectable locally advanced head and neck cancer, the first improvement in surgical treatment of the disease in two decades.","summary":"Phase 3 trial of 714 patients with resectable stage III to IVA head and neck squamous cell carcinoma (excluding HPV-positive oropharynx in most analyses) randomised to two cycles of neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab with radiotherapy or chemoradiotherapy, or surgery and adjuvant radiotherapy or chemoradiotherapy alone.\n\nEvent-free survival was improved in patients with a PD-L1 combined positive score of 10 or more (median 59.7 versus 26.9 months; hazard ratio 0.66) and of 1 or more (hazard ratio 0.70), and major pathological responses occurred in 9.3 percent after neoadjuvant treatment.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2025","url":"https://doi.org/10.1056/NEJMoa2415434"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/40532178/"}],"tags":[],"related":[],"cancers":["hpv-negative-head-and-neck-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-689"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2415434","pmid":"40532178","authors":"Uppaluri R, Haddad RI, Tao Y, et al.","paperType":"rct","findings":["Combined positive score 10 or more: median event-free survival 59.7 vs 26.9 months; hazard ratio 0.66.","Combined positive score 1 or more: hazard ratio 0.70."],"whatItMeans":"Perioperative pembrolizumab is a new standard for resectable head and neck cancer with PD-L1 expression, adding immunotherapy to a treatment pathway that had not changed since postoperative chemoradiation was defined.","caveats":["Overall survival data immature.","Pembrolizumab was continued for up to 15 cycles after surgery, adding cost and immune toxicity."],"changedPractice":true,"participants":714},{"id":"paper-keynote-716-lancet-2022","kind":"paper","name":"KEYNOTE-716: adjuvant pembrolizumab versus placebo in completely resected stage IIB or IIC melanoma","aka":[],"tldr":"A year of pembrolizumab after surgery for stage IIB or IIC melanoma reduced recurrences and distant metastases by about 35 to 40 percent, extending adjuvant immunotherapy to node-negative but thick or ulcerated melanomas.","summary":"Phase 3 placebo-controlled trial of 976 patients aged 12 and over with resected stage IIB or IIC melanoma randomised to pembrolizumab or placebo for up to 17 cycles.\n\nAt the first interim analysis, recurrence-free survival favoured pembrolizumab (hazard ratio 0.65); at longer follow-up, 36-month recurrence-free survival was 76.2 versus 63.4 percent and distant metastasis-free survival hazard ratio 0.59. Immune-related adverse events, mainly endocrine, occurred in about a third.","asOf":"2026-09-17","links":[{"label":"Lancet 2022","url":"https://doi.org/10.1016/S0140-6736(22)00562-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35367007/"}],"tags":[],"related":[],"cancers":["stage-ii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-716"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2022,"doi":"10.1016/S0140-6736(22)00562-1","pmid":"35367007","authors":"Luke JJ, Rutkowski P, Queirolo P, et al.","paperType":"rct","findings":["Recurrence-free survival hazard ratio 0.65 at first analysis; 36-month rate 76.2 percent vs 63.4 percent.","Distant metastasis-free survival hazard ratio 0.59."],"whatItMeans":"Adjuvant pembrolizumab is approved for stage IIB and IIC melanoma, though the absolute benefit and lack of survival data make observation a reasonable alternative after discussion.","caveats":["No overall survival benefit shown; most patients would not have relapsed.","Permanent endocrine side effects in a minority."],"changedPractice":true,"participants":976},{"id":"paper-keynote-775-nejm-2022","kind":"paper","name":"KEYNOTE-775: lenvatinib plus pembrolizumab versus chemotherapy for previously treated advanced endometrial cancer","aka":[],"tldr":"After platinum chemotherapy, the combination of the kinase inhibitor lenvatinib and pembrolizumab lengthened survival compared with doxorubicin or paclitaxel in advanced endometrial cancer, including in the mismatch repair-proficient majority.","summary":"Phase 3 trial of 827 patients with advanced endometrial cancer after one prior platinum regimen randomised to lenvatinib plus pembrolizumab or physician's choice of doxorubicin or weekly paclitaxel.\n\nIn mismatch repair-proficient disease median overall survival was 17.4 versus 12.0 months (hazard ratio 0.68) and median progression-free survival 6.6 versus 3.8 months; results were similar in the whole population. Grade 3 or higher adverse events occurred in 89 percent of the combination arm.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2108330"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35045221/"}],"tags":[],"related":[],"cancers":["advanced-recurrent-endometrial-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["lenvatinib","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-775"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2108330","pmid":"35045221","authors":"Makker V, Colombo N, Casado Herráez A, et al.","paperType":"rct","findings":["Mismatch repair-proficient: median overall survival 17.4 vs 12.0 months; hazard ratio 0.68.","All patients: median overall survival 18.3 vs 11.4 months; hazard ratio 0.62."],"whatItMeans":"Lenvatinib-pembrolizumab is the standard second-line treatment for mismatch repair-proficient endometrial cancer after platinum, though its toxicity is considerable and its place after first-line immunotherapy is unclear.","caveats":["Hypertension, hypothyroidism, diarrhoea and weight loss led to frequent dose reductions.","Patients had not received prior immunotherapy, unlike many today."],"changedPractice":true,"participants":827},{"id":"paper-keynote-811-janjigian-lancet-2023","kind":"paper","name":"KEYNOTE-811: pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma","aka":[],"tldr":"Adding pembrolizumab to trastuzumab and chemotherapy improved response and progression-free survival in HER2-positive advanced gastric cancer, with the benefit concentrated in tumours that also express PD-L1.","summary":"Phase 3 placebo-controlled trial of 698 patients with untreated HER2-positive advanced gastric or junctional adenocarcinoma randomised to pembrolizumab or placebo with trastuzumab and fluoropyrimidine-platinum chemotherapy.\n\nMedian progression-free survival was 10.0 versus 8.1 months (hazard ratio 0.72) overall and 10.8 versus 7.2 months in PD-L1 combined positive score 1 or more (hazard ratio 0.70); response was 73 versus 60 percent, and the final analysis showed an overall survival benefit in the PD-L1-positive population (20.0 versus 15.7 months).","asOf":"2026-09-17","links":[{"label":"Lancet 2023","url":"https://doi.org/10.1016/S0140-6736(23)02033-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37871604/"}],"tags":[],"related":[],"cancers":["gastric-her2-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-811"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"doi":"10.1016/S0140-6736(23)02033-0","pmid":"37871604","authors":"Janjigian YY, Kawazoe A, Bai Y, et al.","paperType":"rct","findings":["Median progression-free survival 10.0 vs 8.1 months; hazard ratio 0.72.","Combined positive score 1 or more: overall survival 20.0 vs 15.7 months at final analysis."],"whatItMeans":"Pembrolizumab with trastuzumab and chemotherapy is the first-line standard for HER2-positive gastric cancer with a PD-L1 combined positive score of 1 or more.","caveats":["No benefit in PD-L1-negative tumours (about 15 percent), leading to a label restriction."],"changedPractice":true,"participants":698},{"id":"paper-keynote-826-nejm-2021","kind":"paper","name":"KEYNOTE-826: pembrolizumab plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer","aka":[],"tldr":"Adding pembrolizumab to first-line chemotherapy, with or without bevacizumab, lengthened survival in advanced cervical cancer, the first improvement in the disease since bevacizumab was added seven years earlier.","summary":"Phase 3 placebo-controlled trial of 617 patients with persistent, recurrent or metastatic cervical cancer randomised to pembrolizumab or placebo with platinum-paclitaxel chemotherapy, with bevacizumab at investigator discretion.\n\nIn the PD-L1 combined positive score 1 or more population, median overall survival was not reached versus 16.3 months at the first analysis (hazard ratio 0.64) and 28.6 versus 16.5 months on update; progression-free survival was 10.4 versus 8.2 months.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2021","url":"https://doi.org/10.1056/NEJMoa2112435"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34534429/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-826"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2112435","pmid":"34534429","authors":"Colombo N, Dubot C, Lorusso D, et al.","paperType":"rct","findings":["Combined positive score 1 or more: overall survival hazard ratio 0.64; updated median 28.6 vs 16.5 months.","Median progression-free survival 10.4 vs 8.2 months."],"whatItMeans":"Pembrolizumab plus chemotherapy with bevacizumab is the first-line standard for recurrent or metastatic cervical cancer with PD-L1 expression, which covers about nine in ten patients.","caveats":["Benefit in PD-L1-negative tumours was uncertain.","Bevacizumab use was not randomised."],"changedPractice":true,"participants":617},{"id":"paper-keynote-859-lancet-oncol-2023","kind":"paper","name":"KEYNOTE-859: pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer","aka":[],"tldr":"Adding pembrolizumab to platinum-fluoropyrimidine chemotherapy lengthened survival in HER2-negative advanced gastric cancer, with the largest gain in tumours with a PD-L1 combined positive score of 10 or more, confirming chemo-immunotherapy as first-line standard.","summary":"Phase 3 placebo-controlled trial of 1,579 patients with untreated HER2-negative locally advanced or metastatic gastric or junctional adenocarcinoma randomised to pembrolizumab or placebo with fluoropyrimidine-platinum chemotherapy.\n\nMedian overall survival was 12.9 versus 11.5 months overall (hazard ratio 0.78), 13.0 versus 11.4 months in combined positive score 1 or more (hazard ratio 0.74) and 15.7 versus 11.8 months in score 10 or more (hazard ratio 0.65).","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2023","url":"https://doi.org/10.1016/S1470-2045(23)00515-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37875143/"}],"tags":[],"related":[],"cancers":["gastric-pdl1-high"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-859"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2023,"doi":"10.1016/S1470-2045(23)00515-6","pmid":"37875143","authors":"Rha SY, Oh DY, Yañez P, et al.","paperType":"rct","findings":["Median overall survival 12.9 vs 11.5 months overall; hazard ratio 0.78.","Combined positive score 10 or more: 15.7 vs 11.8 months; hazard ratio 0.65."],"whatItMeans":"Pembrolizumab plus chemotherapy is approved for HER2-negative advanced gastric cancer, alongside nivolumab plus chemotherapy from CheckMate 649, with strongest evidence at higher PD-L1 scores.","caveats":["Benefit in PD-L1-low tumours is small, and European approval is restricted to combined positive score 1 or more."],"changedPractice":true,"participants":1579},{"id":"paper-keynote-942-lancet-2024","kind":"paper","name":"KEYNOTE-942: a personalised mRNA cancer vaccine plus pembrolizumab after melanoma surgery","aka":[],"tldr":"A vaccine custom-made from each patient's own tumour mutations, given with pembrolizumab after surgery for high-risk melanoma, reduced recurrence by about 44% compared with pembrolizumab alone in a mid-sized randomised trial, the first sign that personalised cancer vaccines can work.","summary":"Open-label randomised phase 2b trial of 157 patients with completely resected stage IIIB-IV melanoma randomised 2:1 to mRNA-4157 (V940, intismeran autogene, encoding up to 34 patient-specific neoantigens) plus pembrolizumab or pembrolizumab alone for about a year. Primary endpoint was recurrence-free survival.\n\nRecurrence-free survival HR was 0.56 (18-month RFS 78.6% vs 62.2%) and distant metastasis-free survival HR 0.35, with benefit regardless of tumour mutational burden or PD-L1. Toxicity was mainly injection-site reactions and flu-like symptoms. It triggered the phase 3 INTerpath-001 trial and a wave of investment in individualised neoantigen vaccines.","asOf":"2026-09-08","links":[{"label":"PubMed search: KEYNOTE-942 mRNA-4157 Lancet 2024","url":"https://pubmed.ncbi.nlm.nih.gov/?term=mRNA-4157+V940+pembrolizumab+melanoma+KEYNOTE-942+Lancet"},{"label":"ClinicalTrials.gov NCT03897881","url":"https://clinicaltrials.gov/study/NCT03897881"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":["neoantigen-mrna-vaccine","checkpoint-inhibitor","wes-wgs"],"targets":["pd1"],"drugs":["intismeran-autogene","pembrolizumab"],"companies":["moderna","merck"],"institutions":[],"pathways":[],"terms":["neoantigen","tmb","neoadjuvant-adjuvant"],"trials":["interpath-001"],"people":["ryan-sullivan"],"bottlenecks":["b-immunotherapy-response","b-manufacturing-cell-therapy","b-trial-design"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"authors":"Weber JS, Carlino MS, Khattak A, et al.","paperType":"rct","findings":["Recurrence-free survival HR 0.561 (95% CI 0.309-1.017); 18-month RFS 78.6% vs 62.2%.","Distant metastasis-free survival HR 0.347 (95% CI 0.145-0.828).","Benefit was seen in both high and low tumour mutational burden and in PD-L1-negative tumours.","Three-year update: RFS HR 0.51, with the curves continuing to separate.","Grade 3 or higher treatment-related adverse events 25% vs 18%; vaccine-related events were mostly grade 1-2 fatigue, injection-site pain and chills.","Manufacturing took about six to eight weeks per patient from biopsy sequencing to first dose."],"whatItMeans":"For the first time a randomised trial suggests that a vaccine tailored to an individual's tumour can reduce relapse when combined with immunotherapy, which is a proof of concept for a field that had failed for decades. Nothing changes for patients yet: the trial was small, the confidence interval crossed one, and the phase 3 trial in melanoma (and parallel trials in lung and other cancers) must confirm it. If it does, personalised mRNA vaccines could become a routine adjunct to checkpoint inhibitors after surgery.","caveats":["Phase 2b with 157 patients and an upper confidence limit above 1.0; the prespecified one-sided p-value was met but the result needs confirmation.","Open-label; recurrence assessments were investigator-based.","Individualised manufacturing is slow and expensive and has never been scaled to thousands of patients.","No biomarker predicts who benefits, and the mechanism (neoantigen-specific T-cell expansion) has been shown in only a subset."],"changedPractice":false,"participants":157},{"id":"paper-keynote-966-lancet-2023","kind":"paper","name":"KEYNOTE-966: pembrolizumab plus gemcitabine and cisplatin for advanced biliary tract cancer","aka":[],"tldr":"Adding pembrolizumab to gemcitabine-cisplatin, with gemcitabine continued as maintenance, lengthened survival in advanced biliary tract cancer by about two months, confirming the role of chemo-immunotherapy shown by TOPAZ-1.","summary":"Phase 3 placebo-controlled trial of 1,069 patients with untreated metastatic or unresectable biliary tract cancer randomised to pembrolizumab or placebo with gemcitabine-cisplatin, with gemcitabine continued beyond eight cycles.\n\nMedian overall survival was 12.7 versus 10.9 months (hazard ratio 0.83), with a consistent effect across subgroups and no new safety signals.","asOf":"2026-09-17","links":[{"label":"Lancet 2023","url":"https://doi.org/10.1016/S0140-6736(23)00727-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37075781/"}],"tags":[],"related":[],"cancers":["intrahepatic-cholangiocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","gemcitabine","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-966"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"doi":"10.1016/S0140-6736(23)00727-4","pmid":"37075781","authors":"Kelley RK, Ueno M, Yoo C, et al.","paperType":"rct","findings":["Median overall survival 12.7 vs 10.9 months; hazard ratio 0.83.","Median progression-free survival 6.5 vs 5.6 months."],"whatItMeans":"Pembrolizumab with gemcitabine-cisplatin is an approved first-line option for advanced biliary tract cancer alongside durvalumab-based therapy.","caveats":["Modest absolute gain; no biomarker enrichment."],"changedPractice":true,"participants":1069},{"id":"paper-keynote-a18-lancet-2024","kind":"paper","name":"KEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer","aka":[],"tldr":"Adding pembrolizumab to standard chemoradiotherapy for high-risk locally advanced cervical cancer reduced progression by 30% and later improved survival, the first systemic advance in this setting since cisplatin was added to radiotherapy in 1999.","summary":"Double-blind, placebo-controlled phase 3 trial of 1,060 patients with newly diagnosed, high-risk locally advanced cervical cancer (FIGO 2014 stage IB2-IIB with node-positive disease, or stage III-IVA) randomised to pembrolizumab or placebo with cisplatin-based chemoradiotherapy and brachytherapy, followed by pembrolizumab or placebo maintenance for about 15 cycles. Primary endpoints were PFS and OS.\n\n24-month PFS was about 68% vs 57% (HR 0.70) and a second report showed 36-month OS 82.6% vs 74.8% (HR 0.67). It established chemoradiotherapy plus pembrolizumab as a new standard for high-risk locally advanced cervical cancer, a disease that predominantly affects women in low- and middle-income countries.","asOf":"2026-09-08","links":[{"label":"PubMed search: KEYNOTE-A18 pembrolizumab chemoradiotherapy cervical","url":"https://pubmed.ncbi.nlm.nih.gov/?term=KEYNOTE-A18+pembrolizumab+chemoradiotherapy+cervical+Lancet"},{"label":"ClinicalTrials.gov NCT04221945","url":"https://clinicaltrials.gov/study/NCT04221945"}],"tags":[],"related":[],"cancers":["cervical"],"sections":[],"technologies":["checkpoint-inhibitor","imrt-igrt","brachytherapy","platinum"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":["gemelli"],"pathways":[],"terms":["pfs","os","cps","standard-of-care"],"trials":[],"people":["giovanni-scambia"],"bottlenecks":["b-global-access","b-immunotherapy-response","b-drug-pricing"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"authors":"Lorusso D, Xiang Y, Hasegawa K, et al.","paperType":"rct","findings":["24-month progression-free survival about 68% vs 57%; HR 0.70 (95% CI 0.55-0.89).","Overall survival (Lancet 2024 second analysis): 36-month OS 82.6% vs 74.8%; HR 0.67 (95% CI 0.50-0.90).","Benefit was largest in stage III-IVA disease and consistent across PD-L1 subgroups (almost all tumours were CPS 1 or more).","Grade 3 or higher adverse events 75% vs 69%, mostly haematological from chemoradiotherapy; immune-mediated events 33% vs 12%, mainly hypothyroidism.","The earlier CALLA trial of durvalumab with chemoradiotherapy in a broader population was negative, highlighting the importance of enrolling high-risk patients."],"whatItMeans":"Women with locally advanced cervical cancer that is node-positive or stage III-IVA should now be offered pembrolizumab alongside and after chemoradiotherapy, which improves the chance of cure. The result matters most in countries where cervical cancer is common but immunotherapy access is poorest, so its global impact depends on pricing and health-system capacity. It does not apply to early-stage disease treated with surgery or to lower-risk locally advanced disease without nodal involvement.","caveats":["High-risk population only; the negative CALLA trial suggests lower-risk patients may not benefit.","Radiotherapy quality (including brachytherapy) varied and is a major determinant of outcome; the trial was conducted mainly in well-resourced centres.","About two years of pembrolizumab is costly where cervical cancer burden is highest.","Follow-up remains relatively short for a disease with late recurrences."],"changedPractice":true,"participants":1060},{"id":"paper-heinrich-kit-mutation-imatinib-response-jco-2003","kind":"paper","name":"Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumour","aka":[],"tldr":"This analysis showed that the type of KIT mutation predicts response to imatinib: tumours with exon 11 mutations responded in over 80 percent of cases, exon 9 mutations in under half, and tumours without a KIT or PDGFRA mutation rarely responded.","summary":"Mutation analysis of tumours from 127 patients with advanced GIST treated with imatinib in the phase 2 B2222 trial, correlating KIT and PDGFRA genotype with response and progression-free survival.\n\nPartial response was 83.5 percent in KIT exon 11-mutant tumours, 47.8 percent in exon 9-mutant tumours and 0 percent in tumours without a detectable KIT or PDGFRA mutation, with corresponding differences in event-free survival.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2003","url":"https://doi.org/10.1200/JCO.2003.04.190"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/14645423/"}],"tags":[],"related":[],"cancers":["gist-kit-exon-11"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2003,"doi":"10.1200/JCO.2003.04.190","pmid":"14645423","authors":"Heinrich MC, Corless CL, Demetri GD, et al.","paperType":"translational","findings":["Response 83.5 percent (exon 11) vs 47.8 percent (exon 9) vs 0 percent (no mutation).","PDGFRA mutations found in a subset of KIT wild-type tumours."],"whatItMeans":"Mutation testing is standard before imatinib in GIST: exon 11 tumours receive 400 mg, exon 9 tumours are dosed at 800 mg, and PDGFRA D842V tumours are given avapritinib instead.","caveats":["Retrospective analysis of a trial cohort."],"changedPractice":true,"participants":127},{"id":"paper-klass-01-kim-jama-oncol-2019","kind":"paper","name":"KLASS-01: laparoscopic versus open distal gastrectomy for stage I gastric cancer, long-term survival","aka":[],"tldr":"Keyhole removal of the lower stomach for early gastric cancer gave the same five-year survival as open surgery in this large Korean trial, confirming laparoscopic gastrectomy as a standard for stage I disease.","summary":"Phase 3 non-inferiority trial of 1,416 patients with clinical stage I gastric cancer randomised to laparoscopic or open distal gastrectomy in 13 Korean centres.\n\nFive-year overall survival was 94.2 percent with laparoscopic and 93.3 percent with open surgery, cancer-specific survival 97.1 versus 97.2 percent, with fewer wound complications after laparoscopic surgery as reported earlier.","asOf":"2026-09-17","links":[{"label":"JAMA Oncol 2019","url":"https://doi.org/10.1001/jamaoncol.2018.6727"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30730546/"}],"tags":[],"related":[],"cancers":["early-gastric-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["klass-01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2019,"doi":"10.1001/jamaoncol.2018.6727","pmid":"30730546","authors":"Kim HH, Han SU, Kim MC, et al.","paperType":"rct","findings":["Five-year overall survival 94.2 percent vs 93.3 percent (non-inferior).","Five-year cancer-specific survival 97.1 percent vs 97.2 percent."],"whatItMeans":"Laparoscopic distal gastrectomy is the standard operation for stage I gastric cancer outside endoscopic criteria in East Asia and increasingly elsewhere.","caveats":["High-volume Korean surgeons; results may not generalise to low-volume settings."],"changedPractice":true,"participants":1416},{"id":"paper-krystal-1-crc-yaeger-nejm-2023","kind":"paper","name":"KRYSTAL-1: adagrasib with or without cetuximab in KRAS G12C-mutated colorectal cancer","aka":[],"tldr":"The KRAS G12C inhibitor adagrasib on its own shrank about one in five previously treated colorectal cancers, but combined with the EGFR antibody cetuximab the response rate rose to nearly half, showing the two drugs are needed together in this disease.","summary":"Phase 1/2 study including 44 patients with KRAS G12C-mutated metastatic colorectal cancer treated with adagrasib alone and 32 treated with adagrasib plus cetuximab, all heavily pretreated.\n\nObjective response was 19 percent with monotherapy (median progression-free survival 5.6 months) and 46 percent with the combination (median progression-free survival 6.9 months, median overall survival 13.4 months).","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2212419"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36546659/"}],"tags":[],"related":[],"cancers":["kras-g12c-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["adagrasib","cetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2212419","pmid":"36546659","authors":"Yaeger R, Weiss J, Pelster MS, et al.","paperType":"observational","findings":["Objective response 19 percent with adagrasib alone vs 46 percent with adagrasib plus cetuximab.","Median overall survival 13.4 months with the combination."],"whatItMeans":"Adagrasib plus cetuximab is an approved option for previously treated KRAS G12C colorectal cancer, alongside sotorasib plus panitumumab; monotherapy is not enough because EGFR signalling reactivates the pathway.","caveats":["Small single-arm cohorts.","Responses are shorter than in KRAS G12C lung cancer."],"changedPractice":true,"participants":76},{"id":"paper-lacc-nejm-2018","kind":"paper","name":"LACC: minimally invasive versus open radical hysterectomy for early cervical cancer","aka":[],"tldr":"Against expectations, keyhole radical hysterectomy for early cervical cancer led to more recurrences and more deaths than open surgery, reversing a decade of practice towards laparoscopic and robotic operations.","summary":"Phase 3 non-inferiority trial of 631 women with stage IA1 (with lymphovascular invasion) to IB1 cervical cancer randomised to minimally invasive (laparoscopic or robotic) or open abdominal radical hysterectomy.\n\nDisease-free survival at 4.5 years was 86.0 percent with minimally invasive surgery against 96.5 percent with open surgery, with a hazard ratio for recurrence of 3.74 and for death of 6.00; the trial was stopped early for harm.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1806395"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30380365/"}],"tags":[],"related":[],"cancers":["early-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["lacc"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1806395","pmid":"30380365","authors":"Ramirez PT, Frumovitz M, Pareja R, et al.","paperType":"rct","findings":["4.5-year disease-free survival 86.0 percent vs 96.5 percent; hazard ratio for recurrence 3.74.","Hazard ratio for death from any cause 6.00."],"whatItMeans":"Open radical hysterectomy is again the standard for early cervical cancer; minimally invasive approaches are used only within protocols that avoid tumour spillage, and the trial is a lesson in adopting surgical innovation without randomised evidence.","caveats":["Mechanism (uterine manipulator, CO2 insufflation, intracorporeal colpotomy) remains debated.","Surgical technique modifications have not yet been proven safe in randomised trials."],"changedPractice":true,"participants":631},{"id":"paper-lamouille-emt-molecular-mechanisms-nrmcb-2014","kind":"paper","name":"Lamouille 2014: molecular mechanisms of epithelial-mesenchymal transition","aka":[],"tldr":"The detailed molecular account of how cells switch from a fixed epithelial state to a mobile mesenchymal one, from the TGF-beta signals that start it to the transcription factors, microRNAs and cytoskeletal changes that carry it out.","summary":"Lamouille, Xu and Derynck reviewed the machinery of epithelial-mesenchymal transition: TGF-beta signalling through SMAD and non-SMAD routes as the best-characterised trigger, the core transcription factors Snail, ZEB and Twist that repress E-cadherin and epithelial genes, the miR-200 and miR-34 families that hold those factors in check, and the changes in junctions, polarity and actin cytoskeleton that produce motility and invasion. They stressed that EMT is often partial and reversible, with cells occupying intermediate states, and described how the programme is co-opted in fibrosis and cancer.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nrm3758"}],"tags":[],"related":["paper-kalluri-weinberg-emt-basics-jci-2009","paper-thiery-emt-tumour-progression-nrc-2002"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["emt","tgf-beta"],"terms":["metastasis","activating-invasion-metastasis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Reviews Molecular Cell Biology","year":2014,"doi":"10.1038/nrm3758","authors":"Lamouille S, Xu J, Derynck R.","paperType":"review","findings":["TGF-beta is the best-characterised EMT inducer, acting through SMAD-dependent and independent pathways alongside Wnt, Notch and growth factor signals.","Snail, ZEB and Twist transcription factors repress E-cadherin and drive the mesenchymal programme; miR-200 and miR-34 microRNAs oppose them in feedback loops.","EMT is frequently partial and reversible, producing hybrid cell states."],"whatItMeans":"This is the reference for the mechanics behind invasion and metastasis and for why partial EMT states, rather than a full switch, are now thought to matter most in cancer. It also explains the appeal and the difficulty of drugging EMT, since its drivers are transcription factors.","caveats":["A review, largely of cell culture and developmental systems.","Direct evidence for EMT in human metastasis remains harder to obtain than in models."],"changedPractice":false},{"id":"paper-drilon-larotrectinib-nejm-2018","kind":"paper","name":"Larotrectinib in TRK fusion-positive cancers in adults and children","aka":[],"tldr":"The selective TRK inhibitor larotrectinib shrank tumours in three quarters of patients with NTRK fusions across 17 different cancer types and ages from infancy to old age, leading to the first tumour-agnostic approval of a targeted drug.","summary":"Pooled analysis of 55 patients (adults and children) with TRK fusion-positive solid tumours across 17 tumour types from three phase 1 and 2 trials treated with larotrectinib.\n\nObjective response was 75 percent by independent review with 71 percent of responses ongoing at one year, activity independent of tumour type, fusion partner or age, and mostly low-grade toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1714448"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29466156/"}],"tags":[],"related":[],"cancers":["ntrk-fusion-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["larotrectinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1714448","pmid":"29466156","authors":"Drilon A, Laetsch TW, Kummar S, et al.","paperType":"observational","findings":["Objective response 75 percent across 17 tumour types.","71 percent of responses ongoing at one year; 55 percent of patients progression-free at one year."],"whatItMeans":"NTRK fusion testing is now recommended in lung and other cancers without a common driver, and larotrectinib or entrectinib is the standard treatment when a fusion is found.","caveats":["NTRK fusions are rare (under 1 percent) in lung cancer.","Acquired resistance mutations in the kinase domain develop; repotrectinib addresses some."],"changedPractice":true,"participants":55},{"id":"paper-latitude-nejm-2017","kind":"paper","name":"LATITUDE: abiraterone plus prednisone in newly diagnosed high-risk metastatic castration-sensitive prostate cancer","aka":[],"tldr":"Adding abiraterone to hormone therapy at the time of diagnosis of high-risk metastatic prostate cancer cut deaths by more than a third, establishing early intensification instead of waiting for castration resistance.","summary":"Phase 3 placebo-controlled trial of 1,199 men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (at least two of Gleason 8 or more, three or more bone lesions, visceral metastases) randomised to androgen deprivation with abiraterone plus prednisone or placebo.\n\nAt the first analysis overall survival at three years was 66 versus 49 percent (hazard ratio 0.62) and radiographic progression-free survival 33.0 versus 14.8 months; the final analysis showed median survival of 53.3 versus 36.5 months.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1704174"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28578607/"}],"tags":[],"related":[],"cancers":["prostate-mhspc"],"sections":[],"technologies":[],"targets":[],"drugs":["prednisone"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["latitude"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1704174","pmid":"28578607","authors":"Fizazi K, Tran N, Fein L, et al.","paperType":"rct","findings":["Median overall survival 53.3 vs 36.5 months at final analysis; hazard ratio 0.66.","Radiographic progression-free survival 33.0 vs 14.8 months; hazard ratio 0.47."],"whatItMeans":"Abiraterone with androgen deprivation is a standard first-line doublet for metastatic hormone-sensitive prostate cancer, consistent with the STAMPEDE result.","caveats":["Restricted to high-risk disease; STAMPEDE showed benefit across risk groups.","Hypertension and hypokalaemia require monitoring."],"changedPractice":true,"participants":1199},{"id":"paper-le-mmr-deficiency-pd1-nejm-2015","kind":"paper","name":"Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ","aka":[],"tldr":"Pembrolizumab shrank tumours in 40% of colorectal and 71% of other cancers with faulty DNA mismatch repair, but in none with intact repair, tying immunotherapy response to mutation burden.","summary":"This investigator-initiated phase 2 study tested the hypothesis that tumours with defective DNA mismatch repair (dMMR), which accumulate thousands of mutations and neoantigens, would respond to PD-1 blockade. Forty-one patients with treatment-refractory metastatic cancer were enrolled in three cohorts: dMMR colorectal cancer, MMR-proficient colorectal cancer, and dMMR non-colorectal cancers, all treated with pembrolizumab 10 mg/kg every two weeks. Immune-related objective response rates were 40% (4 of 10) in dMMR colorectal cancer, 0% (0 of 18) in MMR-proficient colorectal cancer and 71% (5 of 7) in dMMR non-colorectal cancers; 20-week PFS was 78% versus 11% in the two colorectal cohorts. Whole-exome sequencing showed a mean of 1782 somatic mutations in dMMR versus 73 in proficient tumours, and higher mutation load correlated with longer PFS.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1500596"},{"label":"ClinicalTrials.gov NCT01876511","url":"https://clinicaltrials.gov/study/NCT01876511"}],"tags":[],"related":["paper-le-mmr-deficiency-science-2017","paper-cercek-dostarlimab-rectal-nejm-2022"],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","tmb","neoantigen","tumour-agnostic"],"trials":[],"people":["dung-le","luis-diaz","drew-pardoll"],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1500596","authors":"Le DT, Uram JN, Wang H, et al.","paperType":"translational","findings":["41 patients: 11 dMMR colorectal, 21 MMR-proficient colorectal, 9 dMMR non-colorectal; pembrolizumab 10 mg/kg every 2 weeks.","Immune-related objective response: 40% dMMR colorectal, 0% proficient colorectal, 71% dMMR non-colorectal.","Immune-related PFS at 20 weeks: 78% (dMMR colorectal) vs 11% (proficient colorectal).","Mean somatic mutations per tumour 1782 (dMMR) vs 73 (proficient); higher load associated with longer PFS.","Benefit occurred in both Lynch-syndrome and sporadic dMMR tumours."],"whatItMeans":"This small trial explained why colorectal cancer had seemed immune-resistant (most is MMR-proficient) and established the principle that a genomic feature, not the tissue of origin, can predict immunotherapy response. It led directly to the 2017 tissue-agnostic approval of pembrolizumab and to routine MMR/MSI testing of many cancers. Every patient with advanced dMMR cancer should now be considered for checkpoint blockade.","caveats":["Very small cohorts; response rates have wide confidence intervals.","Dose of 10 mg/kg is higher than later standard dosing.","Single-arm; no randomised comparison until KEYNOTE-177.","Mutation burden as a biomarker beyond dMMR has proved less clean than this data suggested."],"changedPractice":true,"participants":41},{"id":"paper-le-mmr-deficiency-science-2017","kind":"paper","name":"Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval","aka":[],"tldr":"Across 86 patients with 12 different dMMR cancers, pembrolizumab produced responses in 53% and complete responses in 21%, prompting the first approval of a cancer drug based on a genetic marker rather than tumour site.","summary":"Extending the 2015 study, this report treated 86 patients with treatment-refractory, mismatch-repair-deficient cancers of 12 types (colorectal, endometrial, gastric, biliary, pancreatic, small bowel and others) with pembrolizumab. The objective response rate was 53% (46 of 86) with complete responses in 21% (18); disease control was 77%, and neither median PFS nor OS had been reached at a median follow-up of 12.5 months. Responses were seen in every tumour type. Functional analysis showed rapid in vivo expansion of neoantigen-specific T-cell clones. The FDA approved pembrolizumab for any unresectable or metastatic MSI-H/dMMR solid tumour in May 2017, the first tissue-agnostic cancer drug approval, and the randomised KEYNOTE-177 trial later confirmed first-line benefit in dMMR colorectal cancer (median PFS 16.5 versus 8.2 months).","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.aan6733"},{"label":"ClinicalTrials.gov NCT01876511","url":"https://clinicaltrials.gov/study/NCT01876511"}],"tags":[],"related":["paper-le-mmr-deficiency-pd1-nejm-2015","paper-niche-2-neoadjuvant-colon-nejm-2024"],"cancers":["colorectal","pancreatic"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["pembrolizumab","nivolumab","dostarlimab"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","tumour-agnostic","neoantigen","tmb"],"trials":["keynote-177","checkmate-8hw"],"people":["dung-le","luis-diaz"],"bottlenecks":["b-regulatory-fragmentation","b-biomarker-validation"],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2017,"doi":"10.1126/science.aan6733","authors":"Le DT, Durham JN, Smith KN, et al.","paperType":"translational","findings":["86 patients with dMMR cancers of 12 types; pembrolizumab 10 mg/kg every 2 weeks.","Objective response 53% (46 of 86); complete response 21% (18 of 86); disease control 77%.","Median PFS and OS not reached at 12.5 months median follow-up; responses in all 12 tumour types.","Neoantigen-specific T-cell clones expanded in blood within weeks of starting therapy.","Estimated that dMMR occurs in about 4% of advanced cancers, roughly 60,000 patients a year in the United States."],"whatItMeans":"This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.","caveats":["Single-arm basket study; approvals rested on response rate and durability.","Heterogeneous prior therapies and tumour types; small numbers per type.","Roughly a quarter of dMMR tumours are primary resistant, and mechanisms (B2M loss, JAK mutations) are incompletely understood.","Later data suggest sensitivity varies by MSI assay and tumour type (for example, lower in some dMMR pancreatic and brain tumours)."],"changedPractice":true,"participants":86},{"id":"paper-leach-allison-ctla4-blockade-science-1996","kind":"paper","name":"Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours","aka":[],"tldr":"Injecting mice with an antibody that blocks the T-cell inhibitory receptor CTLA-4 caused established colon carcinomas and fibrosarcomas to be rejected and protected against re-challenge, the experiment that founded checkpoint immunotherapy.","summary":"Allison's laboratory had shown that CTLA-4 is a negative regulator of T-cell activation, opposing the co-stimulatory receptor CD28. This paper tested whether removing that brake would enhance anti-tumour immunity. Mice bearing transplantable 51BLim10 colon carcinoma or fibrosarcoma tumours were treated with anti-CTLA-4 antibodies.\n\nAnti-CTLA-4 treatment led to rejection of established tumours, including those that were poorly immunogenic when combined with a vaccine, and treated mice were immune to a second tumour challenge. The effect did not require engineering the tumour to express co-stimulatory molecules.\n\nThe finding was met with industry scepticism, but Medarex developed the human antibody that became ipilimumab, approved for melanoma in 2011 as the first drug to extend survival in metastatic melanoma. Allison shared the 2018 Nobel Prize with Tasuku Honjo.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1126/science.271.5256.1734"}],"tags":[],"related":["paper-iwai-pdl1-tumour-escape-pnas-2002"],"cancers":["melanoma"],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor"],"targets":["ctla4"],"drugs":["ipilimumab"],"companies":[],"institutions":["md-anderson"],"pathways":["pd1-checkpoint"],"terms":[],"trials":["checkmate-067"],"people":["james-allison","padmanee-sharma"],"bottlenecks":["b-immunotherapy-response","b-translational-valley"],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":1996,"doi":"10.1126/science.271.5256.1734","pmid":"8596936","authors":"Leach DR, Krummel MF, Allison JP","paperType":"basic","findings":["Anti-CTLA-4 antibody induced rejection of established, pre-implanted colon carcinoma and fibrosarcoma tumours in mice","Rejected mice were protected against re-challenge with the same tumour, indicating immunological memory","Efficacy against a poorly immunogenic tumour required combination with a GM-CSF-secreting vaccine, foreshadowing combination immunotherapy","Established the principle that removing inhibitory signals on T cells, rather than adding stimulation, can treat cancer"],"whatItMeans":"Every checkpoint inhibitor, from ipilimumab to pembrolizumab, rests on this idea: the immune system can already recognise cancer and just needs its brakes released. It changed the goal of immunotherapy from vaccinating against tumours to unleashing existing T cells.","caveats":["Mouse transplantable tumours are far more immunogenic than most human cancers","CTLA-4 blockade in humans causes substantial immune-related toxicity (colitis, hypophysitis) not evident in these models","Response rates to single-agent ipilimumab in humans are low (about 10-15% in melanoma)","Mechanism (Treg depletion versus effector T-cell release) remained debated for two decades"],"changedPractice":false},{"id":"paper-leap-012-lancet-2025","kind":"paper","name":"LEAP-012: transarterial chemoembolisation with lenvatinib plus pembrolizumab versus placebo for unresectable non-metastatic hepatocellular carcinoma","aka":[],"tldr":"Adding lenvatinib and pembrolizumab to chemoembolisation delayed progression in intermediate-stage liver cancer, the second trial to show that systemic therapy improves on embolisation alone, at the cost of more side effects.","summary":"Phase 3 placebo-controlled trial of 480 patients with unresectable, non-metastatic hepatocellular carcinoma suitable for chemoembolisation randomised to transarterial chemoembolisation with lenvatinib plus pembrolizumab or with dual placebo.\n\nMedian progression-free survival was 14.6 versus 10.0 months (hazard ratio 0.66), with an early trend in overall survival (hazard ratio 0.80, not significant) and grade 3 to 4 treatment-related adverse events of 71 versus 32 percent.","asOf":"2026-09-17","links":[{"label":"Lancet 2025","url":"https://doi.org/10.1016/S0140-6736(24)02575-3"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/39798578/"}],"tags":[],"related":[],"cancers":["hcc-intermediate"],"sections":[],"technologies":[],"targets":[],"drugs":["lenvatinib","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["leap-012"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2025,"doi":"10.1016/S0140-6736(24)02575-3","pmid":"39798578","authors":"Kudo M, Ren Z, Guo Y, et al.","paperType":"rct","findings":["Median progression-free survival 14.6 vs 10.0 months; hazard ratio 0.66.","Grade 3 to 4 treatment-related adverse events 71 percent vs 32 percent."],"whatItMeans":"Lenvatinib-pembrolizumab with chemoembolisation is an emerging option for intermediate-stage disease, balanced against substantial toxicity.","caveats":["Overall survival not yet significant.","High toxicity may limit uptake."],"changedPractice":true,"participants":480},{"id":"paper-lemmon-schlessinger-rtk-signalling-cell-2010","kind":"paper","name":"Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases","aka":[],"tldr":"The standard review of the receptor family behind many cancer drugs, explaining how growth factor receptors such as EGFR and HER2 switch on when they pair up, how mutations lock them on in cancer, and how inhibitors turn them off.","summary":"Lemmon and Schlessinger surveyed the 58 human receptor tyrosine kinases in 20 subfamilies, describing how ligand binding drives receptor dimerisation and trans-autophosphorylation, the structural diversity of activation mechanisms across families, and the intracellular pathways (RAS-MAPK, PI3K-AKT, PLC-gamma and STAT) that carry the signal. They explained how overexpression, amplification, point mutations and fusions deregulate these receptors in cancer and how antibodies and small-molecule kinase inhibitors exploit the same mechanisms, with resistance mutations as the predictable consequence.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/j.cell.2010.06.011"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":["egfr","her2","met","alk","kit"],"drugs":[],"companies":[],"institutions":[],"pathways":["rtk-activation"],"terms":["tki-term","signalling-pathway"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cell","year":2010,"doi":"10.1016/j.cell.2010.06.011","authors":"Lemmon MA, Schlessinger J.","paperType":"review","findings":["Humans have 58 receptor tyrosine kinases in 20 subfamilies, activated by ligand-induced dimerisation and trans-autophosphorylation with family-specific mechanisms.","Signals propagate through RAS-MAPK, PI3K-AKT, PLC-gamma and STAT pathways and are shaped by negative feedback and endocytosis.","Cancers deregulate RTKs by amplification, mutation and fusion; therapeutic antibodies and kinase inhibitors target the receptors and select for resistance mutations."],"whatItMeans":"Almost every targeted therapy on this site, from trastuzumab and EGFR inhibitors to ALK, MET, RET and FGFR drugs, acts on the receptors this review describes. It is the mechanistic background for understanding both why these drugs work and why resistance mutations arise.","caveats":["A review; structural details for several families have been refined since.","Does not cover the clinical trials of the drugs it explains."],"changedPractice":false},{"id":"paper-levine-p53-gatekeeper-cell-1997","kind":"paper","name":"Levine 1997: p53, the cellular gatekeeper for growth and division","aka":[],"tldr":"The classic account of how the p53 protein senses DNA damage and other stress and then stops a cell dividing or makes it die, and why losing p53, as about half of cancers do, removes a central safeguard against cancer.","summary":"Levine's review described p53 as a transcription factor kept at low levels by MDM2 and stabilised by signals including DNA damage, hypoxia and oncogene activation. Activated p53 induces genes that arrest the cell cycle, chiefly p21, or trigger apoptosis, so that damaged cells are repaired or removed. The review explained how p53 mutation in roughly half of human cancers, inheritance of a mutant allele in Li-Fraumeni syndrome, and viral proteins that inactivate p53 all remove this checkpoint, and it set out the MDM2 feedback loop that later became a drug target.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/S0092-8674(00)81871-1"}],"tags":[],"related":["paper-hollstein-p53-mutations-science-1991","paper-el-deiry-waf1-p21-cell-1993"],"cancers":[],"sections":[],"technologies":[],"targets":["tp53","mdm2"],"drugs":[],"companies":[],"institutions":[],"pathways":["p53-cell-cycle","p53-mdm2-axis"],"terms":["tp53-mutated","tumour-suppressor-gene","li-fraumeni","apoptosis","cell-cycle"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cell","year":1997,"doi":"10.1016/S0092-8674(00)81871-1","authors":"Levine AJ.","paperType":"review","findings":["p53 is stabilised by DNA damage, hypoxia and oncogene activation and acts as a transcription factor.","Its main outputs are cell cycle arrest through p21 and apoptosis, removing damaged cells.","MDM2 binds and degrades p53 in a negative feedback loop; p53 is mutated in about half of human cancers and inherited mutation causes Li-Fraumeni syndrome."],"whatItMeans":"This review fixed the picture of p53 as the guardian of the genome that every textbook uses. It explains why TP53-mutant cancers are aggressive and hard to treat, why MDM2 inhibitors are being developed to reactivate wild-type p53, and why germline TP53 testing matters in families.","caveats":["Written before the discovery of many p53 targets and of gain-of-function effects of mutant p53.","A review; specific mechanisms have been refined since."],"changedPractice":false},{"id":"paper-li-timer-tumour-infiltrating-immune-cells-cancerres-2017","kind":"paper","name":"Li 2017: TIMER, a web server for estimating immune cells in tumour genomic data","aka":[],"tldr":"A free online tool that estimates how many of six kinds of immune cell are present in a tumour from its gene expression data, applied to more than ten thousand tumours in The Cancer Genome Atlas and used in thousands of studies since.","summary":"Li, Liu and colleagues built TIMER (Tumor IMmune Estimation Resource), a computational method and web server that infers the abundance of B cells, CD4 and CD8 T cells, neutrophils, macrophages and dendritic cells from bulk tumour RNA sequencing. They applied it to 10,897 tumours across 32 cancer types from TCGA and let users explore how immune infiltration relates to gene expression, mutations, copy number and survival. TIMER2.0 followed in 2020 with additional deconvolution methods.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1158/0008-5472.CAN-17-0307"},{"label":"TIMER2.0","url":"http://timer.cistrome.org/"}],"tags":[],"related":["tcga-gdc","paper-thorsson-immune-landscape-of-cancer-immunity-2018"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["dana-farber"],"pathways":[],"terms":["tils","immune-system"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cancer Research","year":2017,"doi":"10.1158/0008-5472.CAN-17-0307","authors":"Li T, Fan J, Wang B, et al.","paperType":"methods","findings":["Statistical deconvolution of bulk RNA sequencing to estimate six immune cell types.","Applied to 10,897 TCGA tumours across 32 cancer types, with a public web interface for exploring immune infiltration against genomic and clinical features.","Updated as TIMER2.0 in 2020 with multiple deconvolution algorithms."],"whatItMeans":"TIMER made immune infiltration analysis accessible to any group with tumour expression data, which is why it is cited so heavily; it is a standard first step in linking a gene or mutation to the immune state of a cancer.","caveats":["Inferred, not measured, cell abundances; different deconvolution methods can disagree.","Bulk expression cannot resolve where immune cells sit within the tumour."],"changedPractice":false},{"id":"paper-li-timer2-nar-2020","kind":"paper","name":"Li 2020: TIMER2.0 for analysis of tumour-infiltrating immune cells","aka":[],"tldr":"The updated version of the TIMER web tool, which estimates immune cell content in tumour gene expression data using six different algorithms side by side so users can see where they agree.","summary":"Li, Liu and colleagues released TIMER2.0, extending their immune estimation web server with multiple deconvolution methods, including TIMER, CIBERSORT, quanTIseq, xCell, MCP-counter and EPIC, applied to TCGA tumours and to user-uploaded expression data. The server lets users relate immune infiltration estimates to gene expression, somatic mutations, copy number and survival across cancer types, and to compare the estimates from different algorithms, which often disagree.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1093/nar/gkaa407"},{"label":"TIMER2.0","url":"http://timer.cistrome.org/"}],"tags":[],"related":["paper-li-timer-tumour-infiltrating-immune-cells-cancerres-2017","tcga-gdc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["dana-farber"],"pathways":[],"terms":["tils","immune-system"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nucleic Acids Research","year":2020,"doi":"10.1093/nar/gkaa407","authors":"Li T, Fu J, Zeng Z, et al.","paperType":"methods","findings":["Six immune deconvolution algorithms available side by side on one web server.","Modules link immune estimates to gene expression, mutation, copy number and outcome across TCGA cancer types.","Accepts user-uploaded expression profiles for estimation."],"whatItMeans":"TIMER2.0 is one of the most used tools in cancer immunogenomics and its multi-algorithm design is a reminder that computational immune cell estimates are model-dependent and should be cross-checked.","caveats":["Estimates are inferred from bulk expression and vary by algorithm.","Cannot resolve spatial location of immune cells."],"changedPractice":false},{"id":"paper-libretto-001-selpercatinib-nsclc-nejm-2020","kind":"paper","name":"LIBRETTO-001: selpercatinib in RET fusion-positive non-small-cell lung cancer","aka":[],"tldr":"The selective RET inhibitor selpercatinib shrank tumours in 64 percent of previously treated and 85 percent of untreated patients with RET fusion-positive lung cancer, including brain metastases, and led to the first approval for this driver.","summary":"Phase 1/2 study of 105 previously treated and 39 treatment-naive patients with RET fusion-positive non-small-cell lung cancer treated with selpercatinib.\n\nObjective response was 64 percent in previously treated patients with median duration of response 17.5 months and median progression-free survival 16.5 months; 85 percent in treatment-naive patients; intracranial response 91 percent among evaluable patients. Hypertension, liver enzyme rise and QT prolongation were the main toxicities.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa2005653"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32846060/"}],"tags":[],"related":[],"cancers":["ret-fusion-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["selpercatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2005653","pmid":"32846060","authors":"Drilon A, Oxnard GR, Tan DSW, et al.","paperType":"observational","findings":["Objective response 64 percent (previously treated) and 85 percent (treatment-naive).","Median progression-free survival 16.5 months in previously treated patients."],"whatItMeans":"RET fusion testing is standard in lung adenocarcinoma and selpercatinib the preferred first-line RET inhibitor, confirmed against chemo-immunotherapy in LIBRETTO-431.","caveats":["Single-arm study.","Hypersensitivity reactions in patients recently treated with immunotherapy."],"changedPractice":true,"participants":144},{"id":"paper-libretto-431-nejm-2023","kind":"paper","name":"LIBRETTO-431: first-line selpercatinib versus chemotherapy with or without pembrolizumab in RET fusion-positive lung cancer","aka":[],"tldr":"Given as first treatment, selpercatinib more than doubled the time to progression compared with platinum-pemetrexed chemotherapy plus pembrolizumab in RET fusion-positive lung cancer, and protected against brain metastases.","summary":"Phase 3 trial of 261 patients with untreated advanced RET fusion-positive non-squamous non-small-cell lung cancer randomised to selpercatinib or platinum-pemetrexed with or without pembrolizumab.\n\nMedian progression-free survival was 24.8 versus 11.2 months (hazard ratio 0.46) in the intention-to-exclude-pembrolizumab population, response 84 versus 65 percent, and the cumulative incidence of central nervous system progression was lower with selpercatinib.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2309457"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37870973/"}],"tags":[],"related":[],"cancers":["ret-fusion-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","selpercatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["libretto-431"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2309457","pmid":"37870973","authors":"Zhou C, Solomon B, Loong HH, et al.","paperType":"rct","findings":["Median progression-free survival 24.8 vs 11.2 months; hazard ratio 0.46.","Objective response 84 percent vs 65 percent."],"whatItMeans":"Selpercatinib is the established first-line treatment for RET fusion-positive lung cancer, and the trial adds to evidence that targeted therapy should precede chemo-immunotherapy in driver-positive disease.","caveats":["Open-label; overall survival immature.","Crossover to selpercatinib at progression was permitted."],"changedPractice":true,"participants":261},{"id":"paper-libretto-531-nejm-2023","kind":"paper","name":"LIBRETTO-531: selpercatinib versus cabozantinib or vandetanib in advanced RET-mutant medullary thyroid cancer","aka":[],"tldr":"The selective RET inhibitor selpercatinib cut the risk of progression by more than 70 percent compared with the older multikinase drugs cabozantinib and vandetanib in RET-mutant medullary thyroid cancer, with fewer side effects.","summary":"Phase 3 trial of 291 patients with progressive advanced RET-mutant medullary thyroid cancer randomised 2:1 to selpercatinib or physician's choice of cabozantinib or vandetanib.\n\nProgression-free survival at 12 months was 86.8 versus 65.7 percent (hazard ratio 0.28), response 69.4 versus 38.8 percent, and treatment-failure-free survival also favoured selpercatinib; grade 3 or higher adverse events were 52.8 versus 76.3 percent.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2309719"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37870969/"}],"tags":[],"related":[],"cancers":["medullary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["selpercatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["libretto-531"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2309719","pmid":"37870969","authors":"Hadoux J, Elisei R, Brose MS, et al.","paperType":"rct","findings":["Twelve-month progression-free survival 86.8 percent vs 65.7 percent; hazard ratio 0.28.","Objective response 69.4 percent vs 38.8 percent."],"whatItMeans":"Selpercatinib is the first-line standard for advanced RET-mutant medullary thyroid cancer; RET testing at diagnosis is essential.","caveats":["Overall survival data immature.","Open-label design."],"changedPractice":true,"participants":291},{"id":"paper-mazzaferro-milan-criteria-nejm-1996","kind":"paper","name":"Liver transplantation for small hepatocellular carcinomas in patients with cirrhosis (the Milan criteria)","aka":[],"tldr":"This study showed that liver transplantation cures most patients with cirrhosis whose liver cancer is limited to one tumour up to 5 cm or up to three tumours each up to 3 cm, the Milan criteria that have governed transplant selection ever since.","summary":"Prospective cohort of 48 patients with cirrhosis and unresectable hepatocellular carcinoma meeting size criteria (single tumour 5 cm or less, or up to three tumours each 3 cm or less) who underwent liver transplantation.\n\nFour-year overall survival was 75 percent and recurrence-free survival 83 percent, with 85 percent overall survival among the 35 patients whose explants confirmed the criteria, compared with poor historical results in unselected patients.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 1996","url":"https://doi.org/10.1056/NEJM199603143341104"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/8594428/"}],"tags":[],"related":[],"cancers":["hcc-early"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1996,"doi":"10.1056/NEJM199603143341104","pmid":"8594428","authors":"Mazzaferro V, Regalia E, Doci R, et al.","paperType":"observational","findings":["Four-year overall survival 75 percent; recurrence-free survival 83 percent.","85 percent four-year survival when explant pathology confirmed the criteria."],"whatItMeans":"The Milan criteria remain the global standard for transplant eligibility in hepatocellular carcinoma, with downstaging protocols extending access to patients just outside them.","caveats":["Small single-centre series; expanded criteria (UCSF, up-to-seven) have since been proposed."],"changedPractice":true,"participants":48},{"id":"paper-lms-04-doxorubicin-trabectedin-lancet-oncol-2022","kind":"paper","name":"LMS-04: doxorubicin plus trabectedin followed by trabectedin maintenance versus doxorubicin alone in metastatic leiomyosarcoma","aka":[],"tldr":"Combining trabectedin with doxorubicin as first-line treatment for metastatic leiomyosarcoma nearly doubled the time to progression compared with doxorubicin alone, and later showed a survival benefit, making it the first combination to beat single-agent doxorubicin in a sarcoma subtype.","summary":"Phase 3 trial of 150 patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma randomised to six cycles of doxorubicin alone or doxorubicin plus trabectedin followed by trabectedin maintenance, with surgery of residual disease allowed.\n\nMedian progression-free survival was 12.2 versus 6.2 months (hazard ratio 0.41) and response 36 versus 13 percent; the final analysis showed median overall survival of 33 versus 24 months. Grade 3 to 4 haematological toxicity was much higher with the combination.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2022","url":"https://doi.org/10.1016/S1470-2045(22)00380-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35835135/"}],"tags":[],"related":[],"cancers":["extremity-soft-tissue-sarcoma","leiomyosarcoma","retroperitoneal-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["doxorubicin","trabectedin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["lms-04"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2022,"doi":"10.1016/S1470-2045(22)00380-1","pmid":"35835135","authors":"Pautier P, Italiano A, Piperno-Neumann S, et al.","paperType":"rct","findings":["Median progression-free survival 12.2 vs 6.2 months; hazard ratio 0.41.","Median overall survival 33 vs 24 months at final analysis."],"whatItMeans":"Doxorubicin-trabectedin is a first-line standard for fit patients with metastatic leiomyosarcoma, one of the few histology-specific first-line regimens in sarcoma.","caveats":["Substantial haematological toxicity and treatment delays.","Single-country (French) trial; confirmatory data awaited."],"changedPractice":true,"participants":150},{"id":"paper-klotz-active-surveillance-jco-2015","kind":"paper","name":"Long-term follow-up of a large active surveillance cohort of patients with prostate cancer (Sunnybrook)","aka":[],"tldr":"In nearly a thousand men with low-risk prostate cancer followed for up to 20 years on active surveillance, only 1.5 percent died of the disease and most never needed treatment, the strongest evidence that surveillance is safe.","summary":"Prospective single-centre cohort of 993 men with low-risk (and some favourable intermediate-risk) prostate cancer managed with active surveillance, with treatment triggered by PSA doubling time, grade progression or clinical progression.\n\nAt a median follow-up of 6.4 years (up to 20 years), 15 men (1.5 percent) died of prostate cancer and 13 developed metastases; 10- and 15-year cancer-specific survival were 98.1 and 94.3 percent, and about a quarter of men had been treated.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2015","url":"https://doi.org/10.1200/JCO.2014.55.1192"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25512465/"}],"tags":[],"related":[],"cancers":["prostate-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2015,"doi":"10.1200/JCO.2014.55.1192","pmid":"25512465","authors":"Klotz L, Vesprini D, Sethukavalan P, et al.","paperType":"observational","findings":["Prostate cancer mortality 1.5 percent at a median of 6.4 years.","15-year cancer-specific survival 94.3 percent; 27 percent of men had definitive treatment."],"whatItMeans":"Active surveillance is the preferred management for low-risk prostate cancer, and this cohort's triggers for intervention shaped surveillance protocols worldwide.","caveats":["Single-centre cohort with PSA-kinetics-based triggers later found to be unreliable; MRI is now integral."],"changedPractice":true,"participants":993},{"id":"paper-rtog-91-11-long-term-forastiere-jco-2013","kind":"paper","name":"Long-term results of RTOG 91-11: three non-surgical strategies to preserve the larynx","aka":[],"tldr":"Ten-year follow-up confirmed that concurrent chemoradiation gives the best larynx preservation and local control in advanced laryngeal cancer, but also revealed more late deaths unrelated to cancer in that arm, raising questions about long-term toxicity.","summary":"Ten-year update of the RTOG 91-11 trial comparing induction chemotherapy then radiotherapy, concurrent cisplatin chemoradiation, and radiotherapy alone in 547 patients with advanced laryngeal cancer.\n\nLaryngectomy-free survival was similar between the two chemotherapy arms and better than radiotherapy alone; locoregional control and laryngeal preservation remained best with concurrent treatment (ten-year preservation 81.7 percent versus 67.5 percent with induction), but overall survival showed a non-significant trend against the concurrent arm because of more non-cancer deaths.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2013","url":"https://doi.org/10.1200/JCO.2012.43.6097"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23182993/"}],"tags":[],"related":[],"cancers":["laryngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rtog-91-11"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2013,"doi":"10.1200/JCO.2012.43.6097","pmid":"23182993","authors":"Forastiere AA, Zhang Q, Weber RS, et al.","paperType":"rct","findings":["Ten-year laryngeal preservation 81.7 percent (concurrent) vs 67.5 percent (induction) vs 63.8 percent (radiotherapy alone).","Ten-year overall survival 27.5 percent, 38.8 percent and 31.5 percent (not significantly different)."],"whatItMeans":"Concurrent chemoradiation remains standard, but the excess of late non-cancer deaths is a reminder that swallowing dysfunction and aspiration after chemoradiation carry long-term risk.","caveats":["Cause of the late non-cancer deaths is uncertain.","Radiotherapy technique predates intensity modulation."],"changedPractice":true,"participants":547},{"id":"paper-patil-low-dose-nivolumab-jco-2023","kind":"paper","name":"Low-dose immunotherapy in head and neck cancer: a randomised study (Tata Memorial)","aka":[],"tldr":"Giving about one-twentieth of the standard dose of nivolumab alongside cheap oral chemotherapy nearly tripled one-year survival in advanced head and neck cancer, showing that immunotherapy can be made affordable without losing its effect.","summary":"Open-label phase 3 randomising 151 patients with advanced head and neck squamous cell carcinoma being treated with palliative intent to triple oral metronomic chemotherapy with or without nivolumab 20 mg flat every 3 weeks. One-year overall survival was 43.4% (95% CI 30.8-55.3) with nivolumab versus 16.3% (8.0-27.4) without; median overall survival 10.1 versus 6.7 months (hazard ratio 0.545; 95% CI 0.362-0.820; P=0.0036); grade 3 or worse adverse events 46.1% versus 50%.\n\nThe dose is roughly 6% of the approved flat dose and the drug cost correspondingly small. The trial has become the reference case for dose-optimisation in immuno-oncology and for pragmatic trials in low- and middle-income countries.","asOf":"2026-09-10","links":[{"label":"JCO 2023","url":"https://doi.org/10.1200/JCO.22.01015"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":[],"drugs":["nivolumab"],"companies":[],"institutions":["tata-memorial"],"pathways":[],"terms":[],"trials":["low-dose-nivolumab-tmh"],"people":["patil-vijay","prabhash-kumar","noronha-vanita"],"bottlenecks":["b-dose-optimisation","b-drug-pricing"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2023,"doi":"10.1200/JCO.22.01015","authors":"Patil VM, Noronha V, Menon N, et al.","paperType":"rct","findings":["One-year overall survival 43.4% with low-dose nivolumab versus 16.3% without.","Median overall survival 10.1 versus 6.7 months; hazard ratio 0.545 (95% CI 0.362-0.820).","No increase in grade 3 or worse adverse events (46.1% versus 50%).","Nivolumab dose was a flat 20 mg every 3 weeks, a small fraction of the licensed dose."],"whatItMeans":"For the majority of the world's head and neck cancer patients who cannot afford full-dose checkpoint inhibitors, a low dose added to oral metronomic chemotherapy is a tested alternative that improves survival. It also challenges the assumption that approved doses are the necessary doses: pharmacology had long suggested receptor saturation at far lower exposures.","caveats":["Single-centre and open-label; the comparator was metronomic chemotherapy rather than the standard-dose immunotherapy used in high-income settings.","Whether low-dose nivolumab matches full-dose nivolumab head to head is untested.","Patients were mostly tobacco-related, HPV-negative oral cancers, so applicability to oropharyngeal HPV-positive disease is unknown."],"changedPractice":true,"participants":151},{"id":"paper-magnetismm-3-elranatamab-natmed-2023","kind":"paper","name":"MagnetisMM-3: elranatamab, a second BCMA bispecific, with a switch to fortnightly dosing after response","aka":[],"tldr":"Elranatamab produced responses in 61% of heavily pretreated myeloma patients and showed that dosing can be thinned to every two weeks once patients respond.","summary":"MagnetisMM-3 was a phase 2 single-arm study of elranatamab, a subcutaneous BCMA x CD3 bispecific, in 123 patients with triple-class-exposed relapsed or refractory multiple myeloma who had not received prior BCMA-directed therapy (cohort A). After two step-up doses and weekly dosing, patients who had responded for at least six months moved to every-two-week dosing. The overall response rate was 61% with complete response or better in 35%; most responses were ongoing at a year. CRS occurred in about 58% of patients, all grade 1-2 with the priming regimen, and neurotoxicity in a small minority. Infections were the main serious toxicity. The FDA granted accelerated approval in 2023.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=MagnetisMM-3%20elranatamab%20Lesokhin%20Nature%20Medicine%202023"},{"label":"ClinicalTrials.gov NCT04649359","url":"https://clinicaltrials.gov/study/NCT04649359"}],"tags":[],"related":["paper-majestec-1-teclistamab-nejm-2022","bispecific-infection-prophylaxis"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["bispecific-antibody","t-cell-engager"],"targets":["bcma","cd3","gprc5d"],"drugs":["elranatamab","teclistamab","talquetamab"],"companies":["pfizer"],"institutions":[],"pathways":[],"terms":["crs","orr"],"trials":["magnetismm-3","linker-mm1"],"people":[],"bottlenecks":["b-dose-optimisation","b-toxicity-qol"],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2023,"authors":"Lesokhin AM, Tomasson MH, Arnulf B, et al.","paperType":"translational","findings":["123 BCMA-naive, triple-class-exposed patients (cohort A); median 5 prior lines.","Overall response 61%; complete response or better 35%.","Responses were durable, with most responders still in response at 12 months.","CRS in about 58%, all grade 1-2 after two step-up doses; ICANS uncommon.","Responders switched to every-two-week dosing after 6 months without loss of response in most cases."],"whatItMeans":"Elranatamab confirmed that BCMA bispecifics are a class, not a one-off, and its protocol-built dose reduction after response set a precedent for lowering the immunosuppressive burden of T-cell engagers. Patients now have two approved BCMA bispecifics and one against GPRC5D (talquetamab). Choosing between them, and sequencing them with CAR-T, remains guided by availability and toxicity profile rather than head-to-head data.","caveats":["Single-arm; no comparator or randomised evidence at approval.","Excluded patients with prior BCMA therapy in the registrational cohort; cohort B (BCMA-exposed) had lower responses.","Infection risk and hypogammaglobulinaemia similar to teclistamab.","Durability beyond two years still being reported."],"changedPractice":true,"participants":123},{"id":"paper-magnolia-zanubrutinib-mzl-ccr-2021","kind":"paper","name":"MAGNOLIA: zanubrutinib in relapsed or refractory marginal zone lymphoma","aka":[],"tldr":"The BTK inhibitor zanubrutinib produced responses in about two thirds of patients with relapsed marginal zone lymphoma across all subtypes with few of the cardiac side effects seen with ibrutinib, leading to its approval.","summary":"Phase 2 study of 68 patients with relapsed or refractory marginal zone lymphoma after at least one anti-CD20-based regimen treated with zanubrutinib 160 mg twice daily.\n\nObjective response by independent review was 68 percent with complete response in 26 percent, similar across extranodal, nodal and splenic subtypes, with 15-month progression-free survival of 83 percent and low rates of atrial fibrillation or major bleeding.","asOf":"2026-09-17","links":[{"label":"Clin Cancer Res 2021","url":"https://doi.org/10.1158/1078-0432.CCR-21-1704"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34526366/"}],"tags":[],"related":[],"cancers":["marginal-zone-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["zanubrutinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2021,"doi":"10.1158/1078-0432.CCR-21-1704","pmid":"34526366","authors":"Opat S, Tedeschi A, Linton K, et al.","paperType":"observational","findings":["Objective response 68 percent; complete response 26 percent.","15-month progression-free survival 83 percent."],"whatItMeans":"Zanubrutinib is an approved option for relapsed marginal zone lymphoma after anti-CD20 therapy, chosen for its tolerability profile.","caveats":["Single-arm; accelerated approval pending confirmatory data."],"changedPractice":true,"participants":68},{"id":"paper-maia-daratumumab-rd-nejm-2019","kind":"paper","name":"MAIA: adding daratumumab to lenalidomide-dexamethasone for older patients with newly diagnosed myeloma who cannot have a transplant","aka":[],"tldr":"Adding the CD38 antibody daratumumab to standard lenalidomide-dexamethasone cut the risk of progression or death by about 44% in older myeloma patients, and later extended survival.","summary":"MAIA randomised 737 transplant-ineligible patients with newly diagnosed multiple myeloma (median age 73) to daratumumab plus lenalidomide and dexamethasone (D-Rd) or Rd alone, both continued until progression. The primary endpoint was PFS. At 30 months PFS was 70.6% versus 55.6% (hazard ratio 0.56); complete response or better was 47.6% versus 24.9% and MRD-negativity 24.2% versus 7.3%. Longer follow-up showed a significant overall survival benefit (hazard ratio about 0.68; five-year OS roughly 66% versus 53%). Neutropenia and pneumonia were more frequent with daratumumab.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1817249"},{"label":"ClinicalTrials.gov NCT02252172","url":"https://clinicaltrials.gov/study/NCT02252172"}],"tags":[],"related":["paper-cepheus-dara-vrd-natmed-2025","cd38-plus-triplet"],"cancers":["multiple-myeloma"],"sections":[],"technologies":[],"targets":["cd38"],"drugs":["daratumumab","lenalidomide"],"companies":["johnson-johnson"],"institutions":[],"pathways":[],"terms":["pfs","os","mrd-negativity-myeloma"],"trials":[],"people":[],"bottlenecks":["b-aging-comorbidity","b-drug-pricing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1817249","authors":"Facon T, Kumar S, Plesner T, et al.","paperType":"rct","findings":["737 transplant-ineligible patients; D-Rd vs Rd until progression.","30-month PFS 70.6% vs 55.6%; hazard ratio 0.56.","Complete response or better 47.6% vs 24.9%; MRD-negativity (10^-5) 24.2% vs 7.3%.","Overall survival significantly improved at longer follow-up (HR about 0.68; 5-year OS roughly 66% vs 53%).","Grade 3-4 neutropenia 50.0% vs 35.3%; pneumonia 13.7% vs 7.9%."],"whatItMeans":"MAIA made a daratumumab-based triplet the standard first treatment for older or frail myeloma patients, replacing Rd alone. It proved an anti-CD38 antibody could improve survival, not just delay progression, when used up front. Quadruplets built on this backbone are now being tested in the same population.","caveats":["Continuous therapy until progression; treatment burden and cost are substantial.","Patients over 80 and very frail patients were under-represented.","Median PFS was not reached at the primary analysis; the durability estimate relies on later reports.","Comparator Rd is itself now being displaced by quadruplets."],"changedPractice":true,"participants":737},{"id":"paper-majestec-1-teclistamab-nejm-2022","kind":"paper","name":"MajesTEC-1: teclistamab, an off-the-shelf BCMA bispecific antibody, in heavily pretreated myeloma","aka":[],"tldr":"A ready-made antibody that pulls T cells onto myeloma cells produced responses in 63% of patients after a median of five prior therapies, without the wait for cell manufacturing.","summary":"MajesTEC-1 was a phase 1/2 single-arm study of teclistamab, a BCMA x CD3 bispecific T-cell engager given subcutaneously weekly after step-up dosing, in 165 patients with relapsed or refractory multiple myeloma who were triple-class exposed (median five prior lines). The overall response rate was 63%, with complete response or better in 39.4%; median duration of response was 18.4 months and median PFS 11.3 months. Cytokine release syndrome occurred in 72% (almost all grade 1-2) and neurotoxicity in about 14.5%, but infections were frequent (grade 3-4 in about 45%) and hypogammaglobulinaemia was near universal. Teclistamab received accelerated approval in 2022, the first bispecific for myeloma.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2203478"},{"label":"ClinicalTrials.gov NCT04557098","url":"https://clinicaltrials.gov/study/NCT04557098"}],"tags":[],"related":["bispecific-infection-prophylaxis","bcma-then-gprc5d","paper-magnetismm-3-elranatamab-natmed-2023"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["bispecific-antibody","t-cell-engager"],"targets":["bcma","cd3"],"drugs":["teclistamab","talquetamab","elranatamab"],"companies":["johnson-johnson"],"institutions":[],"pathways":[],"terms":["crs","orr"],"trials":["majestec-1","majestec-3"],"people":[],"bottlenecks":["b-toxicity-qol","b-dose-optimisation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2203478","authors":"Moreau P, Garfall AL, van de Donk NWCJ, et al.","paperType":"translational","findings":["165 triple-class-exposed patients; median 5 prior lines.","Overall response 63.0%; complete response or better 39.4%; MRD-negativity in 26.7% of all patients.","Median duration of response 18.4 months; median PFS 11.3 months.","CRS 72.1% (grade 3 0.6%); neurotoxicity 14.5% (ICANS 3%).","Infections 76.4% (grade 3-4 44.8%); 5 COVID-19 deaths; hypogammaglobulinaemia common."],"whatItMeans":"Teclistamab showed that an off-the-shelf bispecific can approach CAR-T-like response rates in late myeloma, giving patients who cannot wait for or access cell therapy a real option. It also exposed the price: prolonged T-cell engagement causes profound immunosuppression, so infection prophylaxis and immunoglobulin replacement are now routine. Less frequent dosing after response is being adopted to reduce this burden.","caveats":["Single-arm study; MajesTEC-3 later provided randomised evidence in earlier lines.","Continuous weekly dosing until progression in the original protocol; optimal duration and schedule still being defined.","Infection-related deaths were substantial; many patients were treated during the COVID-19 pandemic.","Responses are shorter than with cilta-cel, and BCMA-directed sequencing (CAR-T then bispecific or vice versa) reduces subsequent efficacy."],"changedPractice":true,"participants":165},{"id":"paper-mani-emt-stem-cell-properties-cell-2008","kind":"paper","name":"Mani 2008: the epithelial-mesenchymal transition generates cells with properties of stem cells","aka":[],"tldr":"Switching on the invasion programme in normal breast cells also gave them stem cell properties, linking two ideas about how cancers spread and resist treatment, and suggesting that the mobile cells that seed metastases are the same ones that can regrow a tumour.","summary":"Mani, Weinberg and colleagues induced an epithelial-mesenchymal transition in immortalised human mammary epithelial cells by expressing the transcription factors Snail or Twist or by exposing them to TGF-beta1. The cells acquired a mesenchymal appearance, a CD44-high CD24-low surface profile matching that of breast cancer stem cells, and a much greater ability to form mammospheres and colonies. Conversely, stem-like cells isolated from normal and cancerous breast tissue expressed EMT markers. The paper connected the EMT and cancer stem cell fields.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/j.cell.2008.03.027"}],"tags":[],"related":["paper-kalluri-weinberg-emt-basics-jci-2009","paper-al-hajj-breast-cancer-stem-cells-pnas-2003"],"cancers":["breast-hr-positive","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["mit-koch"],"pathways":["emt","tgf-beta"],"terms":["stem-cell","metastasis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cell","year":2008,"doi":"10.1016/j.cell.2008.03.027","authors":"Mani SA, Guo W, Liao MJ, et al.","paperType":"basic","findings":["Inducing EMT in human mammary epithelial cells produced CD44-high CD24-low cells with increased mammosphere and colony formation.","Stem-like cells from normal and malignant breast tissue expressed EMT markers.","EMT-inducing factors also increased the tumour-initiating ability of transformed cells."],"whatItMeans":"This paper is why metastasis, stemness and therapy resistance are now studied as one problem. It suggests that the cells most able to spread are also the ones most able to regrow, and it motivates therapies that target the mesenchymal or stem-like state.","caveats":["Cell culture and mouse work with engineered cells; relevance to spontaneous human tumours is inferred.","Later work suggests partial EMT states, rather than complete transitions, carry the most stemness and metastatic ability."],"changedPractice":false},{"id":"paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020","kind":"paper","name":"Marginal zone lymphomas: ESMO clinical practice guidelines","aka":[],"tldr":"The ESMO guideline for marginal zone lymphomas sets out the treatment of gastric and non-gastric extranodal, splenic and nodal forms, including antibiotic eradication, low-dose radiotherapy, watch and wait, rituximab-based therapy and BTK inhibitors at relapse.","summary":"Evidence-based guideline covering diagnosis, staging, and first-line and relapsed treatment of extranodal (MALT), splenic and nodal marginal zone lymphomas, including the role of infectious agents (Helicobacter pylori, hepatitis C), involved-site radiotherapy, chemoimmunotherapy and novel agents.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2020","url":"https://doi.org/10.1016/j.annonc.2019.10.010"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31912792/"}],"tags":[],"related":[],"cancers":["marginal-zone-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2020,"doi":"10.1016/j.annonc.2019.10.010","pmid":"31912792","authors":"Zucca E, Arcaini L, Buske C, et al.","paperType":"guideline","findings":[],"whatItMeans":"The site-specific and stage-specific approach on the marginal zone lymphoma page follows this guideline.","caveats":["Randomised evidence is limited for most decisions in these indolent lymphomas."],"changedPractice":true},{"id":"paper-mariposa-nejm-2024","kind":"paper","name":"MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer","aka":[],"tldr":"Combining an EGFR-MET bispecific antibody with a third-generation EGFR pill beat osimertinib alone, delaying progression by about seven months and later improving survival, at the cost of more side effects.","summary":"Phase 3 trial of 1,074 patients with untreated EGFR-mutated (exon 19 deletion or L858R) advanced NSCLC, randomised 2:2:1 to amivantamab plus lazertinib, osimertinib, or lazertinib alone. Primary endpoint was PFS by blinded review for the combination versus osimertinib.\n\nMedian PFS was 23.7 vs 16.6 months (HR 0.70). A 2025 final overall survival analysis reported a significant improvement (HR about 0.75) with median survival in the combination arm not reached and projected to exceed osimertinib by more than a year. It is the first regimen to beat osimertinib on survival, but adds infusion reactions, venous thromboembolism, rash and paronychia.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2403614"},{"label":"ClinicalTrials.gov NCT04487080","url":"https://clinicaltrials.gov/study/NCT04487080"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["bispecific-antibody","kinase-inhibitors"],"targets":["egfr","met"],"drugs":["amivantamab","osimertinib"],"companies":["johnson-johnson"],"institutions":["severance"],"pathways":[],"terms":["pfs","os","resistance","first-line","ctdna"],"trials":["mariposa","flaura2"],"people":["cho-byoung-chul","lu-shun","enriqueta-felip","lee-se-hoon","benjamin-besse","prabhash-kumar"],"bottlenecks":["b-resistance","b-toxicity-qol","b-drug-pricing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2403614","authors":"Cho BC, Lu S, Felip E, et al.","paperType":"rct","findings":["Median PFS 23.7 vs 16.6 months; HR 0.70 (95% CI 0.58-0.85).","Overall survival at final analysis (2025): HR about 0.75; median not reached vs 36.7 months for osimertinib.","Benefit was seen in high-risk subgroups (TP53 co-mutation, detectable ctDNA, brain or liver metastases).","Grade 3 or higher adverse events 75% vs 43%; venous thromboembolism about 37% vs 9%, prompting prophylactic anticoagulation in the first four months.","Lazertinib alone performed similarly to osimertinib."],"whatItMeans":"Patients newly diagnosed with EGFR-mutated advanced lung cancer now have a first-line option that improves survival over osimertinib, particularly if they have high-risk features. The trade-off is intravenous (now subcutaneous) infusions and considerably more skin, nail and clotting toxicity, so osimertinib alone remains reasonable for those who prioritise convenience and tolerability. Both this regimen and osimertinib plus chemotherapy (FLAURA2) are approved; there is no direct comparison.","caveats":["Toxicity is substantially higher and treatment is more burdensome than an oral tablet alone.","No head-to-head comparison with osimertinib plus chemotherapy.","Cost is very high and access outside wealthy countries is limited.","Whether resistance mechanisms after the combination are more treatable than after osimertinib is unknown."],"changedPractice":true,"participants":1074},{"id":"paper-mars-2-lancet-respir-med-2024","kind":"paper","name":"MARS 2: extended pleurectomy decortication plus chemotherapy versus chemotherapy alone for pleural mesothelioma","aka":[],"tldr":"Adding lung-sparing radical surgery to chemotherapy for pleural mesothelioma did not lengthen life; patients who had surgery lived slightly less long, had more complications and worse quality of life, so routine surgery is no longer recommended.","summary":"Multicentre randomised trial in the United Kingdom of 335 patients with resectable pleural mesothelioma randomised to extended pleurectomy decortication plus platinum-pemetrexed chemotherapy or chemotherapy alone.\n\nMedian overall survival was 19.3 months with surgery against 24.8 months without (hazard ratio 1.28); surgery caused more serious adverse events and worse quality of life in the first year, at higher cost.","asOf":"2026-09-17","links":[{"label":"Lancet Respir Med 2024","url":"https://doi.org/10.1016/S2213-2600(24)00119-x"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38740044/"}],"tags":[],"related":[],"cancers":["pleural-mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["mars-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Lancet Respiratory Medicine","year":2024,"doi":"10.1016/S2213-2600(24)00119-x","pmid":"38740044","authors":"Lim E, Waller D, Lau K, et al.","paperType":"rct","findings":["Median overall survival 19.3 vs 24.8 months; hazard ratio 1.28 favouring no surgery.","Serious adverse events 3.6 times more common in the surgery arm."],"whatItMeans":"Radical surgery for pleural mesothelioma should be confined to trials; effusion is managed with pleurodesis or indwelling catheters and treatment is systemic.","caveats":["Surgical quality varied across centres; proponents argue selected patients in expert hands may still benefit.","Most patients had epithelioid disease."],"changedPractice":true,"participants":335},{"id":"paper-martincorena-somatic-mutations-normal-skin-science-2015","kind":"paper","name":"Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones","aka":[],"tldr":"Deep sequencing of 234 tiny biopsies of normal eyelid skin from four people found thousands of clones carrying cancer driver mutations, with about a fifth to a third of cells carrying NOTCH1 mutations, showing that driver mutations are common in healthy tissue.","summary":"The Sanger Institute group sequenced 74 cancer genes at high depth in 234 punch biopsies (each about 1 mm2) of physiologically normal eyelid skin removed during blepharoplasty from four individuals aged 55-73.\n\nNormal skin carried 2-6 mutations per megabase per cell, a burden comparable to many cancers, dominated by ultraviolet signatures. Positive selection was evident for NOTCH1, NOTCH2, FAT1 and TP53 mutations; clones with NOTCH1 mutations occupied around 20% of the skin surface, and an estimated 140 driver mutations were present per square centimetre. Yet none of the tissue was cancerous.\n\nThe paper began the field of somatic mutation in normal tissues, later extended to oesophagus, colon, bladder, lung, liver and blood, and forced a rethink of what a driver mutation means for cancer risk and for the specificity of mutation-based early detection tests.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1126/science.aaa6806"}],"tags":[],"related":["paper-jaiswal-chip-nejm-2014","idea-field-interception"],"cancers":[],"sections":["early-detection","prevention"],"technologies":["wes-wgs","liquid-biopsy"],"targets":["tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":["field-cancerisation","clonal-evolution","notch"],"terms":["vaf","mutational-signature"],"trials":[],"people":[],"bottlenecks":["b-early-detection","b-overdiagnosis","b-biomarker-validation"],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2015,"doi":"10.1126/science.aaa6806","pmid":"25999502","authors":"Martincorena I, Roshan A, Gerstung M, et al.","paperType":"basic","findings":["Mutation burden in normal skin 2-6 mutations per megabase per cell, similar to many cancers","Positive selection of NOTCH1, NOTCH2, FAT1 and TP53 mutations in normal epidermis","NOTCH1-mutant clones covered about 20% of the skin surface in the individuals studied","About 140 driver mutations estimated per square centimetre of normal sun-exposed skin"],"whatItMeans":"Carrying a cancer mutation is normal; most mutant clones never become cancer. This means blood or tissue tests that look for driver mutations alone will produce false positives, and that the question of what tips a mutant clone into cancer (tissue environment, further hits, immune surveillance) is as important as the mutation itself.","caveats":["Four elderly individuals and one tissue; generalisation came from later studies","Targeted panel of 74 genes; genome-wide selection was inferred","Cannot say which clones would have progressed","Clone sizes depend on the sequencing depth and biopsy size chosen"],"changedPractice":false,"participants":4},{"id":"paper-masai-lancet-oncol-2023","kind":"paper","name":"MASAI: AI-supported mammography screening finds more cancers with half the radiologist workload","aka":[],"tldr":"In the first randomised trial of AI in population mammography, AI-supported reading detected 20% more cancers than standard double reading without increasing false positives, and cut screen-reading work by 44%.","summary":"MASAI randomised 80,033 women aged 40-74 attending screening in Sweden to AI-supported screening (AI risk score used to triage to single or double reading and to flag suspicious findings) or standard double reading. This pre-specified safety analysis compared cancer detection, recall and false positives.\n\nThe cancer detection rate was 6.1 per 1,000 with AI support versus 5.1 per 1,000 with standard reading (ratio 1.2), with recall rates of 2.2% and 2.0% and identical 1.5% false-positive rates. Screen-reading workload fell by 44.3%. The 2025 report on the full cohort (over 105,000 women) confirmed a 29% increase in detection, concentrated in invasive and small cancers.\n\nThis was the first randomised evidence that AI can safely replace one of two human readers in screening.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S1470-2045(23)00298-X"},{"label":"ClinicalTrials.gov NCT04838756","url":"https://clinicaltrials.gov/study/NCT04838756"}],"tags":[],"related":["idea-prev-ai-mammogram-risk-intervals","idea-prev-mammography-ai-stepped-wedge","idea-data-ai-screening-endpoints"],"cancers":["breast-hr-positive","breast-her2-positive","tnbc"],"sections":["early-detection","ai-computation"],"technologies":["radiology-ai-screening","mammography"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-ai-validation","b-early-detection","b-overdiagnosis","b-workforce"],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"Lancet Oncology","year":2023,"doi":"10.1016/S1470-2045(23)00298-X","pmid":"37541274","authors":"Lång K, Josefsson V, Larsson AM, et al.","paperType":"rct","findings":["Cancer detection rate 6.1 vs 5.1 per 1,000 screened (ratio 1.2, 95% CI 1.0-1.5; 244 vs 203 cancers)","Recall rate 2.2% vs 2.0%; false-positive rate 1.5% in both arms","Screen-reading workload reduced 44.3%","Final analysis (Lancet Digital Health 2025, 105,934 women): detection 6.4 vs 5.0 per 1,000, a 29% increase, with a 44% workload reduction"],"whatItMeans":"AI can take over one reader's work in double-reading screening programmes while finding more cancers. Whether the extra cancers found are ones that would have harmed women, and whether interval cancers fall, is the question the trial's primary endpoint will answer.","caveats":["Interval cancer rate, the primary endpoint, has not yet been reported; more detection could be overdiagnosis","Single Swedish site with a double-reading culture; generalisation to single-reader systems (as in the US) is uncertain","One commercial AI system; results do not automatically transfer to others","Radiologists were aware of AI output, so the trial cannot separate AI accuracy from its effect on human reading"],"changedPractice":false,"participants":80033},{"id":"paper-matterhorn-nejm-2025","kind":"paper","name":"MATTERHORN: perioperative durvalumab with FLOT chemotherapy for resectable gastric and gastro-oesophageal junction cancer","aka":[],"tldr":"Adding durvalumab to perioperative FLOT chemotherapy for operable stomach cancer reduced recurrences and doubled the rate of complete pathological response, the first immunotherapy to improve outcomes in curable gastric cancer.","summary":"Phase 3 placebo-controlled trial of 948 patients with resectable stage II to IVA gastric or gastro-oesophageal junction adenocarcinoma randomised to perioperative FLOT with durvalumab or placebo, followed by durvalumab or placebo maintenance.\n\nEvent-free survival at 24 months was 67.4 versus 58.5 percent (hazard ratio 0.71), pathological complete response 19 versus 7 percent, and an interim overall survival analysis favoured durvalumab; surgery rates and toxicity were similar between arms.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2025","url":"https://doi.org/10.1056/NEJMoa2503701"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/40454643/"}],"tags":[],"related":[],"cancers":["gastric-pdl1-high"],"sections":[],"technologies":[],"targets":[],"drugs":["durvalumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["matterhorn"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2025,"doi":"10.1056/NEJMoa2503701","pmid":"40454643","authors":"Janjigian YY, Al-Batran SE, Wainberg ZA, et al.","paperType":"rct","findings":["24-month event-free survival 67.4 percent vs 58.5 percent; hazard ratio 0.71.","Pathological complete response 19 percent vs 7 percent."],"whatItMeans":"Perioperative durvalumab with FLOT is a new standard for resectable gastric and junctional adenocarcinoma irrespective of PD-L1 expression.","caveats":["Overall survival analysis interim.","Applicability to Asian populations receiving adjuvant-only chemotherapy is uncertain."],"changedPractice":true,"participants":948},{"id":"paper-maude-ctl019-all-nejm-2014","kind":"paper","name":"Maude 2014: CD19 CAR-T cells produce complete remission in 27 of 30 children and adults with relapsed ALL","aka":[],"tldr":"The first sizeable series of CD19 CAR-T therapy showed complete remission in 90% of patients with leukaemia that had failed everything else, with persistent engineered cells and a new, treatable toxicity.","summary":"Maude and colleagues reported 30 patients (25 children and 5 adults) with relapsed or refractory ALL, including 18 who had relapsed after allogeneic transplant and 3 refractory to blinatumomab, treated with CTL019, an autologous CD19-directed CAR-T with a 4-1BB costimulatory domain. Complete remission occurred in 27 (90%), including MRD-negative remissions; six-month event-free survival was 67% and overall survival 78%. CAR-T cells persisted for up to two years with ongoing B-cell aplasia. All patients developed cytokine release syndrome, severe in 27%, which was reversed by the IL-6 receptor antibody tocilizumab. Together with the earlier single-patient CLL report (Porter et al., NEJM 2011) and the first two children (Grupp et al., NEJM 2013), it established CAR-T as a realistic therapy and drove the pivotal ELIANA trial.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1407222"},{"label":"First CLL patient report (Porter 2011)","url":"https://doi.org/10.1056/NEJMoa1103849"},{"label":"ClinicalTrials.gov NCT01626495","url":"https://clinicaltrials.gov/study/NCT01626495"}],"tags":[],"related":["paper-eliana-tisagenlecleucel-nejm-2018"],"cancers":["all-leukemia","cll"],"sections":[],"technologies":["car-t"],"targets":["cd19"],"drugs":["tisagenlecleucel"],"companies":["novartis"],"institutions":["penn-abramson"],"pathways":[],"terms":["crs","mrd-negative-cr"],"trials":[],"people":["carl-june","david-porter","bruce-levine"],"bottlenecks":["b-translational-valley","b-manufacturing-cell-therapy"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/NEJMoa1407222","authors":"Maude SL, Frey N, Shaw PA, et al.","paperType":"translational","findings":["30 patients (25 children, 5 adults) with relapsed/refractory ALL; 18 post-transplant, 3 blinatumomab-refractory.","Complete remission in 27 of 30 (90%); 22 of 27 MRD-negative by flow cytometry.","6-month event-free survival 67%; overall survival 78%; 19 patients in sustained remission at report.","CAR-T persistence and B-cell aplasia for up to 2 years in responders.","CRS in 100%, severe in 27%; reversed with tocilizumab; CD19-negative relapse identified as an escape mechanism."],"whatItMeans":"This paper is the proof-of-concept for a living drug: a single infusion of a patient's own engineered T cells could eradicate leukaemia that had survived chemotherapy, transplant and antibody therapy. It defined cytokine release syndrome and its antidote, tocilizumab, and revealed antigen-loss relapse. It led directly to the first approved gene-modified cell therapy three years later.","caveats":["Single-centre, uncontrolled series with short follow-up.","Selected patients able to wait for manufacturing and tolerate lymphodepletion.","Durability was uncertain; about a third relapsed within months, often with CD19-negative disease.","Toxicity management was still empirical."],"changedPractice":true,"participants":30},{"id":"paper-mavoric-mogamulizumab-lancet-oncol-2018","kind":"paper","name":"MAVORIC: mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma","aka":[],"tldr":"The anti-CCR4 antibody mogamulizumab doubled the time to progression compared with vorinostat in previously treated mycosis fungoides and Sezary syndrome, with particularly strong activity in the blood, and became the first antibody approved for these lymphomas.","summary":"Phase 3 trial of 372 patients with relapsed or refractory mycosis fungoides or Sezary syndrome after at least one systemic therapy randomised to mogamulizumab or vorinostat.\n\nMedian progression-free survival was 7.7 versus 3.1 months (hazard ratio 0.53), global response 28 versus 5 percent, with blood responses in 68 percent of mogamulizumab patients; drug rash was the main toxicity.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2018","url":"https://doi.org/10.1016/S1470-2045(18)30379-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30100375/"}],"tags":[],"related":[],"cancers":["cutaneous-t-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["mogamulizumab","vorinostat"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["mavoric"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2018,"doi":"10.1016/S1470-2045(18)30379-6","pmid":"30100375","authors":"Kim YH, Bagot M, Pinter-Brown L, et al.","paperType":"rct","findings":["Median progression-free survival 7.7 vs 3.1 months; hazard ratio 0.53.","Overall response 28 percent vs 5 percent; blood compartment response 68 percent."],"whatItMeans":"Mogamulizumab is a standard for advanced-stage cutaneous T-cell lymphoma with blood involvement, particularly Sezary syndrome.","caveats":["Open-label; vorinostat is a weak comparator.","Mogamulizumab-associated rash can mimic disease progression."],"changedPractice":true,"participants":372},{"id":"paper-ajcc-8-melanoma-gershenwald-ca-2017","kind":"paper","name":"Melanoma staging: evidence-based changes in the AJCC eighth edition cancer staging manual","aka":[],"tldr":"The eighth-edition melanoma staging system, derived from over 46,000 patients, refined thickness cut-offs and node categories and created the stage IIIA to IIID subgroups whose very different outlooks now guide adjuvant therapy decisions.","summary":"Description of the American Joint Committee on Cancer eighth-edition staging for melanoma, based on an international database of 46,000 patients, including changes to T1 subcategories, removal of mitotic rate from T1 staging, revised N categories incorporating microsatellites and in-transit disease, new stage III subgroups, and M1 subcategories with lactate dehydrogenase.","asOf":"2026-09-17","links":[{"label":"CA Cancer J Clin 2017","url":"https://doi.org/10.3322/caac.21409"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29028110/"}],"tags":[],"related":[],"cancers":["stage-ii-melanoma","stage-iii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["ca-cancer-journal"],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2017,"doi":"10.3322/caac.21409","pmid":"29028110","authors":"Gershenwald JE, Scolyer RA, Hess KR, et al.","paperType":"guideline","findings":["Five-year melanoma-specific survival ranges from 93 percent in stage IIIA to 32 percent in stage IIID.","Stage IIB and IIC have worse survival than stage IIIA."],"whatItMeans":"Stage IIB, IIC and III on this site's melanoma pages, and the recognition that stage IIIA has a better prognosis than stage IIB or IIC, come from this system.","caveats":["Survival estimates predate modern adjuvant therapy."],"changedPractice":true},{"id":"paper-frampton-met-exon-14-cancer-discov-2015","kind":"paper","name":"MET exon 14 splicing alterations across tumour types and their sensitivity to MET inhibitors","aka":[],"tldr":"This large sequencing study defined MET exon 14 skipping as a recurrent driver in about 3 percent of lung adenocarcinomas and other cancers, showed the mutations are diverse and easily missed, and reported patients responding to MET inhibitors.","summary":"Analysis of comprehensive genomic profiling from more than 38,000 tumours identifying MET exon 14 splice-site alterations in about 3 percent of lung adenocarcinomas and at lower frequency in other tumours, characterising the wide range of DNA changes involved, and describing responses to crizotinib and capmatinib in patients harbouring them.","asOf":"2026-09-17","links":[{"label":"Cancer Discov 2015","url":"https://doi.org/10.1158/2159-8290.CD-15-0285"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25971938/"}],"tags":[],"related":[],"cancers":["met-altered-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2015,"doi":"10.1158/2159-8290.CD-15-0285","pmid":"25971938","authors":"Frampton GM, Ali SM, Rosenzweig M, et al.","paperType":"translational","findings":["MET exon 14 alterations in about 3 percent of lung adenocarcinomas, more common in older patients and in sarcomatoid histology.","Clinical responses to MET inhibitors in patients with the alteration."],"whatItMeans":"The paper established MET exon 14 skipping as a bona fide lung cancer driver and showed why RNA-based or broad DNA testing is needed to detect it, paving the way for capmatinib and tepotinib.","caveats":["Retrospective sequencing database with case reports of response."],"changedPractice":true},{"id":"paper-minnesota-fobt-nejm-1993","kind":"paper","name":"Minnesota trial: a yearly stool blood test cuts bowel cancer deaths by a third","aka":[],"tldr":"Annual faecal occult blood testing followed by colonoscopy for positives reduced colorectal cancer deaths by 33% over 13 years, the first proof that bowel cancer screening saves lives.","summary":"The Minnesota Colon Cancer Control Study randomised 46,551 volunteers aged 50-80 to annual guaiac faecal occult blood testing, biennial testing, or no screening. Positive tests led to colonoscopy.\n\nAfter 13 years, colorectal cancer mortality was 33% lower with annual screening (5.88 vs 8.83 deaths per 1,000); the biennial arm showed a smaller, initially non-significant reduction that became significant with longer follow-up. Thirty-year follow-up (Shaukat 2013) confirmed relative reductions of 32% for annual and 22% for biennial screening.\n\nThis trial, with the Nottingham and Funen trials, made stool-based screening the backbone of population bowel cancer programmes, later upgraded to the faecal immunochemical test.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJM199305133281901"},{"label":"30-year follow-up (Shaukat 2013)","url":"https://doi.org/10.1056/NEJMoa1300720"}],"tags":[],"related":["paper-nordicc-nejm-2022","idea-prev-fit-risk-adapted-thresholds"],"cancers":["colorectal"],"sections":["early-detection"],"technologies":["colorectal-screening"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["fit-test"],"trials":[],"people":[],"bottlenecks":["b-early-detection","b-prevention-adoption"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1993,"doi":"10.1056/NEJM199305133281901","pmid":"8474513","authors":"Mandel JS, Bond JH, Church TR, et al.","paperType":"rct","findings":["Colorectal cancer mortality reduced 33% with annual testing at 13 years (5.88 vs 8.83 per 1,000)","Thirty-year follow-up: relative risk of colorectal cancer death 0.68 (annual) and 0.78 (biennial)","Rehydrated slides had a high positivity rate (about 10%), so a large share of participants had colonoscopy","Incidence of colorectal cancer also fell by about 20% at 18 years, attributed to polyp removal"],"whatItMeans":"A cheap home stool test, repeated yearly or every two years and followed by colonoscopy when positive, prevents bowel cancer deaths. This is what national bowel screening programmes do today, with FIT replacing the older guaiac test.","caveats":["Much of the benefit may have come from the colonoscopies triggered by a high false-positive rate","Volunteer population; uptake in real programmes is lower","Guaiac testing has been superseded by more sensitive and specific FIT","No all-cause mortality benefit was shown, as expected for a single cancer site"],"changedPractice":true,"participants":46551},{"id":"paper-mirasol-nejm-2023","kind":"paper","name":"MIRASOL: mirvetuximab soravtansine versus chemotherapy in folate receptor alpha-high platinum-resistant ovarian cancer","aka":[],"tldr":"The antibody-drug conjugate mirvetuximab soravtansine lengthened survival compared with chemotherapy in platinum-resistant ovarian cancer with high folate receptor alpha expression, the first drug ever to do so in this setting.","summary":"Phase 3 trial of 453 patients with platinum-resistant high-grade serous ovarian cancer, folate receptor alpha-high tumours and one to three prior regimens, randomised to mirvetuximab soravtansine or investigator's choice chemotherapy (paclitaxel, pegylated liposomal doxorubicin or topotecan).\n\nMedian progression-free survival was 5.62 versus 3.98 months (hazard ratio 0.65), objective response 42.3 versus 15.9 percent and median overall survival 16.46 versus 12.75 months (hazard ratio 0.67); ocular toxicity was frequent but mostly low grade.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2309169"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38055253/"}],"tags":[],"related":[],"cancers":["platinum-resistant-ovarian-cancer","high-grade-serous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["mirvetuximab-soravtansine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["mirasol"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2309169","pmid":"38055253","authors":"Moore KN, Angelergues A, Konecny GE, et al.","paperType":"rct","findings":["Median overall survival 16.46 vs 12.75 months; hazard ratio 0.67.","Objective response 42.3 percent vs 15.9 percent."],"whatItMeans":"Folate receptor alpha testing is now standard in platinum-resistant ovarian cancer and mirvetuximab is the preferred treatment for high-expressing tumours, with an eye-care protocol.","caveats":["Only about 35 to 40 percent of tumours are folate receptor alpha-high.","Blurred vision and keratopathy require ophthalmic monitoring."],"changedPractice":true,"participants":453},{"id":"paper-portec-3-molecular-leon-castillo-jco-2020","kind":"paper","name":"Molecular classification of the PORTEC-3 trial: prognosis and benefit from adjuvant chemotherapy by molecular group","aka":[],"tldr":"Re-analysing the PORTEC-3 trial by molecular class showed that p53-abnormal endometrial cancers gained substantially from adding chemotherapy to radiotherapy, POLE-mutated tumours did well regardless, and the other groups gained little.","summary":"Molecular classification of 410 high-risk endometrial cancers from the PORTEC-3 trial (chemoradiotherapy versus radiotherapy) into p53-abnormal, POLE-mutated, mismatch repair-deficient and no specific molecular profile groups.\n\nFive-year recurrence-free survival for p53-abnormal tumours was 59 percent with chemoradiotherapy against 36 percent with radiotherapy alone; POLE-mutated tumours had 96 to 100 percent recurrence-free survival in both arms; mismatch repair-deficient and no specific molecular profile groups showed no significant benefit from chemotherapy.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2020","url":"https://doi.org/10.1200/JCO.20.00549"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32749941/"}],"tags":[],"related":[],"cancers":["endometrial-mmr-deficient","endometrial-p53-abnormal","endometrial-pole-ultramutated"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["portec-3"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"doi":"10.1200/JCO.20.00549","pmid":"32749941","authors":"León-Castillo A, de Boer SM, Powell ME, et al.","paperType":"translational","findings":["p53-abnormal: five-year recurrence-free survival 59 percent vs 36 percent with chemoradiotherapy vs radiotherapy.","POLE-mutated: recurrence-free survival 96 to 100 percent regardless of treatment."],"whatItMeans":"Molecular class is now a predictive factor for adjuvant therapy: chemotherapy for p53-abnormal disease, de-escalation for POLE-mutated tumours, and trials of immunotherapy for mismatch repair-deficient disease.","caveats":["Retrospective subgroup analysis with small molecular groups.","Confirmation is being sought in the RAINBO programme."],"changedPractice":true,"participants":410},{"id":"paper-ivey-npm1-mrd-nejm-2016","kind":"paper","name":"Molecular measurable residual disease in NPM1-mutated acute myeloid leukaemia (UK NCRI AML17)","aka":[],"tldr":"Detecting leftover NPM1-mutated leukaemia in the blood after the second course of chemotherapy identified patients very likely to relapse, and proved a better guide than genetics at diagnosis to who needs a transplant.","summary":"Prospective study within the AML17 trial of 346 patients with NPM1-mutated AML monitored by quantitative PCR for NPM1 transcripts in blood and marrow after each course.\n\nPersistence of NPM1 transcripts in peripheral blood after the second chemotherapy course was found in 15 percent and predicted a three-year relapse rate of 82 percent against 30 percent when undetectable, with three-year survival of 24 versus 75 percent. The finding was the strongest independent prognostic factor.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2016","url":"https://doi.org/10.1056/NEJMoa1507471"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26789727/"}],"tags":[],"related":[],"cancers":["aml-npm1-kmt2a"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1507471","pmid":"26789727","authors":"Ivey A, Hills RK, Simpson MA, et al.","paperType":"observational","findings":["Three-year relapse 82 percent vs 30 percent by blood NPM1 status after course two.","Three-year overall survival 24 percent vs 75 percent."],"whatItMeans":"Molecular monitoring of NPM1 now decides whether a patient with otherwise favourable-risk disease should go to transplant in first remission, and molecular relapse can be treated pre-emptively.","caveats":["Requires a standardised quantitative PCR assay and defined thresholds.","Studied under intensive chemotherapy; thresholds under venetoclax regimens are being established."],"changedPractice":true,"participants":346},{"id":"paper-taylor-medulloblastoma-consensus-acta-neuropathol-2012","kind":"paper","name":"Molecular subgroups of medulloblastoma: the current consensus","aka":[],"tldr":"An international consensus divided medulloblastoma into four molecular subgroups, WNT, SHH, group 3 and group 4, with different origins, genetics, ages and survival, a scheme now used in diagnosis and to design risk-adapted trials.","summary":"Consensus paper from medulloblastoma researchers reconciling several transcriptomic classifications into four subgroups (WNT, SHH, group 3, group 4), summarising their demographics, histology, genetics, clinical behaviour and outcomes, and proposing nomenclature for research and clinical use.","asOf":"2026-09-17","links":[{"label":"Acta Neuropathol 2012","url":"https://doi.org/10.1007/s00401-011-0922-z"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22134537/"}],"tags":[],"related":[],"cancers":["medulloblastoma-group-3-4","medulloblastoma-shh","medulloblastoma-wnt"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Acta Neuropathologica","year":2012,"doi":"10.1007/s00401-011-0922-z","pmid":"22134537","authors":"Taylor MD, Northcott PA, Korshunov A, et al.","paperType":"guideline","findings":["WNT tumours have over 90 percent survival, SHH intermediate outcomes dependent on TP53, group 3 the worst outlook and group 4 intermediate."],"whatItMeans":"The medulloblastoma subtype pages on this site follow this scheme, which entered the WHO classification in 2016 and drives current de-escalation and intensification trials.","caveats":["Subgroups have since been split into further subtypes (Cavalli 2017) with prognostic differences."],"changedPractice":true},{"id":"paper-momentum-momelotinib-lancet-2023","kind":"paper","name":"MOMENTUM: momelotinib versus danazol for myelofibrosis patients with anaemia after a prior JAK inhibitor","aka":[],"tldr":"A JAK inhibitor that also blocks the anaemia-driving ACVR1 pathway improved symptoms and spleen size without worsening, and often improving, anaemia in previously treated patients.","summary":"MOMENTUM randomised 195 symptomatic, anaemic patients with myelofibrosis previously treated with a JAK inhibitor to momelotinib or danazol (2:1) for 24 weeks, after which danazol patients could cross over. The primary endpoint was a 50% or greater reduction in total symptom score at week 24. This was achieved by 25% versus 9%; transfusion independence at week 24 was 30% versus 20%, meeting non-inferiority, and spleen volume reduction of at least 35% was 22% versus 3%. Momelotinib inhibits JAK1, JAK2 and ACVR1, the last of which lowers hepcidin and improves iron availability. Grade 3 or higher thrombocytopenia and infections were the main toxicities. The drug was approved in 2023 specifically for myelofibrosis with anaemia.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=MOMENTUM%20momelotinib%20danazol%20myelofibrosis%20anaemia%20Verstovsek%20Lancet%202023"},{"label":"ClinicalTrials.gov NCT04173494","url":"https://clinicaltrials.gov/study/NCT04173494"}],"tags":[],"related":["paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012"],"cancers":["myeloproliferative-neoplasms"],"sections":[],"technologies":[],"targets":["jak2"],"drugs":["momelotinib","ruxolitinib","pacritinib"],"companies":["gsk"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"authors":"Verstovsek S, Gerds AT, Vannucchi AM, et al.","paperType":"rct","findings":["195 JAK-inhibitor-experienced patients with symptomatic myelofibrosis and anaemia; momelotinib vs danazol (2:1).","Total symptom score reduction of at least 50% at week 24: 25% vs 9%.","Transfusion independence at week 24: 30% vs 20% (non-inferiority met).","Spleen volume reduction of at least 35%: 22% vs 3%.","Mechanism includes ACVR1 inhibition lowering hepcidin, explaining the anaemia benefit."],"whatItMeans":"MOMENTUM addressed the biggest gap left by ruxolitinib: patients whose anaemia makes standard JAK inhibition hard to give. Momelotinib is now the preferred option for anaemic, previously treated myelofibrosis and is being adopted in first line for anaemic patients. The absolute symptom benefit is modest and durable disease modification has not been shown.","caveats":["Danazol is a weak comparator with limited efficacy of its own.","Symptom response rate of 25% is low in absolute terms.","Short (24-week) randomised period before crossover; long-term comparative data are limited.","Peripheral neuropathy signal seen in earlier momelotinib trials."],"changedPractice":true,"participants":195},{"id":"paper-monarche-jco-2020","kind":"paper","name":"monarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancer","aka":[],"tldr":"Adding two years of the CDK4/6 inhibitor abemaciclib to standard hormone therapy after surgery cut the risk of the cancer coming back by a quarter in women with node-positive, high-risk disease.","summary":"Open-label phase 3 trial of 5,637 patients with hormone-receptor-positive, HER2-negative early breast cancer at high risk of recurrence (four or more positive nodes, or one to three nodes with grade 3, tumour 5 cm or more, or high Ki-67), randomised to standard endocrine therapy with or without two years of abemaciclib. Primary endpoint was invasive disease-free survival (iDFS).\n\nAt the pre-planned interim analysis, iDFS was improved (HR 0.75; 2-year iDFS 92.2% vs 88.7%). The benefit widened with time: at five years iDFS was 83.6% vs 76.0%, a 7.6-point absolute difference (HR 0.68), well after abemaciclib had stopped. It was the first adjuvant CDK4/6 inhibitor to succeed after palbociclib failed in PALLAS and PENELOPE-B.","asOf":"2026-09-08","links":[{"label":"PubMed search: monarchE JCO 2020","url":"https://pubmed.ncbi.nlm.nih.gov/?term=monarchE+abemaciclib+adjuvant+Johnston+2020"},{"label":"ClinicalTrials.gov NCT03155997","url":"https://clinicaltrials.gov/study/NCT03155997"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":["cdk46-inhibitor","endocrine-therapy"],"targets":["cdk4-6","estrogen-receptor"],"drugs":["abemaciclib"],"companies":["eli-lilly"],"institutions":[],"pathways":[],"terms":["neoadjuvant-adjuvant","hazard-ratio"],"trials":["monarche","natalee"],"people":["miguel-martin","shao-zhi-ming","sohn-joohyuk","javier-cortes","andrew-wardley","sara-tolaney"],"bottlenecks":["b-dormancy-mrd","b-drug-pricing","b-toxicity-qol"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"authors":"Johnston SRD, Harbeck N, Hegg R, et al.","paperType":"rct","findings":["Invasive disease-free survival HR 0.75 (95% CI 0.60-0.93) at the interim analysis; 2-year iDFS 92.2% vs 88.7%.","Five-year update (2024): iDFS 83.6% vs 76.0% (HR 0.68) and distant relapse-free survival 86.0% vs 79.2%, with the curves continuing to separate after treatment ended.","Diarrhoea occurred in over 80% of abemaciclib patients (mostly grade 1-2) and roughly one in six discontinued because of adverse events.","Ki-67 of 20% or more identified a higher-risk group but did not predict a larger relative benefit, so the label was later broadened to all high-risk node-positive patients.","Overall survival data remain immature."],"whatItMeans":"Women with hormone-receptor-positive, HER2-negative breast cancer that has spread to lymph nodes and has other high-risk features can now be offered two years of abemaciclib alongside their hormone therapy, with a durable reduction in relapse. It does not apply to node-negative or low-risk disease, and the diarrhoea and cost are real trade-offs to discuss.","caveats":["No overall survival benefit has yet been shown.","Open-label design with an endpoint (iDFS) that includes second primary cancers.","The contrast with the negative PALLAS trial (palbociclib) is not fully explained: differences in drug, dose intensity, or population selection are all possible.","Two years of a costly oral drug for a 7-8 point absolute gain raises access questions in many health systems."],"changedPractice":true,"participants":5637},{"id":"paper-monumental-1-talquetamab-nejm-2022","kind":"paper","name":"MonumenTAL-1: talquetamab, a GPRC5D-directed bispecific antibody for relapsed multiple myeloma","aka":[],"tldr":"Talquetamab, an antibody that pulls T cells onto a new myeloma target called GPRC5D, produced responses in about seven in ten heavily pretreated patients, including those already treated with BCMA-directed therapy.","summary":"Phase 1 dose-escalation and expansion study of 288 patients with relapsed or refractory multiple myeloma treated with subcutaneous talquetamab at 405 micrograms per kilogram weekly or 800 micrograms per kilogram every two weeks.\n\nResponse rates were about 70 percent at both doses with a median duration of response of about 10 months; cytokine release syndrome was common but mostly low grade, and skin, nail and taste changes were characteristic.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2204591"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36507686/"}],"tags":[],"related":[],"cancers":["myeloma-relapsed-refractory"],"sections":[],"technologies":[],"targets":[],"drugs":["mcla-129","talquetamab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["monumental-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2204591","pmid":"36507686","authors":"Chari A, Minnema MC, Berdeja JG, et al.","paperType":"observational","findings":["Overall response about 70 percent at the two recommended doses.","Median duration of response roughly 10 months; cytokine release syndrome in about three quarters, mostly grade 1 to 2."],"whatItMeans":"A second bispecific target beyond BCMA gives patients an option after BCMA-directed CAR-T or bispecifics have failed; it was approved in 2023.","caveats":["Single-arm early-phase data.","Dysgeusia, weight loss and skin toxicity affect quality of life and adherence."],"changedPractice":true,"participants":288},{"id":"paper-mountaineer-lancet-oncol-2023","kind":"paper","name":"MOUNTAINEER: tucatinib plus trastuzumab for HER2-positive, RAS wild-type metastatic colorectal cancer","aka":[],"tldr":"The chemotherapy-free combination of tucatinib and trastuzumab shrank tumours in almost four in ten patients with previously treated HER2-positive colorectal cancer, with responses lasting about a year, and became the first approved HER2 regimen for the disease.","summary":"Phase 2 study of 117 patients with HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer previously treated with chemotherapy, of whom 84 received tucatinib plus trastuzumab.\n\nObjective response was 38.1 percent with a median duration of response of 12.4 months, median progression-free survival 8.2 months and median overall survival 24.1 months; tucatinib alone was less active and patients crossed over to the combination.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2023","url":"https://doi.org/10.1016/S1470-2045(23)00150-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37142372/"}],"tags":[],"related":[],"cancers":["her2-amplified-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","tucatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["mountaineer"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2023,"doi":"10.1016/S1470-2045(23)00150-X","pmid":"37142372","authors":"Strickler JH, Cercek A, Siena S, et al.","paperType":"observational","findings":["Objective response 38.1 percent; median duration of response 12.4 months.","Median overall survival 24.1 months."],"whatItMeans":"HER2 amplification testing is now standard in RAS wild-type metastatic colorectal cancer, and tucatinib-trastuzumab is the approved chemotherapy-free option after first-line therapy.","caveats":["Single-arm study in a RAS wild-type population; activity in RAS-mutant tumours is not expected.","Confirmatory first-line trial (MOUNTAINEER-03) ongoing."],"changedPractice":true,"participants":117},{"id":"paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","kind":"paper","name":"MPACT (Von Hoff 2013): nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer","aka":[],"tldr":"Adding albumin-bound paclitaxel to gemcitabine prolonged survival in metastatic pancreatic cancer in a large international trial, giving patients who are not fit enough for FOLFIRINOX a second effective first-line option.","summary":"MPACT randomised 861 patients with untreated metastatic pancreatic adenocarcinoma to nab-paclitaxel plus gemcitabine or gemcitabine alone. The combination improved overall survival, progression-free survival and response rate, with more neutropenia, fatigue and peripheral neuropathy that was usually reversible on dose reduction. Because it accepted patients up to performance status 2 and was less toxic than FOLFIRINOX, it became the alternative first-line standard and the backbone for many later combination trials.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1304369"},{"label":"ClinicalTrials.gov NCT00844649","url":"https://clinicaltrials.gov/study/NCT00844649"}],"tags":[],"related":["paper-conroy-folfirinox-pancreatic-nejm-2011"],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":[],"drugs":["gemcitabine-nab-paclitaxel","gemcitabine"],"companies":[],"institutions":[],"pathways":[],"terms":["os","pfs"],"trials":[],"people":["daniel-von-hoff"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2013,"doi":"10.1056/NEJMoa1304369","authors":"Von Hoff DD, Ervin T, Arena FP, et al.","paperType":"rct","findings":["861 patients with untreated metastatic pancreatic cancer; nab-paclitaxel plus gemcitabine vs gemcitabine.","Median overall survival 8.5 vs 6.7 months, hazard ratio 0.72.","Median progression-free survival 5.5 vs 3.7 months, hazard ratio 0.69; response rate 23% vs 7%.","Grade 3 or higher neutropenia 38% vs 27% and peripheral neuropathy 17% vs 1%."],"whatItMeans":"With FOLFIRINOX this trial defined the two chemotherapy standards for metastatic pancreatic cancer that still apply, and the gemcitabine and nab-paclitaxel backbone is the comparator in most current first-line pancreatic trials.","caveats":["Open-label design.","The survival gain is measured in months and the disease remains one of the most lethal.","Cross-trial comparison with FOLFIRINOX is unreliable; the populations differed in fitness."],"changedPractice":true,"participants":861},{"id":"paper-mrc-te19-carboplatin-seminoma-oliver-lancet-2005","kind":"paper","name":"MRC TE19/EORTC 30982: radiotherapy versus single-dose carboplatin as adjuvant treatment for stage I seminoma","aka":[],"tldr":"A single dose of carboplatin was as effective as radiotherapy in preventing relapse of stage I seminoma after orchidectomy, with less time off work and fewer second testicular cancers, so it replaced radiotherapy for men who choose adjuvant treatment.","summary":"Phase 3 non-inferiority trial of 1,477 men with stage I seminoma randomised to adjuvant radiotherapy or one cycle of carboplatin (AUC 7).\n\nThree-year relapse-free rates were 94.8 percent with carboplatin and 95.9 percent with radiotherapy (non-inferior), with fewer contralateral germ cell tumours after carboplatin and less acute toxicity; longer follow-up confirmed equivalence.","asOf":"2026-09-17","links":[{"label":"Lancet 2005","url":"https://doi.org/10.1016/S0140-6736(05)66984-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16039331/"}],"tags":[],"related":[],"cancers":["seminoma"],"sections":[],"technologies":[],"targets":[],"drugs":["carboplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2005,"doi":"10.1016/S0140-6736(05)66984-X","pmid":"16039331","authors":"Oliver RT, Mason MD, Mead GM, et al.","paperType":"rct","findings":["Three-year relapse-free rate 94.8 percent (carboplatin) vs 95.9 percent (radiotherapy); non-inferior.","Contralateral germ cell tumours 2 vs 10 cases."],"whatItMeans":"Single-dose carboplatin is the adjuvant option for stage I seminoma where surveillance is not chosen; radiotherapy is now rarely used because of second cancer risk.","caveats":["Surveillance alone cures the same proportion of men after salvage and is preferred for most today."],"changedPractice":true,"participants":1477},{"id":"paper-mslt-ii-faries-nejm-2017","kind":"paper","name":"MSLT-II: completion lymph node dissection or observation for sentinel-node metastasis in melanoma","aka":[],"tldr":"Removing all the remaining lymph nodes after a positive sentinel node did not improve melanoma survival compared with ultrasound surveillance and caused far more lymphoedema, ending routine completion dissection.","summary":"Phase 3 trial of 1,939 patients with sentinel node-positive melanoma randomised to immediate completion lymph node dissection or nodal observation with ultrasound.\n\nThree-year melanoma-specific survival was 86 percent in both groups; dissection improved regional disease control and gave prognostic information but caused lymphoedema in 24 versus 6 percent.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1613210"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28591523/"}],"tags":[],"related":[],"cancers":["stage-iii-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["mslt-ii"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1613210","pmid":"28591523","authors":"Faries MB, Thompson JF, Cochran AJ, et al.","paperType":"rct","findings":["Three-year melanoma-specific survival 86 percent in both groups.","Lymphoedema 24.1 percent vs 6.3 percent."],"whatItMeans":"Patients with a positive sentinel node are now managed with surveillance and adjuvant systemic therapy rather than completion dissection.","caveats":["Most patients had low-volume sentinel node disease; the trial was not powered for those with high nodal burden."],"changedPractice":true,"participants":1939},{"id":"paper-morice-mucinous-ovarian-carcinoma-nejm-2019","kind":"paper","name":"Mucinous ovarian carcinoma (review)","aka":[],"tldr":"This review explains how mucinous ovarian cancer differs from other ovarian cancers, why metastases from the bowel must be excluded, and how surgery, fertility preservation and chemotherapy choices are made in a disease with little trial evidence.","summary":"Review covering the epidemiology, pathology and immunohistochemical distinction of primary mucinous ovarian carcinoma from metastatic gastrointestinal tumours, expansile versus infiltrative patterns, molecular features, surgical staging and fertility-sparing surgery, the role of appendicectomy, adjuvant chemotherapy including gastrointestinal-type regimens, and management of advanced disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2019","url":"https://doi.org/10.1056/NEJMra1813254"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30917260/"}],"tags":[],"related":[],"cancers":["mucinous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMra1813254","pmid":"30917260","authors":"Morice P, Gouy S, Leary A.","paperType":"review","findings":[],"whatItMeans":"The mucinous ovarian cancer page's emphasis on excluding a gastrointestinal primary, omitting chemotherapy for early expansile tumours, and considering gastrointestinal-type regimens follows this review.","caveats":["Randomised evidence is minimal because the disease is rare; the mEOC/GOG 0241 trial closed early."],"changedPractice":false},{"id":"paper-murano-venetoclax-rituximab-nejm-2018","kind":"paper","name":"MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL","aka":[],"tldr":"In relapsed CLL, a time-limited venetoclax-rituximab course cut progression risk by more than 80% compared with bendamustine-rituximab and later improved survival.","summary":"MURANO randomised 389 patients with relapsed or refractory CLL to venetoclax for two years plus six months of rituximab, or six cycles of bendamustine-rituximab. The primary endpoint was investigator-assessed PFS. At 24 months PFS was 84.9% versus 36.3% (hazard ratio 0.17), with benefit across del(17p) and other high-risk subgroups. Rates of undetectable MRD were much higher with venetoclax-rituximab. With five years of follow-up the overall survival advantage held (about 82% versus 62%), and most patients who reached undetectable MRD at end of therapy stayed in remission for years off treatment.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1713976"},{"label":"ClinicalTrials.gov NCT02005471","url":"https://clinicaltrials.gov/study/NCT02005471"}],"tags":[],"related":["paper-cll14-venetoclax-obinutuzumab-nejm-2019"],"cancers":["cll"],"sections":[],"technologies":[],"targets":["bcl2","cd20"],"drugs":["venetoclax","rituximab","bendamustine"],"companies":["abbvie","roche-genentech"],"institutions":[],"pathways":[],"terms":["mrd","pfs","os","del17p-tp53"],"trials":[],"people":[],"bottlenecks":["b-dormancy-mrd","b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1713976","authors":"Seymour JF, Kipps TJ, Eichhorst B, et al.","paperType":"rct","findings":["389 patients with relapsed/refractory CLL; venetoclax (2 years) + rituximab vs bendamustine-rituximab.","24-month PFS 84.9% vs 36.3%; hazard ratio 0.17.","Benefit preserved in del(17p), TP53-mutated and IGHV-unmutated disease.","Peripheral-blood undetectable MRD at end of combination treatment was far more frequent with venetoclax-rituximab.","Five-year overall survival roughly 82% vs 62%; end-of-treatment MRD status predicted subsequent PFS."],"whatItMeans":"MURANO made fixed-duration venetoclax the standard for relapsed CLL and showed that stopping therapy after a deep response is safe for most patients. It also established MRD at end of treatment as a practical guide to who is likely to stay in remission. Retreatment with venetoclax at relapse appears feasible.","caveats":["Bendamustine-rituximab is a weak comparator by today's standards; there is no head-to-head against BTK inhibitors in this setting.","Few patients had prior BTK inhibitor exposure, so results may not apply after BTKi failure.","Open-label design with investigator-assessed endpoints.","Tumour-lysis prophylaxis and ramp-up add complexity."],"changedPractice":true,"participants":389},{"id":"paper-shah-foxl2-granulosa-nejm-2009","kind":"paper","name":"Mutation of FOXL2 in granulosa cell tumours of the ovary","aka":[],"tldr":"Sequencing of adult granulosa cell tumours found a single recurrent mutation in the FOXL2 gene in almost every case, giving this rare ovarian cancer a defining molecular marker and a diagnostic test.","summary":"Whole-transcriptome sequencing of four adult granulosa cell tumours followed by targeted validation in 89 additional adult tumours and other ovarian tumours, identifying the FOXL2 c.402C>G (C134W) mutation in 97 percent of adult granulosa cell tumours and rarely in other tumour types.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2009","url":"https://doi.org/10.1056/NEJMoa0902542"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19516027/"}],"tags":[],"related":[],"cancers":["granulosa-cell-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2009,"doi":"10.1056/NEJMoa0902542","pmid":"19516027","authors":"Shah SP, Köbel M, Senz J, et al.","paperType":"translational","findings":["FOXL2 C134W mutation in 86 of 89 adult granulosa cell tumours (97 percent).","Absent from most other ovarian tumour types and from juvenile granulosa cell tumours."],"whatItMeans":"FOXL2 mutation testing is now used to confirm the diagnosis of adult granulosa cell tumour, and the mutation is central to understanding and treating the disease.","caveats":["Discovery study; no FOXL2-directed therapy exists yet."],"changedPractice":true},{"id":"paper-myxofibrosarcoma-mentzel-ajsp-1996","kind":"paper","name":"Myxofibrosarcoma: clinicopathological analysis of 75 cases with emphasis on the low-grade variant","aka":[],"tldr":"This series defined myxofibrosarcoma as a distinct sarcoma of elderly limbs with characteristic curvilinear blood vessels and a strong tendency to recur locally and progress in grade, features that still guide its wide excision.","summary":"Clinicopathological study of 75 cases of myxofibrosarcoma establishing diagnostic criteria (multinodular growth, myxoid stroma, curvilinear vessels, pleomorphic cells), a grading spectrum from low to high grade, a local recurrence rate of about 50 to 60 percent often with grade progression, and metastasis mainly from high-grade tumours.","asOf":"2026-09-17","links":[{"label":"Am J Surg Pathol 1996","url":"https://doi.org/10.1097/00000478-199604000-00001"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/8604805/"}],"tags":[],"related":[],"cancers":["myxofibrosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"American Journal of Surgical Pathology","year":1996,"doi":"10.1097/00000478-199604000-00001","pmid":"8604805","authors":"Mentzel T, Calonje E, Wadden C, et al.","paperType":"observational","findings":["Local recurrence in over half of cases regardless of grade, with progression to higher grade in a proportion.","Metastasis mostly from intermediate- and high-grade tumours."],"whatItMeans":"The recognition that myxofibrosarcoma infiltrates along tissue planes far beyond the visible mass underlies the wide, MRI-planned excision and adjuvant radiotherapy recommended today.","caveats":["Retrospective pathology series."],"changedPractice":true,"participants":75},{"id":"paper-n107c-brown-lancet-oncol-2017","kind":"paper","name":"N107C/CEC.3: postoperative radiosurgery versus whole-brain radiotherapy after resection of a brain metastasis","aka":[],"tldr":"After surgery to remove a brain metastasis, focused radiosurgery to the cavity preserved thinking and memory far better than whole-brain radiotherapy and gave the same survival, so it became the standard.","summary":"Phase 3 trial of 194 patients with one resected brain metastasis (and up to three unresected) randomised to stereotactic radiosurgery to the surgical cavity or whole-brain radiotherapy.\n\nCognitive deterioration-free survival was 3.7 versus 3.0 months (hazard ratio 0.47) and cognitive decline at six months was 52 versus 85 percent; overall survival was similar (12.2 versus 11.6 months) although whole-brain radiotherapy gave better intracranial control.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2017","url":"https://doi.org/10.1016/S1470-2045(17)30441-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28687377/"}],"tags":[],"related":[],"cancers":["secondary-brain-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2017,"doi":"10.1016/S1470-2045(17)30441-2","pmid":"28687377","authors":"Brown PD, Ballman KV, Cerhan JH, et al.","paperType":"rct","findings":["Cognitive deterioration at six months 52 percent vs 85 percent.","Median overall survival 12.2 vs 11.6 months (no difference)."],"whatItMeans":"Surgical cavity radiosurgery, rather than whole-brain radiotherapy, follows resection of a brain metastasis in fit patients, part of the broader move away from whole-brain treatment.","caveats":["Surgical bed control was lower with radiosurgery than with whole-brain radiotherapy (about 61 vs 81 percent at one year).","Leptomeningeal relapse is a concern after cavity radiosurgery."],"changedPractice":true,"participants":194},{"id":"paper-nadina-nejm-2024","kind":"paper","name":"NADINA: two doses of ipilimumab plus nivolumab before surgery beat a year of nivolumab after surgery in stage III melanoma","aka":[],"tldr":"Giving just two cycles of combination immunotherapy before removing melanoma lymph nodes cut relapses by more than two-thirds compared with a year of standard immunotherapy after surgery, and most patients needed no further treatment.","summary":"Open-label phase 3 trial of 423 patients with resectable, macroscopic stage III melanoma randomised to two cycles of neoadjuvant ipilimumab (80 mg) plus nivolumab (240 mg) followed by lymph node dissection, with adjuvant therapy only for those without a major pathological response, or to upfront surgery followed by 12 cycles of adjuvant nivolumab. Primary endpoint was event-free survival.\n\n12-month EFS was 83.7% vs 57.2% (HR 0.32). A major pathological response occurred in 59% of neoadjuvant patients, and 95% of those were event-free at 12 months without any adjuvant therapy. It established neoadjuvant immunotherapy as the standard for macroscopic stage III melanoma and showed that the pathological response can be used to stop treatment early in most patients.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2402604"},{"label":"ClinicalTrials.gov NCT04949113","url":"https://clinicaltrials.gov/study/NCT04949113"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","ctla4"],"drugs":["nivolumab","ipilimumab"],"companies":["bms"],"institutions":["nki"],"pathways":[],"terms":["efs","neoadjuvant-adjuvant","pcr","irae"],"trials":[],"people":["christian-blank","john-haanen"],"bottlenecks":["b-trial-design","b-dose-optimisation","b-toxicity-qol","b-surgery-radiation-innovation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2402604","authors":"Blank CU, Lucas MW, Scolyer RA, et al.","paperType":"rct","findings":["12-month event-free survival 83.7% vs 57.2%; HR 0.32 (99.9% CI 0.15-0.66).","Major pathological response (10% or less viable tumour) in 59.0% of neoadjuvant patients; 12-month recurrence-free survival 95.1% in those patients with no adjuvant therapy.","Partial pathological responders (12-month RFS 76%) and non-responders (57%) fared progressively worse and received adjuvant nivolumab or BRAF/MEK therapy.","Grade 3 or higher systemic treatment-related adverse events 29.7% vs 14.7%.","Patients in the neoadjuvant arm received a median of two immunotherapy cycles instead of twelve."],"whatItMeans":"Patients with melanoma that has spread to palpable lymph nodes should now be offered immunotherapy before rather than only after surgery: two cycles of low-dose ipilimumab with nivolumab, then surgery, with the pathology result deciding whether any more treatment is needed. Most patients respond well and are spared a year of adjuvant therapy. Serious side effects are more common than with nivolumab alone, mostly endocrine, and the approach requires close coordination between oncologists, surgeons and pathologists.","caveats":["Open-label; follow-up is short and overall survival is not yet reported.","Higher rate of serious immune-related toxicity in the neoadjuvant arm, including permanent endocrinopathies.","Requires expert pathological assessment of response to guide de-escalation, which not all centres can provide.","Patients with in-transit-only disease or BRAF-mutated tumours preferring targeted therapy were handled differently, limiting generalisability."],"changedPractice":true,"participants":423},{"id":"paper-nadofaragene-firadenovec-lancet-oncol-2021","kind":"paper","name":"Nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer","aka":[],"tldr":"A single instillation of a virus carrying the interferon gene into the bladder every three months cleared carcinoma in situ in about half of patients who had failed BCG, and became the first gene therapy approved for bladder cancer.","summary":"Single-arm phase 3 study of 157 patients with BCG-unresponsive high-grade non-muscle-invasive bladder cancer treated with intravesical nadofaragene firadenovec, a non-replicating adenovirus vector expressing interferon alfa-2b, every three months.\n\nAmong patients with carcinoma in situ, 53.4 percent had a complete response within 12 months and about a quarter remained free of high-grade recurrence at one year. Treatment was well tolerated with mostly transient bladder symptoms.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(20)30540-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33253641/"}],"tags":[],"related":[],"cancers":["non-muscle-invasive-bladder-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["nadofaragene-firadenovec"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(20)30540-4","pmid":"33253641","authors":"Boorjian SA, Alemozaffar M, Konety BR, et al.","paperType":"observational","findings":["Complete response in 53.4 percent of patients with carcinoma in situ within 12 months.","45.5 percent of responders remained in complete response at 12 months."],"whatItMeans":"Bladder-sparing gene therapy is a realistic option for BCG-unresponsive disease, given four times a year in clinic. Durability is limited and cystoscopic follow-up continues.","caveats":["Single-arm design with no cystectomy or chemotherapy comparator.","Approval in the United States came in 2022; access outside the United States remains limited."],"changedPractice":true,"participants":157},{"id":"paper-napoli-3-lancet-2023","kind":"paper","name":"NAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancer","aka":[],"tldr":"NAPOLI-3 randomised 770 patients with untreated metastatic pancreatic cancer to NALIRIFOX, a four-drug regimen built on liposomal irinotecan, or to gemcitabine plus nab-paclitaxel, the doublet most patients receive. NALIRIFOX lengthened life and delayed progression, the first positive first-line trial in a decade, though conventional FOLFIRINOX remains the usual choice where affordable.","summary":"Open-label phase 3 trial of 770 patients with untreated metastatic pancreatic adenocarcinoma randomised to NALIRIFOX (liposomal irinotecan, oxaliplatin, fluorouracil, leucovorin) or gemcitabine plus nab-paclitaxel. Primary endpoint was overall survival.\n\nMedian OS was 11.1 vs 9.2 months (HR 0.83) and median PFS 7.4 vs 5.6 months (HR 0.69). It was the first randomised evidence that a FOLFIRINOX-type regimen beats gemcitabine plus nab-paclitaxel, and led to FDA approval of NALIRIFOX in 2024, though conventional FOLFIRINOX remains the usual choice where it is affordable.","asOf":"2026-09-08","links":[{"label":"PubMed search: NAPOLI-3 Lancet 2023","url":"https://pubmed.ncbi.nlm.nih.gov/?term=NAPOLI-3+NALIRIFOX+Wainberg+Lancet"},{"label":"ClinicalTrials.gov NCT04083235","url":"https://clinicaltrials.gov/study/NCT04083235"}],"tags":[],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":["cytotoxic-chemotherapy","topoisomerase-inhibitors","platinum"],"targets":[],"drugs":[],"companies":["servier"],"institutions":[],"pathways":[],"terms":["os","pfs","first-line","standard-of-care"],"trials":[],"people":["tanios-bekaii-saab"],"bottlenecks":["b-undruggable-targets","b-drug-pricing","b-tme-immunosuppression"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"authors":"Wainberg ZA, Melisi D, Macarulla T, et al.","paperType":"rct","findings":["Median overall survival 11.1 vs 9.2 months; HR 0.83 (95% CI 0.70-0.99).","Median PFS 7.4 vs 5.6 months; HR 0.69 (95% CI 0.58-0.83).","Objective response 41.8% vs 36.2%.","Grade 3-4 diarrhoea 20% vs 5% and grade 3-4 neutropenia lower with NALIRIFOX (14% vs 25%); peripheral neuropathy less frequent with NALIRIFOX.","Benefit was consistent across age groups but the trial enrolled fit patients (ECOG 0-1)."],"whatItMeans":"For fit patients with newly diagnosed metastatic pancreatic cancer, a FOLFIRINOX-type regimen is now proven to be better than gemcitabine plus nab-paclitaxel, settling a long-standing debate. The absolute gain is about two months of median survival, and the regimen is more toxic for the gut. Whether liposomal irinotecan adds anything over conventional irinotecan (standard FOLFIRINOX) has never been tested head-to-head.","caveats":["No direct comparison with standard FOLFIRINOX, which is much cheaper; the benefit of the liposomal formulation is inferred, not shown.","Absolute survival gain is modest and the population was fit and relatively young (median 65).","Open-label design.","Highlights how little progress systemic therapy has made in pancreatic cancer: median survival remains under a year."],"changedPractice":true,"participants":770},{"id":"paper-natalee-nejm-2024","kind":"paper","name":"NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer","aka":[],"tldr":"Three years of the CDK4/6 inhibitor ribociclib added to hormone therapy reduced relapses in stage II-III hormone-receptor-positive breast cancer, including some node-negative patients.","summary":"Open-label phase 3 trial of 5,101 patients with hormone-receptor-positive, HER2-negative stage II or III early breast cancer, including node-negative patients with high-risk features, randomised to a non-steroidal aromatase inhibitor with or without three years of ribociclib at a reduced dose (400 mg daily). Primary endpoint was invasive disease-free survival.\n\nThree-year iDFS was 90.4% vs 87.1% (HR 0.75). Together with monarchE it established adjuvant CDK4/6 inhibition, but in a broader, lower-risk population and with a longer, lower-dose schedule.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2305488"},{"label":"ClinicalTrials.gov NCT03701334","url":"https://clinicaltrials.gov/study/NCT03701334"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":["cdk46-inhibitor","endocrine-therapy"],"targets":["cdk4-6","estrogen-receptor"],"drugs":["ribociclib"],"companies":["novartis"],"institutions":[],"pathways":[],"terms":["neoadjuvant-adjuvant","hazard-ratio"],"trials":["natalee","monarche"],"people":["dennis-slamon","im-seock-ah","miguel-martin","loi-sherene","xu-binghe","sara-hurvitz","barrios-carlos"],"bottlenecks":["b-dormancy-mrd","b-drug-pricing","b-dose-optimisation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2305488","authors":"Slamon D, Lipatov O, Nowecki Z, et al.","paperType":"rct","findings":["Three-year invasive disease-free survival 90.4% vs 87.1%; HR 0.75 (95% CI 0.62-0.91).","Benefit was consistent across stage II and III and in node-negative and node-positive subgroups.","Distant disease-free survival HR 0.74.","Grade 3 or higher neutropenia in roughly 44% and liver enzyme elevation in roughly 8% of ribociclib patients; about one in five discontinued for adverse events.","Overall survival immature at the primary analysis."],"whatItMeans":"Ribociclib is a second adjuvant CDK4/6 option, and the only one with data in node-negative stage II disease. Roughly 3 in 100 patients avoid a relapse or death at three years, so the decision depends heavily on individual risk, tolerance of a three-year oral drug, and cost. Whether the benefit persists after treatment ends, as it did with abemaciclib, needs longer follow-up.","caveats":["Absolute benefit at three years is about 3 percentage points and the trial included many patients whose baseline risk was modest.","Follow-up beyond the three years of treatment is limited, so durability is not yet established.","Open-label; a large proportion of patients stopped ribociclib early.","Cost of three years of therapy is substantial; cost-effectiveness has been questioned in several health systems."],"changedPractice":true,"participants":5101},{"id":"paper-navigator-avapritinib-heinrich-lancet-oncol-2020","kind":"paper","name":"NAVIGATOR: avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour","aka":[],"tldr":"Avapritinib shrank tumours in almost nine in ten patients with PDGFRA D842V-mutant gastrointestinal stromal tumour, a subtype completely resistant to imatinib and every other kinase inhibitor, and became its first effective treatment.","summary":"Phase 1 dose-escalation and expansion study; this analysis covers 56 patients with PDGFRA D842V-mutant advanced GIST treated with avapritinib at 300 or 400 mg daily.\n\nObjective response was 88 percent (9 percent complete), median duration of response not reached, and 12-month progression-free survival 81 percent; cognitive effects, periorbital oedema and anaemia were the characteristic toxicities, with rare intracranial bleeding.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2020","url":"https://doi.org/10.1016/S1470-2045(20)30269-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32615108/"}],"tags":[],"related":[],"cancers":["gist-pdgfra-d842v"],"sections":[],"technologies":[],"targets":[],"drugs":["avapritinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["navigator"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2020,"doi":"10.1016/S1470-2045(20)30269-2","pmid":"32615108","authors":"Heinrich MC, Jones RL, von Mehren M, et al.","paperType":"observational","findings":["Objective response 88 percent in PDGFRA D842V-mutant GIST.","Twelve-month progression-free survival 81 percent."],"whatItMeans":"Avapritinib 300 mg is the standard first-line treatment for advanced PDGFRA D842V GIST, and mutation testing before starting imatinib is essential to identify these patients.","caveats":["Single-arm; cognitive side effects need monitoring and dose adjustment.","In non-D842V GIST avapritinib was not superior to regorafenib (VOYAGER)."],"changedPractice":true,"participants":56},{"id":"paper-ncic-sr2-preoperative-vs-postoperative-radiotherapy-osullivan-lancet-2002","kind":"paper","name":"NCIC SR2: preoperative versus postoperative radiotherapy in soft tissue sarcoma of the limbs","aka":[],"tldr":"Radiotherapy before surgery for limb sarcoma doubled the rate of wound complications compared with radiotherapy after surgery, but gave the same tumour control with lower doses and less late fibrosis, leaving the timing as a trade between early and late side effects.","summary":"Phase 3 trial of 190 patients with extremity soft tissue sarcoma randomised to preoperative radiotherapy (50 Gy) or postoperative radiotherapy (66 Gy).\n\nMajor wound complications occurred in 35 percent after preoperative radiotherapy versus 17 percent after postoperative; local control and survival were similar (with a small non-significant survival advantage for preoperative), and later reports showed less fibrosis, oedema and joint stiffness with preoperative treatment.","asOf":"2026-09-17","links":[{"label":"Lancet 2002","url":"https://doi.org/10.1016/S0140-6736(02)09292-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12103287/"}],"tags":[],"related":[],"cancers":["extremity-soft-tissue-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2002,"doi":"10.1016/S0140-6736(02)09292-9","pmid":"12103287","authors":"O'Sullivan B, Davis AM, Turcotte R, et al.","paperType":"rct","findings":["Major wound complications 35 percent (preoperative) vs 17 percent (postoperative).","Local control and overall survival equivalent."],"whatItMeans":"Both sequences are standard; preoperative radiotherapy is favoured for large deep tumours because of better long-term function, with postoperative radiotherapy where wound risk is high.","caveats":["Small trial; the late toxicity comparison came from secondary analysis."],"changedPractice":true,"participants":190},{"id":"paper-nelson-nejm-2020","kind":"paper","name":"NELSON: volume-based CT screening reduces lung cancer deaths with fewer false alarms","aka":[],"tldr":"In a Dutch-Belgian trial, CT screening using nodule volume rather than diameter cut lung cancer deaths in men by about a quarter at 10 years, with a far lower false-positive rate than NLST.","summary":"NELSON randomised 15,789 current or former smokers (13,195 men and 2,594 women) aged 50-74 to CT screening at baseline, 1, 3 and 5.5 years or to no screening. Nodules were managed by volume and volume-doubling time, with an indeterminate category that triggered a repeat scan rather than a biopsy.\n\nThe primary analysis in men showed a lung cancer mortality rate ratio of 0.76 at 10 years. Screen-detected cancers were much more often stage I. The positive-screen rate was around 2%, far below NLST's, because the indeterminate category absorbed most small nodules.\n\nNELSON confirmed NLST against a no-screening control and gave European programmes a workable protocol.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1911793"},{"label":"NEJM full text","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1911793"}],"tags":[],"related":["paper-nlst-nejm-2011","idea-prev-lung-screening-risk-model-eligibility"],"cancers":["nsclc"],"sections":["early-detection"],"technologies":["low-dose-ct-screening","ct","radiology-ai-screening"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["stage-shift","ppv"],"trials":["nlst-nelson"],"people":[],"bottlenecks":["b-early-detection","b-overdiagnosis"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa1911793","pmid":"31995683","authors":"de Koning HJ, van der Aalst CM, de Jong PA, et al.","paperType":"rct","findings":["Lung cancer mortality rate ratio in men 0.76 (95% CI 0.61-0.94) at 10 years","In the smaller female cohort the rate ratio was 0.67 (95% CI 0.38-1.14), not statistically significant but consistent with benefit","Overall positive-screen rate about 2%, with the majority of screen-detected cancers at stage IA-IB","Comparator was no screening, removing the concern that chest X-ray in NLST masked part of the effect"],"whatItMeans":"Lung screening works when it uses volumetric nodule management, and it works against a no-screening control. The protocol underpins the UK Targeted Lung Health Check programme and European recommendations. Benefit in women remains less precisely estimated.","caveats":["Women were under-represented, so the female estimate is imprecise","Screening intervals lengthened to 2.5 years in the final round; the optimal interval is still debated","Some overdiagnosis is likely; the authors estimated a modest excess of cancers in the screened arm at 10 years","Participants were volunteers responding to a population mailing, which may not reflect routine uptake"],"changedPractice":true,"participants":15789},{"id":"paper-gross-neoadjuvant-cemiplimab-cscc-nejm-2022","kind":"paper","name":"Neoadjuvant cemiplimab for stage II to IV cutaneous squamous cell carcinoma","aka":[],"tldr":"Giving four doses of cemiplimab before surgery for resectable cutaneous squamous cell carcinoma eliminated all viable tumour in half of patients and left only minimal residual disease in another 13 percent, opening the way to smaller operations and less radiotherapy.","summary":"Phase 2 study of 79 patients with resectable stage II to IV (M0) cutaneous squamous cell carcinoma treated with up to four doses of neoadjuvant cemiplimab followed by surgery.\n\nPathological complete response was 50.6 percent and major pathological response (10 percent or less viable tumour) a further 12.7 percent; radiological response underestimated pathological response, and adverse events were consistent with PD-1 blockade.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2022","url":"https://doi.org/10.1056/NEJMoa2209813"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36094839/"}],"tags":[],"related":[],"cancers":["advanced-cutaneous-scc"],"sections":[],"technologies":[],"targets":[],"drugs":["cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2209813","pmid":"36094839","authors":"Gross ND, Miller DM, Khushalani NI, et al.","paperType":"observational","findings":["Pathological complete response 50.6 percent; major pathological response 12.7 percent.","Objective radiological response 68.4 percent."],"whatItMeans":"Neoadjuvant cemiplimab is now used to shrink large or function-threatening cutaneous squamous cell carcinomas before surgery, and pathological response is being studied as a guide to omitting adjuvant radiotherapy.","caveats":["Single-arm; long-term recurrence-free survival data are maturing.","Surgical de-escalation after complete response is not yet standard."],"changedPractice":true,"participants":79},{"id":"paper-netter-1-nejm-2017","kind":"paper","name":"NETTER-1: 177Lu-Dotatate for midgut neuroendocrine tumours progressing on octreotide","aka":[],"tldr":"Radioligand therapy with lutetium-177 dotatate reduced the risk of progression or death by nearly 80 percent compared with high-dose octreotide in midgut neuroendocrine tumours, the first randomised proof that targeted radiation works in these cancers.","summary":"Phase 3 trial of 229 patients with advanced, progressive, somatostatin receptor-positive midgut neuroendocrine tumours randomised to four cycles of 177Lu-Dotatate plus octreotide LAR 30 mg or high-dose octreotide LAR 60 mg.\n\nProgression-free survival at 20 months was 65.2 versus 10.8 percent (hazard ratio 0.21), response 18 versus 3 percent, and an interim analysis suggested improved overall survival; myelosuppression was modest.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1607427"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28076709/"}],"tags":[],"related":[],"cancers":["small-intestinal-net"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["netter-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1607427","pmid":"28076709","authors":"Strosberg J, El-Haddad G, Wolin E, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.21; 20-month rate 65.2 percent vs 10.8 percent.","Objective response 18 percent vs 3 percent."],"whatItMeans":"Lutetium-177 dotatate is a standard treatment for progressive small bowel neuroendocrine tumours after somatostatin analogues, and NETTER-2 has since moved it into first-line use for higher-grade tumours.","caveats":["Final overall survival difference (48.0 vs 36.3 months) did not reach significance, partly because of crossover.","Rare late myelodysplasia and leukaemia."],"changedPractice":true,"participants":229},{"id":"paper-netter-2-lancet-2024","kind":"paper","name":"NETTER-2: lutetium-177 dotatate as first treatment for higher-grade gastroenteropancreatic neuroendocrine tumours","aka":[],"tldr":"Using the radioactive drug lutetium dotatate as the first treatment for faster-growing neuroendocrine tumours, rather than saving it for later, nearly tripled the time without progression compared with high-dose octreotide.","summary":"Open-label phase 3 trial of 226 patients with newly diagnosed, somatostatin-receptor-positive grade 2-3 (Ki-67 10-55%) advanced gastroenteropancreatic neuroendocrine tumours randomised 2:1 to four cycles of 177Lu-dotatate plus octreotide LAR 30 mg or high-dose octreotide LAR (60 mg). Primary endpoint was PFS by blinded review.\n\nMedian PFS was 22.8 vs 8.5 months (HR 0.28) with an objective response rate of 43% vs 9%. Following NETTER-1 (which established lutetium dotatate in progressive midgut tumours), it moved radioligand therapy to the first line for higher-grade disease, where somatostatin analogues alone are weak.","asOf":"2026-09-08","links":[{"label":"PubMed search: NETTER-2 Lancet 2024","url":"https://pubmed.ncbi.nlm.nih.gov/?term=NETTER-2+lutetium+dotatate+first-line+Singh+Lancet"},{"label":"ClinicalTrials.gov NCT03972488","url":"https://clinicaltrials.gov/study/NCT03972488"}],"tags":[],"related":[],"cancers":["neuroendocrine"],"sections":[],"technologies":["radioligand-therapy","pet-ct"],"targets":["sstr2"],"drugs":["lutathera"],"companies":["novartis"],"institutions":[],"pathways":[],"terms":["theranostics","pfs","orr","first-line","dosimetry"],"trials":[],"people":["oh-do-youn"],"bottlenecks":["b-rare-cancers","b-global-access","b-trial-design"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"authors":"Singh S, Halperin D, Myrehaug S, et al.","paperType":"rct","findings":["Median PFS 22.8 vs 8.5 months; HR 0.28 (95% CI 0.18-0.42).","Objective response 43.0% vs 9.3%.","Benefit consistent in grade 2 and grade 3 tumours and in pancreatic and small-bowel primaries.","Grade 3 or higher adverse events about 35% vs 28%; no cases of treatment-related myelodysplasia or leukaemia at the primary analysis.","Overall survival data immature; crossover to lutetium dotatate was permitted at progression."],"whatItMeans":"Patients newly diagnosed with an advanced grade 2 or 3 neuroendocrine tumour of the gut or pancreas that shows somatostatin receptors on imaging can now receive lutetium dotatate as their first treatment, gaining more than a year of additional disease control and a much higher chance of tumour shrinkage. It does not settle whether radioligand therapy is better than other first-line options such as capecitabine-temozolomide or everolimus, and long-term marrow safety with earlier use needs surveillance.","caveats":["Comparator was high-dose octreotide, which has limited anti-proliferative activity in grade 2-3 tumours.","Overall survival not yet shown; crossover will make it hard to demonstrate.","Long-term risks of earlier radioligand exposure (marrow, kidney, secondary leukaemia) require follow-up.","Requires somatostatin-receptor PET and nuclear medicine capacity; grade 3 tumours with Ki-67 above 55% were excluded."],"changedPractice":true,"participants":226},{"id":"paper-nhs-galleri-design-cancers-2022","kind":"paper","name":"NHS-Galleri: design of the largest randomised trial of a multi-cancer blood test","aka":[],"tldr":"The NHS-Galleri design paper is the protocol for a 140,000-person randomised trial in England testing whether three annual Galleri blood tests reduce late-stage (III-IV) cancer diagnoses, the first MCED trial powered for a stage-shift endpoint.","summary":"NHS-Galleri (ISRCTN91431511) enrolled about 140,000 asymptomatic adults aged 50-77 through NHS England, randomised 1:1 to annual Galleri testing for three years with results returned, or to blood draws stored without testing. The design paper set out the primary endpoint of a reduction in stage III-IV cancer incidence between arms, with secondary endpoints including stage IV incidence, cancer-specific mortality and test performance.\n\nThe trial deliberately over-sampled deprived and ethnically diverse communities using mobile clinics. Results were reported in 2026; the trial record in this corpus tracks the primary and secondary outcomes and the regulatory response.\n\nThe design is important in its own right: it established stage shift as a pragmatic proxy endpoint for screening trials of multi-cancer tests, a choice that remains contested.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.3390/cancers14194818"},{"label":"NHS-Galleri trial site","url":"https://www.nhs-galleri.org"}],"tags":[],"related":["early-detection-roadmap","idea-prev-mced-stage-endpoint-surrogate","idea-prev-mced-registry-randomised"],"cancers":[],"sections":["early-detection"],"technologies":["mced","liquid-biopsy"],"targets":[],"drugs":["galleri"],"companies":[],"institutions":[],"pathways":[],"terms":["stage-shift","ppv"],"trials":["nhs-galleri","pathfinder-2"],"people":[],"bottlenecks":["b-early-detection","b-trial-design","b-overdiagnosis"],"keyPapers":[],"journals":["cancers-mdpi"],"dependsOn":[],"notes":[],"journal":"Cancers","year":2022,"doi":"10.3390/cancers14194818","authors":"Neal RD, Johnson P, Clarke CA, et al.","paperType":"methods","findings":["About 140,000 participants randomised, recruited through mobile clinics across NHS regions in England","Primary endpoint: absolute reduction in stage III-IV cancers in the intervention arm; key secondary endpoint: stage IV incidence","Test results were not returned in the control arm, preserving blinding of the population and clinicians","Population enriched for deprived and minority communities, unusual for a screening trial"],"whatItMeans":"NHS-Galleri is the trial that will decide whether a blood test for many cancers at once should be offered by a health system. Its endpoint is a reduction in late-stage cancer rather than deaths, so even a positive result leaves the mortality question to be settled by longer follow-up.","caveats":["Stage shift is a surrogate: fewer late-stage cancers does not guarantee fewer deaths, and lead-time and overdiagnosis can distort it","Three annual rounds is short for detecting slow-growing cancers","A single commercial test; results may not generalise to other MCED assays","Sponsor involvement in design and analysis (GRAIL) was substantial"],"changedPractice":false,"participants":140000},{"id":"paper-niagara-nejm-2024","kind":"paper","name":"NIAGARA: durvalumab before and after cystectomy for muscle-invasive bladder cancer","aka":[],"tldr":"Adding the immunotherapy durvalumab to chemotherapy before bladder removal, and continuing it afterwards, reduced relapse and death in muscle-invasive bladder cancer, the first improvement on neoadjuvant chemotherapy in two decades.","summary":"Open-label phase 3 trial of 1,063 patients with cisplatin-eligible muscle-invasive bladder cancer randomised to neoadjuvant gemcitabine-cisplatin with or without durvalumab, followed by radical cystectomy and, in the durvalumab arm, eight cycles of adjuvant durvalumab. Primary endpoints were event-free survival and pathological complete response.\n\n24-month EFS was 67.8% vs 59.8% (HR 0.68) and 24-month OS 82.2% vs 75.2% (HR 0.75); pCR was 37.3% vs 27.5%. It made perioperative durvalumab a new standard for cisplatin-eligible patients and, following CheckMate 274 (adjuvant nivolumab), completed the move of checkpoint inhibitors into curative-intent bladder cancer treatment.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2408154"},{"label":"ClinicalTrials.gov NCT03732677","url":"https://clinicaltrials.gov/study/NCT03732677"}],"tags":[],"related":[],"cancers":["urothelial"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","platinum"],"targets":["pdl1"],"drugs":["durvalumab"],"companies":["astrazeneca"],"institutions":["mount-sinai"],"pathways":[],"terms":["efs","pcr","neoadjuvant-adjuvant"],"trials":[],"people":["matthew-galsky"],"bottlenecks":["b-immunotherapy-response","b-trial-design","b-dormancy-mrd"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2408154","authors":"Powles T, Catto JWF, Galsky MD, et al.","paperType":"rct","findings":["24-month event-free survival 67.8% vs 59.8%; HR 0.68 (95% CI 0.56-0.82).","24-month overall survival 82.2% vs 75.2%; HR 0.75 (95% CI 0.59-0.93).","Pathological complete response 37.3% vs 27.5% (the pCR endpoint narrowly missed statistical significance in the initial analysis but was significant on re-analysis of all patients).","Cystectomy was performed in 88% of both arms; durvalumab did not delay surgery or increase surgical complications.","Grade 3-4 treatment-related adverse events about 41% in both arms."],"whatItMeans":"Patients fit enough for cisplatin whose bladder cancer has invaded the muscle wall should now be offered durvalumab with their pre-operative chemotherapy and for about a year after surgery, which improves the chance of cure without compromising the operation. The trial cannot say whether the adjuvant phase is necessary, or how to treat cisplatin-ineligible patients, for whom other trials are ongoing.","caveats":["Open-label; the contribution of the adjuvant phase versus the neoadjuvant phase is not separable.","Cisplatin-ineligible patients (about half of real-world patients) were excluded.","Absolute EFS gain of about 8 points at two years; longer follow-up is needed.","Overlaps with adjuvant nivolumab (CheckMate 274) for patients with residual disease; sequencing is undefined."],"changedPractice":true,"participants":1063},{"id":"paper-niche-2-nejm-2024","kind":"paper","name":"NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients","aka":[],"tldr":"Two doses of immunotherapy over four weeks before surgery left little or no living tumour in 95% of patients with mismatch-repair-deficient colon cancer, and none had relapsed at three years.","summary":"Single-arm phase 2 trial of 115 patients with non-metastatic, mismatch-repair-deficient colon cancer (mostly stage III, including bulky T4 and node-positive tumours) treated with one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) over four weeks, followed by surgery within six weeks. Primary endpoints were safety and three-year disease-free survival.\n\nOf 111 patients evaluable, 109 (98%) had a pathological response, 105 (95%) a major pathological response (10% or less residual tumour), and 75 (68%) a complete response. At three years no patient had relapsed. The result challenges the need for adjuvant chemotherapy in dMMR colon cancer and raises the possibility of avoiding surgery altogether in some patients.","asOf":"2026-09-08","links":[{"label":"NEJM 2024","url":"https://doi.org/10.1056/NEJMoa2400634"},{"label":"ClinicalTrials.gov NCT03026140","url":"https://clinicaltrials.gov/study/NCT03026140"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","ctla4"],"drugs":["nivolumab","ipilimumab"],"companies":["bms"],"institutions":["nki"],"pathways":[],"terms":["msi","pcr","neoadjuvant-adjuvant","irae"],"trials":[],"people":["myriam-chalabi","emile-voest","ton-schumacher","john-haanen"],"bottlenecks":["b-immunotherapy-response","b-surgery-radiation-innovation","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2400634","authors":"Chalabi M, Verschoor YL, Tan PB, et al.","paperType":"rct","findings":["Pathological response in 109 of 111 evaluable patients (98%); major pathological response 95%; pathological complete response 68%.","Three-year disease-free survival 100% at a median follow-up of about 26 months.","Grade 3-4 immune-related adverse events in 4% of patients; 98% underwent surgery on time.","Responses were independent of PD-L1, tumour mutational burden or Lynch syndrome status.","Radiological response underestimated pathological response, as in other neoadjuvant immunotherapy studies."],"whatItMeans":"For colon cancer that is mismatch-repair deficient (about 10-15% of colon cancers, more in older patients), a single short course of immunotherapy before surgery is now a reasonable standard and is far more effective than chemotherapy, which barely works in this subtype. It requires testing every colon cancer for mismatch repair at diagnosis, before surgery. Whether some patients can safely skip surgery, as in dMMR rectal cancer, is the next question.","caveats":["Single-arm phase 2 without a control; the 100% disease-free survival is remarkable but from a single-centre network with limited follow-up.","Surgery was still performed in all patients, so organ preservation is not yet demonstrated in colon cancer.","Requires reliable pre-operative mismatch repair testing and rapid access to immunotherapy, which many systems lack.","Two-drug regimen with ipilimumab; whether nivolumab alone would suffice is untested."],"changedPractice":true,"participants":115},{"id":"paper-niche-2-neoadjuvant-colon-nejm-2024","kind":"paper","name":"NICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patients","aka":[],"tldr":"In NICHE-2, four weeks of checkpoint blockade before surgery eliminated nearly all tumour in 95% of patients with mismatch-repair-deficient colon cancer, and none had relapsed at three years.","summary":"NICHE-2 was a single-arm phase 2 trial at the Netherlands Cancer Institute in 115 patients with non-metastatic, mismatch-repair-deficient colon cancer, most with locally advanced (cT3-4 and/or node-positive) disease. Patients received one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) and underwent surgery within six weeks. The co-primary endpoints were safety (timely surgery) and three-year disease-free survival. Among 111 evaluable patients, 98% had a pathological response, 95% a major pathological response (10% or less residual tumour) and 68% a pathological complete response; 98% had surgery on time, and grade 3-4 immune-related adverse events occurred in 4%. Three-year disease-free survival was 100%. The earlier NICHE study (Chalabi et al., Nature Medicine 2020) had shown pathological responses in 20 of 20 dMMR tumours and, unexpectedly, in 4 of 15 MMR-proficient tumours.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=NICHE-2%20neoadjuvant%20nivolumab%20ipilimumab%20dMMR%20colon%20cancer%20Chalabi%20NEJM%202024"},{"label":"ClinicalTrials.gov NCT03026140","url":"https://clinicaltrials.gov/study/NCT03026140"}],"tags":[],"related":["paper-cercek-dostarlimab-rectal-nejm-2022","paper-le-mmr-deficiency-science-2017"],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","ctla4"],"drugs":["nivolumab","ipilimumab"],"companies":["bms"],"institutions":["nki"],"pathways":[],"terms":["msi","pcr","irae"],"trials":["niche-2"],"people":["myriam-chalabi","ton-schumacher"],"bottlenecks":["b-surgery-radiation-innovation","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"authors":"Chalabi M, Verschoor YL, Tan PB, et al.","paperType":"translational","findings":["115 patients with non-metastatic dMMR colon cancer (74% high-risk stage III); ipilimumab x1 + nivolumab x2, surgery within 6 weeks.","Pathological response 98%; major pathological response 95%; pathological complete response 68%.","Three-year disease-free survival 100% (co-primary endpoint met).","Grade 3-4 immune-related adverse events 4%; 98% had surgery within the planned window.","NICHE (2020): pathological response in 20 of 20 dMMR and 4 of 15 MMR-proficient tumours after the same short course."],"whatItMeans":"NICHE-2 shows that a month of immunotherapy before surgery can effectively cure locally advanced dMMR colon cancer, where chemotherapy after surgery has limited benefit. It is changing guidelines towards neoadjuvant checkpoint blockade for this group and raises the question of whether surgery can be omitted altogether, as in dMMR rectal cancer. Whether the same applies to MMR-proficient tumours is being tested but is not established.","caveats":["Single-arm, single-country study; no randomised comparison with upfront surgery plus adjuvant chemotherapy.","Pathological response is a surrogate; longer follow-up will confirm survival.","Patients still had surgery; organ preservation was not the design.","Only 4% grade 3-4 toxicity with one ipilimumab dose, but late endocrine effects are possible."],"changedPractice":true,"participants":115},{"id":"paper-dangelo-mucosal-melanoma-pooled-jco-2017","kind":"paper","name":"Nivolumab alone or with ipilimumab in mucosal melanoma: pooled analysis","aka":[],"tldr":"Pooling several trials showed that mucosal melanoma responds to nivolumab less often than skin melanoma, but that adding ipilimumab raised the response rate from about a quarter to more than a third, supporting combination immunotherapy first.","summary":"Pooled analysis of 889 patients from six nivolumab trials, including 86 with mucosal melanoma treated with nivolumab monotherapy and 35 with nivolumab plus ipilimumab, compared with 665 and 326 cutaneous melanoma patients.\n\nIn mucosal melanoma, objective response was 23.3 percent with nivolumab and 37.1 percent with the combination (versus 40.9 and 60.4 percent in cutaneous melanoma), with median progression-free survival 3.0 versus 5.9 months.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2017","url":"https://doi.org/10.1200/JCO.2016.67.9258"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28056206/"}],"tags":[],"related":[],"cancers":["mucosal-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["ipilimumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2017,"doi":"10.1200/JCO.2016.67.9258","pmid":"28056206","authors":"D'Angelo SP, Larkin J, Sosman JA, et al.","paperType":"observational","findings":["Mucosal melanoma objective response 23.3 percent (nivolumab) vs 37.1 percent (nivolumab plus ipilimumab).","Median progression-free survival 3.0 vs 5.9 months."],"whatItMeans":"Nivolumab plus ipilimumab is the preferred first-line immunotherapy for mucosal melanoma where tolerated, given its lower intrinsic sensitivity to single-agent PD-1 blockade.","caveats":["Retrospective pooled analysis with small mucosal cohorts."],"changedPractice":true,"participants":889},{"id":"paper-nlst-nejm-2011","kind":"paper","name":"NLST: yearly low-dose CT scans cut lung cancer deaths in heavy smokers","aka":[],"tldr":"Three annual low-dose CT scans reduced lung cancer deaths by a fifth compared with chest X-rays in current and former heavy smokers.","summary":"The National Lung Screening Trial randomised 53,454 current or former smokers aged 55-74 with at least 30 pack-years to three annual screens with low-dose helical CT or chest radiography at 33 US centres.\n\nThe primary endpoint was lung cancer mortality. After a median 6.5 years of follow-up there were 247 lung cancer deaths per 100,000 person-years in the CT arm and 309 in the radiography arm, a 20% relative reduction; all-cause mortality also fell by 6.7%. The trial was stopped early for benefit.\n\nNLST is the evidence base for US Preventive Services Task Force lung screening recommendations and for national programmes that followed.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1102873"},{"label":"ClinicalTrials.gov NCT00047385","url":"https://clinicaltrials.gov/study/NCT00047385"}],"tags":[],"related":["cdas-nlst-plco","idea-prev-lung-screening-risk-model-eligibility","idea-prev-mobile-lung-screening-deprived-areas"],"cancers":["nsclc","sclc"],"sections":["early-detection","prevention"],"technologies":["low-dose-ct-screening","ct"],"targets":[],"drugs":[],"companies":[],"institutions":["nci"],"pathways":[],"terms":["ppv","stage-shift"],"trials":["nlst-nelson"],"people":[],"bottlenecks":["b-early-detection","b-overdiagnosis","b-prevention-adoption"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1102873","pmid":"21714641","authors":"Aberle DR, Adams AM, Berg CD, et al. (National Lung Screening Trial Research Team)","paperType":"rct","findings":["Lung cancer mortality reduced by 20.0% (95% CI 6.8-26.7) with low-dose CT versus chest radiography","All-cause mortality reduced by 6.7% (95% CI 1.2-13.6)","24.2% of CT screens were positive, and 96.4% of positive screens were false positives","Roughly 320 people had to be screened to prevent one lung cancer death over the trial period"],"whatItMeans":"For people with a heavy smoking history, an annual low-dose CT scan is one of the few screening tests proven to reduce cancer deaths. Most abnormal scans are not cancer, so screening must be paired with careful nodule management. It does not apply to never-smokers or light smokers.","caveats":["High false-positive rate with the 4 mm nodule threshold used in 2002-2004; modern Lung-RADS criteria reduce this","Comparator was chest X-ray, itself of no proven benefit, so the effect versus no screening may differ","Participants were younger, better educated and more often former smokers than the US smoking population","Uptake of screening among eligible people remains low in most countries"],"changedPractice":true,"participants":53454},{"id":"paper-esmo-non-epithelial-ovarian-ray-coquard-ann-oncol-2018","kind":"paper","name":"Non-epithelial ovarian cancer: ESMO clinical practice guidelines","aka":[],"tldr":"The ESMO guideline on the rarer ovarian cancers, including granulosa cell and other sex cord-stromal tumours and germ cell tumours, sets out surgery, when chemotherapy is needed, fertility preservation and long-term follow-up.","summary":"Evidence-based guideline covering diagnosis, staging, surgical management including fertility-sparing surgery, adjuvant and recurrent-disease chemotherapy, hormonal therapy and follow-up for malignant germ cell tumours and sex cord-stromal tumours of the ovary.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2018","url":"https://doi.org/10.1093/annonc/mdy001"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29697741/"}],"tags":[],"related":[],"cancers":["granulosa-cell-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2018,"doi":"10.1093/annonc/mdy001","pmid":"29697741","authors":"Ray-Coquard I, Morice P, Lorusso D, et al.","paperType":"guideline","findings":[],"whatItMeans":"The observation after complete surgery for stage I granulosa cell tumour, lifelong inhibin monitoring and endocrine or bevacizumab-based options at relapse follow this guideline.","caveats":["Evidence in sex cord-stromal tumours is largely retrospective."],"changedPractice":true},{"id":"paper-nordic-nec-sorbye-ann-oncol-2013","kind":"paper","name":"NORDIC NEC: predictive and prognostic factors in 305 patients with advanced gastrointestinal neuroendocrine carcinoma","aka":[],"tldr":"This large Nordic series showed that gastrointestinal neuroendocrine carcinomas with a Ki-67 below 55 percent respond poorly to platinum-etoposide yet live longer than those above it, which led to the separation of grade 3 neuroendocrine tumours from carcinomas.","summary":"Retrospective analysis of 305 patients with advanced gastrointestinal high-grade (grade 3) neuroendocrine carcinoma treated at Nordic centres, examining response to first-line platinum-based chemotherapy and survival by clinical and pathological features.\n\nResponse to platinum chemotherapy was 42 percent for Ki-67 of 55 percent or more but 15 percent below it, while survival was longer in the lower Ki-67 group (median 14 versus 10 months); performance status, primary site and lactate dehydrogenase were also prognostic.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2013","url":"https://doi.org/10.1093/annonc/mds276"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22967994/"}],"tags":[],"related":[],"cancers":["extrapulmonary-nec"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2013,"doi":"10.1093/annonc/mds276","pmid":"22967994","authors":"Sorbye H, Welin S, Langer SW, et al.","paperType":"observational","findings":["Response to platinum chemotherapy 42 percent with Ki-67 of 55 percent or more vs 15 percent below.","Median survival 14 months with Ki-67 under 55 percent vs 10 months above."],"whatItMeans":"The 55 percent Ki-67 threshold and the recognition that well-differentiated grade 3 tumours behave differently from carcinomas, now embedded in the WHO classification, came from this analysis.","caveats":["Retrospective; morphology (well versus poorly differentiated) was not systematically recorded."],"changedPractice":true,"participants":305},{"id":"paper-nordicc-nejm-2022","kind":"paper","name":"NordICC: inviting people to a screening colonoscopy reduced bowel cancer, but less than expected","aka":[],"tldr":"NordICC, the first randomised trial of colonoscopy screening, invited 84,585 people aged 55 to 64 to a single colonoscopy or to no screening. Bowel cancer incidence fell 18% over ten years among those invited, but only 42% attended, and the fall in bowel cancer deaths did not reach statistical significance, fuelling debate over colonoscopy versus stool-test programmes.","summary":"NordICC randomised 84,585 people aged 55-64 in Poland, Norway and Sweden to an invitation to a single screening colonoscopy or to usual care with no screening. The primary endpoints were colorectal cancer incidence and death at 10 years, analysed by intention to screen.\n\nThe 10-year risk of colorectal cancer was 0.98% in the invited group and 1.20% in usual care (risk ratio 0.82). Colorectal cancer death was 0.28% versus 0.31%, not significantly different. In the adjusted per-protocol analysis, assuming everyone invited had attended, incidence fell 31% and death 50%.\n\nThe trial prompted a wide debate about the real-world effect of colonoscopy programmes versus stool-test programmes.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa2208375"},{"label":"ClinicalTrials.gov NCT00883792","url":"https://clinicaltrials.gov/study/NCT00883792"}],"tags":[],"related":["paper-minnesota-fobt-nejm-1993","idea-prev-fit-risk-adapted-thresholds","idea-prev-screening-default-appointments"],"cancers":["colorectal"],"sections":["early-detection"],"technologies":["colorectal-screening"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["fit-test"],"trials":[],"people":[],"bottlenecks":["b-early-detection","b-prevention-adoption","b-overdiagnosis"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2208375","pmid":"36214590","authors":"Bretthauer M, Løberg M, Wieszczy P, et al.","paperType":"rct","findings":["Colorectal cancer incidence at 10 years: 0.98% vs 1.20% (RR 0.82, 95% CI 0.70-0.93) by intention to screen","Colorectal cancer death: 0.28% vs 0.31% (RR 0.90, 95% CI 0.64-1.16)","Only 42% of those invited underwent colonoscopy","Adjusted per-protocol estimate: incidence RR 0.69, death RR 0.50 among those who attended","Number needed to invite to prevent one cancer over 10 years: 455"],"whatItMeans":"A colonoscopy probably does reduce bowel cancer risk for the person who has it, but a programme that offers colonoscopy achieves much less if most people decline. Programmes based on stool tests with high uptake may deliver as much population benefit at lower cost and risk.","caveats":["Low participation dilutes the intention-to-screen effect; the per-protocol estimate relies on modelling assumptions","Ten years is short for a mortality endpoint after polyp removal; a 15-year analysis is planned","Adenoma detection rates varied between endoscopists and some were below quality thresholds","Results apply to a one-off colonoscopy at 55-64, not to repeated colonoscopy programmes as practised in the US"],"changedPractice":false,"participants":84585},{"id":"paper-tallman-atra-apl-nejm-1997","kind":"paper","name":"North American Intergroup: all-trans retinoic acid in acute promyelocytic leukaemia","aka":[],"tldr":"This randomised trial showed that the vitamin A derivative retinoic acid, used in induction and as maintenance, sharply improved survival in acute promyelocytic leukaemia compared with chemotherapy alone.","summary":"Phase 3 trial of 346 patients with newly diagnosed APL randomised to induction with all-trans retinoic acid or with daunorubicin plus cytarabine, and then to maintenance retinoic acid or observation.\n\nThree-year disease-free survival was 67 percent after retinoic acid induction against 32 percent after chemotherapy, and maintenance retinoic acid further reduced relapse. The trial established retinoic acid as essential to APL therapy.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 1997","url":"https://doi.org/10.1056/NEJM199710093371501"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/9321529/"}],"tags":[],"related":[],"cancers":["apl"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1997,"doi":"10.1056/NEJM199710093371501","pmid":"9321529","authors":"Tallman MS, Andersen JW, Schiffer CA, et al.","paperType":"rct","findings":["Three-year disease-free survival 67 percent with retinoic acid induction vs 32 percent with chemotherapy induction.","Maintenance retinoic acid improved disease-free survival compared with observation."],"whatItMeans":"Differentiation therapy, making leukaemic cells mature rather than killing them, became the first targeted treatment in leukaemia. Every modern APL regimen starts with retinoic acid on suspicion of the diagnosis.","caveats":["Retinoic acid syndrome caused deaths before steroid prophylaxis became routine.","Modern regimens combine retinoic acid with arsenic trioxide, which was not available at the time."],"changedPractice":true,"participants":346},{"id":"paper-nrg-cc001-brown-jco-2020","kind":"paper","name":"NRG CC001: hippocampal-avoidance whole-brain radiotherapy plus memantine for brain metastases","aka":[],"tldr":"When whole-brain radiotherapy is needed, shaping the beams to spare the hippocampus and adding memantine reduced the memory and thinking decline that the treatment causes, with no loss of tumour control.","summary":"Phase 3 trial of 518 patients with brain metastases randomised to whole-brain radiotherapy with memantine, with or without hippocampal avoidance using intensity-modulated techniques.\n\nCognitive failure was less frequent with hippocampal avoidance (hazard ratio 0.74), driven by less decline in executive function and memory, with no difference in overall survival, intracranial progression or toxicity.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2020","url":"https://doi.org/10.1200/JCO.19.02767"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32058845/"}],"tags":[],"related":[],"cancers":["secondary-brain-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["nrg-cc001"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2020,"doi":"10.1200/JCO.19.02767","pmid":"32058845","authors":"Brown PD, Gondi V, Pugh S, et al.","paperType":"rct","findings":["Risk of cognitive failure reduced by 26 percent with hippocampal avoidance.","No difference in survival or intracranial progression."],"whatItMeans":"Where whole-brain radiotherapy is still chosen, for many metastases or leptomeningeal disease, hippocampal avoidance with memantine is the recommended technique.","caveats":["Excluded patients with metastases within 5 mm of the hippocampus.","Requires intensity-modulated planning capability."],"changedPractice":true,"participants":518},{"id":"paper-rtog-1016-lancet-2019","kind":"paper","name":"NRG Oncology RTOG 1016: radiotherapy plus cetuximab versus cisplatin in HPV-positive oropharyngeal cancer","aka":[],"tldr":"Trying to reduce toxicity by swapping cisplatin for cetuximab during radiotherapy in HPV-positive oropharyngeal cancer backfired: cetuximab gave worse survival and more recurrences with no reduction in toxicity, so cisplatin remains standard.","summary":"Phase 3 non-inferiority trial of 849 patients with HPV-positive (p16-positive) oropharyngeal cancer randomised to accelerated intensity-modulated radiotherapy with cisplatin or with cetuximab.\n\nFive-year overall survival was 77.9 percent with cetuximab against 84.6 percent with cisplatin (hazard ratio 1.45, non-inferiority not met) and five-year locoregional failure 17.3 versus 9.9 percent; acute and late toxicity rates were similar.","asOf":"2026-09-17","links":[{"label":"Lancet 2019","url":"https://doi.org/10.1016/S0140-6736(18)32779-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30449625/"}],"tags":[],"related":[],"cancers":["hpv-positive-oropharyngeal-cancer","oropharyngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["cetuximab","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rtog-1016"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2019,"doi":"10.1016/S0140-6736(18)32779-X","pmid":"30449625","authors":"Gillison ML, Trotti AM, Harris J, et al.","paperType":"rct","findings":["Five-year overall survival 77.9 percent (cetuximab) vs 84.6 percent (cisplatin); hazard ratio 1.45.","Five-year locoregional failure 17.3 percent vs 9.9 percent."],"whatItMeans":"Cisplatin chemoradiation is the standard for HPV-positive oropharyngeal cancer; cetuximab is reserved for patients who cannot receive cisplatin.","caveats":["Accelerated radiotherapy fractionation differs from standard practice in some countries."],"changedPractice":true,"participants":849},{"id":"paper-nrg-gy018-nejm-2023","kind":"paper","name":"NRG-GY018: pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer","aka":[],"tldr":"Adding pembrolizumab to carboplatin-paclitaxel and continuing it as maintenance cut the risk of progression by 70 percent in mismatch repair-deficient endometrial cancer and by 46 percent in mismatch repair-proficient disease.","summary":"Phase 3 placebo-controlled trial of 816 patients with measurable stage III to IVA, stage IVB or recurrent endometrial cancer randomised to pembrolizumab or placebo with carboplatin-paclitaxel followed by up to 14 maintenance cycles, analysed separately by mismatch repair status.\n\nIn mismatch repair-deficient disease, 12-month progression-free survival was 74 versus 38 percent (hazard ratio 0.30); in proficient disease median progression-free survival was 13.1 versus 8.7 months (hazard ratio 0.54).","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2302312"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36972022/"}],"tags":[],"related":[],"cancers":["advanced-recurrent-endometrial-cancer","endometrial-mmr-deficient","endometrial-nsmp"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2302312","pmid":"36972022","authors":"Eskander RN, Sill MW, Beffa L, et al.","paperType":"rct","findings":["Mismatch repair-deficient: progression-free survival hazard ratio 0.30.","Mismatch repair-proficient: median progression-free survival 13.1 vs 8.7 months; hazard ratio 0.54."],"whatItMeans":"Together with RUBY, this trial made chemo-immunotherapy the first-line standard for advanced endometrial cancer in both molecular groups, with the largest effect in mismatch repair-deficient tumours.","caveats":["Overall survival data were immature at first report.","Excluded carcinosarcoma, unlike RUBY."],"changedPractice":true,"participants":816},{"id":"paper-dangelo-ny-eso-1-tcr-synovial-sarcoma-cancer-discov-2018","kind":"paper","name":"NY-ESO-1 c259 T-cell receptor therapy in synovial sarcoma: prolonged persistence and antitumour activity","aka":[],"tldr":"Engineering patients' own T cells with a receptor recognising the NY-ESO-1 antigen shrank tumours in half of a small group with advanced synovial sarcoma, the first convincing evidence that T-cell receptor therapy can work in a solid tumour.","summary":"Pilot study of 12 patients with HLA-A*02-positive, NY-ESO-1-expressing advanced synovial sarcoma treated with autologous T cells transduced with an affinity-enhanced NY-ESO-1 c259 T-cell receptor after lymphodepleting chemotherapy.\n\nObjective response was 50 percent including one complete response, with responses associated with T-cell persistence and higher lymphodepletion intensity; toxicity included cytokine release syndrome and cytopenias.","asOf":"2026-09-17","links":[{"label":"Cancer Discov 2018","url":"https://doi.org/10.1158/2159-8290.CD-17-1417"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29891538/"}],"tags":[],"related":[],"cancers":["synovial-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2018,"doi":"10.1158/2159-8290.CD-17-1417","pmid":"29891538","authors":"D'Angelo SP, Melchiori L, Merchant MS, et al.","paperType":"observational","findings":["Objective response 6 of 12 patients (50 percent), one complete response.","Response correlated with T-cell persistence and lymphodepletion dose."],"whatItMeans":"This study opened the path to engineered T-cell receptor therapy in synovial sarcoma, leading to afamitresgene autoleucel targeting MAGE-A4 (SPEARHEAD-1) and its approval in 2024.","caveats":["Twelve patients; requires HLA-A*02 and antigen expression."],"changedPractice":true,"participants":12},{"id":"paper-olympia-nejm-2021","kind":"paper","name":"OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer","aka":[],"tldr":"In women born with a BRCA1 or BRCA2 mutation whose early breast cancer was high risk, a year of the PARP inhibitor olaparib after standard treatment cut relapses by more than 40% and later improved survival.","summary":"Double-blind, placebo-controlled phase 3 trial of 1,836 patients with germline BRCA1/2 mutations and HER2-negative early breast cancer at high risk of recurrence, randomised to one year of olaparib or placebo after completing local therapy and chemotherapy. Primary endpoint was invasive disease-free survival.\n\nThree-year iDFS was 85.9% vs 77.1% (HR 0.58) and distant disease-free survival 87.5% vs 80.4%. A 2022 update showed improved overall survival (HR 0.68). It was the first adjuvant PARP inhibitor and made germline testing part of treatment planning rather than only risk counselling.","asOf":"2026-09-08","links":[{"label":"NEJM 2021","url":"https://doi.org/10.1056/NEJMoa2105215"},{"label":"ClinicalTrials.gov NCT02032823","url":"https://clinicaltrials.gov/study/NCT02032823"}],"tags":[],"related":[],"cancers":["tnbc","breast-hr-positive"],"sections":[],"technologies":["parp-inhibitor","germline-testing","synthetic-lethality-approaches"],"targets":["parp","brca"],"drugs":["olaparib"],"companies":["astrazeneca","merck"],"institutions":[],"pathways":[],"terms":["germline-vs-somatic","synthetic-lethality","neoadjuvant-adjuvant","rcb"],"trials":["olympia"],"people":["andrew-tutt","judy-garber","evandro-de-azambuja","susan-domchek","shao-zhi-ming","sibylle-loibl","martine-piccart","charles-geyer"],"bottlenecks":["b-hereditary-risk","b-dormancy-mrd"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2105215","authors":"Tutt ANJ, Garber JE, Kaufman B, et al.","paperType":"rct","findings":["Three-year invasive disease-free survival 85.9% vs 77.1%, an 8.8-point gain; HR 0.58 (99.5% CI 0.41-0.82).","Three-year distant disease-free survival 87.5% vs 80.4%; HR 0.57.","Overall survival HR 0.68 at the second interim analysis (2022), with 4-year OS 89.8% vs 86.4%.","Fewer new primary cancers, including ovarian, in the olaparib arm.","Olaparib was generally well tolerated; anaemia was the main grade 3 toxicity and no excess of myelodysplasia or leukaemia was seen at this follow-up."],"whatItMeans":"Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.","caveats":["Most patients had not received platinum chemotherapy or pembrolizumab, so the benefit alongside the current KEYNOTE-522 regimen is extrapolated.","Long-term risk of second haematological malignancies with PARP inhibitors needs continued surveillance.","The hormone-receptor-positive subgroup was small (under a fifth of patients) and its benefit is less certain.","Access to germline testing is uneven, particularly in lower-income settings."],"changedPractice":true,"participants":1836},{"id":"paper-olympiad-nejm-2017","kind":"paper","name":"OlympiAD: olaparib versus chemotherapy in metastatic breast cancer with a germline BRCA mutation","aka":[],"tldr":"In women with metastatic HER2-negative breast cancer and an inherited BRCA mutation, the PARP inhibitor tablet olaparib delayed progression by almost three months compared with chemotherapy and caused fewer severe side effects.","summary":"Phase 3 trial of 302 patients with HER2-negative metastatic breast cancer and a germline BRCA1 or BRCA2 mutation, previously treated with up to two chemotherapy lines, randomised 2:1 to olaparib or single-agent chemotherapy of physician's choice.\n\nMedian progression-free survival was 7.0 versus 4.2 months (hazard ratio 0.58) with a response rate of 59.9 versus 28.8 percent; overall survival was not significantly different, though a benefit appeared in patients who had not received chemotherapy for metastatic disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1706450"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28578601/"}],"tags":[],"related":[],"cancers":["tnbc-metastatic"],"sections":[],"technologies":[],"targets":[],"drugs":["olaparib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["olympiad"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1706450","pmid":"28578601","authors":"Robson M, Im SA, Senkus E, et al.","paperType":"rct","findings":["Median progression-free survival 7.0 vs 4.2 months; hazard ratio 0.58.","Objective response 59.9 percent vs 28.8 percent; grade 3 or worse adverse events 36.6 percent vs 50.5 percent."],"whatItMeans":"Germline BRCA testing became part of metastatic breast cancer work-up, and olaparib (with talazoparib after EMBRACA) is a standard option, especially for triple-negative disease.","caveats":["No overall survival benefit in the whole population.","Platinum chemotherapy was not in the comparator arm."],"changedPractice":true,"participants":302},{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","aka":[],"tldr":"Using disulfide-tethering screens, Shokat's laboratory found small molecules that bind covalently to the mutant cysteine of KRAS G12C in a previously unknown pocket beneath switch II, locking the oncoprotein in its inactive GDP-bound state.","summary":"KRAS had been considered undruggable for three decades because it binds GTP with picomolar affinity and has no obvious deep pocket. Ostrem and colleagues exploited the cysteine introduced by the G12C mutation, present in about 13% of lung adenocarcinomas, screening a library of cysteine-reactive fragments by tethering.\n\nCrystal structures revealed that the hits bound in a cryptic pocket (switch-II pocket, S-IIP) that exists only in the GDP-bound state. The compounds impaired SOS-catalysed nucleotide exchange, shifted KRAS towards GDP binding, and reduced Raf effector binding, selectively killing G12C-mutant cells. The compounds were weak but demonstrated mechanism.\n\nThis work led directly to ARS-853, ARS-1620 and then sotorasib (approved 2021) and adagrasib (2022), the first KRAS inhibitors, and inspired covalent and non-covalent approaches to other RAS mutants.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1038/nature12796"}],"tags":[],"related":["paper-drug-dosing-conundrum-nejm-2021"],"cancers":["nsclc","colorectal","pancreatic"],"sections":["targeted-therapy","drug-discovery"],"technologies":["kras-inhibitors","kinase-inhibitors"],"targets":["kras"],"drugs":["sotorasib","adagrasib","daraxonrasib"],"companies":[],"institutions":["ucsf"],"pathways":["ras-mapk"],"terms":[],"trials":[],"people":["kevan-shokat"],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2013,"doi":"10.1038/nature12796","pmid":"24256730","authors":"Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM","paperType":"basic","findings":["Identified covalent compounds binding cysteine 12 of KRAS G12C in a cryptic switch-II pocket visible only in the GDP-bound state","Compounds impaired SOS-mediated nucleotide exchange and shifted the nucleotide preference from GTP to GDP","Effector (Raf) binding was decreased and G12C-mutant cell viability selectively reduced","Mutant-specific mechanism: wild-type KRAS was unaffected, giving a therapeutic window"],"whatItMeans":"The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.","caveats":["The original compounds were micromolar tools, not drugs; a decade of medicinal chemistry was required","Applies only to G12C; other KRAS mutants lack a reactive cysteine, though pan-RAS(ON) inhibitors are now emerging","Clinical responses to G12C inhibitors are shorter than for EGFR or ALK inhibitors, and resistance is rapid","Tumour-type dependence: colorectal G12C cancers respond poorly to monotherapy"],"changedPractice":false},{"id":"paper-outback-lancet-oncol-2023","kind":"paper","name":"OUTBACK: adjuvant carboplatin-paclitaxel after chemoradiotherapy for locally advanced cervical cancer","aka":[],"tldr":"Adding four cycles of carboplatin-paclitaxel chemotherapy after standard chemoradiation did not improve survival in locally advanced cervical cancer and caused more side effects, so adjuvant chemotherapy is not recommended.","summary":"Phase 3 trial of 919 women with locally advanced cervical cancer randomised to cisplatin chemoradiotherapy alone or followed by four cycles of adjuvant carboplatin and paclitaxel.\n\nFive-year overall survival was 72 versus 71 percent and progression-free survival 63 versus 61 percent, with more grade 3 to 5 adverse events with adjuvant chemotherapy (81 versus 62 percent) and a fifth of patients never starting it.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2023","url":"https://doi.org/10.1016/S1470-2045(23)00147-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37080223/"}],"tags":[],"related":[],"cancers":["locally-advanced-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["outback"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2023,"doi":"10.1016/S1470-2045(23)00147-X","pmid":"37080223","authors":"Mileshkin LR, Moore KN, Barnes EH, et al.","paperType":"rct","findings":["Five-year overall survival 72 percent vs 71 percent.","Grade 3 to 5 adverse events 81 percent vs 62 percent."],"whatItMeans":"Chemotherapy after chemoradiation adds toxicity without benefit; the search for improvement has moved to induction chemotherapy (INTERLACE) and immunotherapy (KEYNOTE-A18).","caveats":["Compliance with adjuvant chemotherapy was incomplete, which may have diluted any effect."],"changedPractice":true,"participants":919},{"id":"paper-maniakas-neoadjuvant-braf-atc-jama-oncol-2020","kind":"paper","name":"Overall survival in anaplastic thyroid carcinoma 2000 to 2019: impact of targeted therapy and neoadjuvant BRAF-MEK inhibition","aka":[],"tldr":"At MD Anderson, survival in anaplastic thyroid cancer improved dramatically over two decades as BRAF testing, targeted therapy and neoadjuvant BRAF-MEK inhibition followed by surgery were introduced, with one-year survival rising from 35 to 59 percent.","summary":"Retrospective cohort study of 479 patients with anaplastic thyroid carcinoma treated at a single centre between 2000 and 2019, divided into three eras, examining the association of targeted therapy, immunotherapy and neoadjuvant BRAF-MEK inhibitor therapy with survival.\n\nOne-year overall survival rose from 35 percent (2000 to 2013) to 47 percent (2014 to 2016) and 59 percent (2017 to 2019); BRAF-mutant patients treated with neoadjuvant BRAF-directed therapy and surgery had 94 percent one-year survival.","asOf":"2026-09-17","links":[{"label":"JAMA Oncol 2020","url":"https://doi.org/10.1001/jamaoncol.2020.3362"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32761153/"}],"tags":[],"related":[],"cancers":["anaplastic-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2020,"doi":"10.1001/jamaoncol.2020.3362","pmid":"32761153","authors":"Maniakas A, Dadu R, Busaidy NL, et al.","paperType":"observational","findings":["One-year overall survival 35 percent, 47 percent and 59 percent across three eras.","Neoadjuvant BRAF-directed therapy with surgery: one-year survival 94 percent."],"whatItMeans":"Neoadjuvant dabrafenib-trametinib to convert unresectable BRAF-mutant anaplastic thyroid cancer into operable disease is now a guideline-endorsed strategy.","caveats":["Single-centre retrospective data with era and selection effects."],"changedPractice":true,"participants":479},{"id":"paper-pace-ponatinib-nejm-2013","kind":"paper","name":"PACE: ponatinib in Philadelphia chromosome-positive leukaemias resistant to earlier tyrosine kinase inhibitors","aka":[],"tldr":"Ponatinib produced deep responses in patients with chronic myeloid leukaemia or Philadelphia-positive acute lymphoblastic leukaemia whose disease had resisted other kinase inhibitors, including the T315I mutation that no other drug could reach.","summary":"Phase 2 study of 449 heavily pretreated patients with chronic, accelerated or blast-phase CML or Ph-positive ALL, including 128 with the T315I gatekeeper mutation, treated with ponatinib 45 mg daily.\n\nIn chronic phase, 56 percent achieved a major cytogenetic response (70 percent of those with T315I); responses in accelerated and blast phase were lower and shorter. Arterial occlusive events emerged as the defining toxicity, later prompting dose reduction strategies.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2013","url":"https://doi.org/10.1056/NEJMoa1306494"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24180494/"}],"tags":[],"related":[],"cancers":["cml-advanced-phase"],"sections":[],"technologies":[],"targets":[],"drugs":["ponatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2013,"doi":"10.1056/NEJMoa1306494","pmid":"24180494","authors":"Cortes JE, Kim DW, Pinilla-Ibarz J, et al.","paperType":"observational","findings":["Major cytogenetic response in 56 percent of chronic-phase patients and 70 percent of those with T315I.","Major haematological response in 55 percent of accelerated-phase and 31 percent of blast-phase or Ph-positive ALL patients."],"whatItMeans":"Ponatinib is the drug for T315I-mutated disease and for patients who have failed several inhibitors, including in accelerated and blast phase as a bridge to transplant. Cardiovascular risk must be managed actively.","caveats":["Serious arterial thrombotic events in a substantial minority, increasing with time on treatment.","Single-arm design; response-based dose reduction (OPTIC) came later."],"changedPractice":true,"participants":449},{"id":"paper-pacific-nejm-2017","kind":"paper","name":"PACIFIC: a year of durvalumab after chemoradiotherapy for stage III lung cancer","aka":[],"tldr":"Giving the immunotherapy durvalumab for a year after chemoradiotherapy for unresectable stage III lung cancer tripled the time to progression and raised five-year survival from about a third to over 40%.","summary":"Double-blind, placebo-controlled phase 3 trial of 713 patients with unresectable stage III NSCLC who had not progressed after concurrent platinum-based chemoradiotherapy, randomised 2:1 to up to 12 months of durvalumab or placebo. Co-primary endpoints were PFS and overall survival.\n\nMedian PFS was 16.8 vs 5.6 months (HR 0.52) and overall survival was significantly improved (HR 0.68 in the 2018 report). Five-year OS was 42.9% vs 33.4%. It was the first change in stage III standard of care in two decades and the model for consolidation immunotherapy in small-cell lung cancer (ADRIATIC) and other tumours.","asOf":"2026-09-08","links":[{"label":"NEJM 2017","url":"https://doi.org/10.1056/NEJMoa1709937"},{"label":"NEJM 2018 (OS)","url":"https://doi.org/10.1056/NEJMoa1809697"},{"label":"ClinicalTrials.gov NCT02125461","url":"https://clinicaltrials.gov/study/NCT02125461"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["checkpoint-inhibitor","imrt-igrt","platinum"],"targets":["pdl1"],"drugs":["durvalumab"],"companies":["astrazeneca"],"institutions":[],"pathways":[],"terms":["pfs","os","standard-of-care","irae"],"trials":[],"people":["cho-byoung-chul"],"bottlenecks":["b-immunotherapy-response","b-surgery-radiation-innovation","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1709937","authors":"Antonia SJ, Villegas A, Daniel D, et al.","paperType":"rct","findings":["Median PFS 16.8 vs 5.6 months; HR 0.52 (95% CI 0.42-0.65).","Overall survival (2018): HR 0.68; 24-month OS 66.3% vs 55.6%.","Five-year update (JCO 2022): OS 42.9% vs 33.4%; PFS 33.1% vs 19.0%.","Grade 3-4 pneumonitis or radiation pneumonitis 3.4% vs 2.6%; any-grade pneumonitis about 34% vs 25%.","Post hoc analysis suggested little benefit in PD-L1 below 1%, leading the EMA (but not FDA) to restrict the label to PD-L1 of 1% or more."],"whatItMeans":"Patients with stage III lung cancer that cannot be removed surgically should receive a year of durvalumab after completing chemoradiotherapy, provided they have not progressed. This roughly doubles the chance of being alive without progression at five years. Whether the benefit extends to PD-L1-negative tumours is contested, and the EGFR-mutated subgroup is better served by osimertinib (LAURA).","caveats":["PD-L1 status was not required for enrolment and the subgroup analysis by PD-L1 below 1% was unplanned and post hoc.","Patients had to have completed chemoradiotherapy without progression, a selected fitter population.","Combined radiation and immune pneumonitis requires careful monitoring, especially in Asian populations where rates were higher.","The trial did not test whether concurrent immunotherapy during radiotherapy is better; PACIFIC-2 was negative."],"changedPractice":true,"participants":713},{"id":"paper-kothari-paget-disease-nipple-multifocal-cancer-2002","kind":"paper","name":"Paget disease of the nipple as a marker of multifocal, higher-risk underlying breast cancer","aka":[],"tldr":"This pathological study found that the cancer underlying Paget disease of the nipple is often multifocal and spread away from the nipple, which is why full imaging and careful surgical planning are needed rather than simple nipple excision.","summary":"Review of 70 mastectomy specimens with Paget disease of the nipple, mapping the extent and location of the underlying in situ and invasive carcinoma.\n\nMost cases had underlying carcinoma, frequently multifocal and often distant from the nipple, with a high proportion of high-grade and HER2-positive tumours, arguing that Paget disease marks a higher-risk breast.","asOf":"2026-09-17","links":[{"label":"Cancer 2002","url":"https://doi.org/10.1002/cncr.10638"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12115309/"}],"tags":[],"related":[],"cancers":["paget-disease-of-the-nipple"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-wiley"],"dependsOn":[],"notes":[],"journal":"Cancer","year":2002,"doi":"10.1002/cncr.10638","pmid":"12115309","authors":"Kothari AS, Beechey-Newman N, Hamed H, et al.","paperType":"observational","findings":[],"whatItMeans":"Breast MRI to map disease and central excision with clear margins or mastectomy, rather than removing the nipple alone, follow from findings like these.","caveats":["Single-institution mastectomy series, which selects for more extensive disease."],"changedPractice":false,"participants":70},{"id":"paper-paola-1-nejm-2019","kind":"paper","name":"PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours","aka":[],"tldr":"Adding the PARP inhibitor olaparib to bevacizumab after first-line chemotherapy for advanced ovarian cancer roughly doubled the time without progression in women whose tumours had defective DNA repair, but did nothing for those without it.","summary":"Double-blind, placebo-controlled phase 3 trial of 806 patients with newly diagnosed advanced high-grade ovarian cancer who had responded to platinum-taxane chemotherapy with bevacizumab, randomised 2:1 to two years of olaparib or placebo added to bevacizumab maintenance. Primary endpoint was investigator-assessed PFS.\n\nMedian PFS was 22.1 vs 16.6 months overall (HR 0.59), but 37.2 vs 17.7 months (HR 0.33) in homologous-recombination-deficient (HRD) tumours and no different in HRD-negative tumours (HR 1.00). The 2023 OS analysis showed a survival benefit in HRD-positive disease (5-year OS 65.5% vs 48.4%, HR 0.62). It established HRD testing as a decision tool and olaparib plus bevacizumab as a first-line maintenance standard for HRD-positive ovarian cancer.","asOf":"2026-09-08","links":[{"label":"NEJM 2019","url":"https://doi.org/10.1056/NEJMoa1911361"},{"label":"ClinicalTrials.gov NCT02477644","url":"https://clinicaltrials.gov/study/NCT02477644"}],"tags":[],"related":[],"cancers":["ovarian"],"sections":[],"technologies":["parp-inhibitor","hrd-testing","antiangiogenic","synthetic-lethality-approaches"],"targets":["parp","brca","vegf"],"drugs":["olaparib"],"companies":["astrazeneca","merck"],"institutions":["gemelli"],"pathways":[],"terms":["hrd","synthetic-lethality","pfs","os","germline-vs-somatic"],"trials":[],"people":["giovanni-scambia"],"bottlenecks":["b-biomarker-validation","b-dormancy-mrd","b-drug-pricing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1911361","authors":"Ray-Coquard I, Pautier P, Pignata S, et al.","paperType":"rct","findings":["Overall population: median PFS 22.1 vs 16.6 months; HR 0.59 (95% CI 0.49-0.72).","HRD-positive (including BRCA-mutated): median PFS 37.2 vs 17.7 months; HR 0.33.","HRD-positive without BRCA mutation: median PFS 28.1 vs 16.6 months; HR 0.43.","HRD-negative or unknown: no benefit (HR about 1.0).","Overall survival (Annals of Oncology 2023): HRD-positive 5-year OS 65.5% vs 48.4%, HR 0.62; no OS benefit in the ITT population (HR 0.92)."],"whatItMeans":"Women with newly diagnosed advanced ovarian cancer should have their tumour tested for BRCA mutations and homologous recombination deficiency, because those who are HRD-positive gain years of additional disease control and better survival from adding olaparib to bevacizumab maintenance. Those who are HRD-negative gain nothing from olaparib in this combination and should not be exposed to its toxicity and cost. HRD testing has become a routine part of ovarian cancer care as a result.","caveats":["HRD assays (Myriad myChoice and alternatives) have imperfect concordance and a substantial proportion of tests are inconclusive.","All patients received bevacizumab, so the trial cannot say whether olaparib alone would be as good in HRD-positive non-BRCA tumours (PRIMA suggests niraparib alone works).","No ITT overall survival benefit; the HRD-positive OS result is from a prespecified subgroup.","Two years of olaparib plus bevacizumab is expensive and adds anaemia, fatigue and nausea."],"changedPractice":true,"participants":806},{"id":"paper-papmet-pal-lancet-2021","kind":"paper","name":"PAPMET (SWOG 1500): cabozantinib versus sunitinib for metastatic papillary renal cell carcinoma","aka":[],"tldr":"In the first randomised trial to show a benefit in papillary kidney cancer, the MET-targeting kinase inhibitor cabozantinib delayed progression and tripled the response rate compared with sunitinib, while two other MET inhibitors did not.","summary":"Randomised phase 2 trial of 147 patients with metastatic papillary renal cell carcinoma randomised to sunitinib, cabozantinib, crizotinib or savolitinib; the crizotinib and savolitinib arms closed early for futility.\n\nMedian progression-free survival was 9.0 months with cabozantinib against 5.6 months with sunitinib (hazard ratio 0.60) and response 23 versus 4 percent.","asOf":"2026-09-17","links":[{"label":"Lancet 2021","url":"https://doi.org/10.1016/S0140-6736(21)00152-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33592176/"}],"tags":[],"related":[],"cancers":["papillary-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["cabozantinib","crizotinib","savolitinib","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["papmet"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"doi":"10.1016/S0140-6736(21)00152-5","pmid":"33592176","authors":"Pal SK, Tangen C, Thompson IM, et al.","paperType":"rct","findings":["Median progression-free survival 9.0 vs 5.6 months; hazard ratio 0.60.","Objective response 23 percent vs 4 percent."],"whatItMeans":"Cabozantinib is the preferred first-line targeted therapy for metastatic papillary renal cell carcinoma; immunotherapy combinations are being tested on top of it.","caveats":["Small phase 2 with unselected MET status.","Savolitinib may still have a role in MET-driven tumours."],"changedPractice":true,"participants":147},{"id":"paper-pardoll-immune-checkpoint-blockade-nrc-2012","kind":"paper","name":"Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy","aka":[],"tldr":"The review that named and organised the field of checkpoint blockade: tumours switch off attacking T cells through brakes such as CTLA-4 and PD-1, and antibodies that release those brakes can produce lasting responses.","summary":"Written as the first PD-1 antibody results appeared, Pardoll's review explained how immune checkpoints, receptors that normally protect tissues from autoimmunity, are exploited by tumours, and why blocking them is a fundamentally different approach from vaccines or cytokines. It contrasted CTLA-4, which acts early in lymph nodes, with PD-1 and its ligand PD-L1, which act in the tumour itself, catalogued further checkpoints such as LAG-3 and TIM-3, and set out the questions that have shaped the decade since: biomarkers, combinations, and the autoimmune side effects that come with releasing the brakes.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nrc3239"}],"tags":[],"related":["paper-hodi-ipilimumab-melanoma-nejm-2010","paper-topalian-anti-pd1-nejm-2012"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["ctla4","pd1","pdl1","lag3","tim3"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":[],"terms":["immune-checkpoint","irae"],"trials":[],"people":["drew-pardoll"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Reviews Cancer","year":2012,"doi":"10.1038/nrc3239","authors":"Pardoll DM.","paperType":"review","findings":["Immune checkpoints are inhibitory receptors on T cells that tumours co-opt; CTLA-4 acts mainly during T cell priming and PD-1 during the effector phase in tissues.","PD-L1 expression by tumour cells offers a mechanism-based biomarker and a rationale for anti-PD-1 and anti-PD-L1 antibodies.","Multiple additional checkpoints (LAG-3, TIM-3, BTLA, adenosine and others) offer combination targets."],"whatItMeans":"This is the most cited map of the immunotherapy revolution and a good first read before the trials. Its predictions largely held: PD-1 pathway antibodies became the most widely used cancer drugs, PD-L1 testing entered practice, and LAG-3 blockade was approved in melanoma a decade later.","caveats":["A review written before most phase 3 evidence existed.","Biomarkers for checkpoint blockade remain imperfect despite the mechanistic case for PD-L1."],"changedPractice":false},{"id":"paper-parkin-global-cancer-statistics-2002-cacancer-2005","kind":"paper","name":"Parkin 2005: Global cancer statistics, 2002","aka":[],"tldr":"The world cancer count for 2002: about 10.9 million new cases and about 24.6 million people living within three years of a cancer diagnosis, with lung, breast and colorectal cancers the three most common.","summary":"Parkin, Bray, Ferlay and Pisani presented the GLOBOCAN 2002 estimates of incidence, mortality and prevalence for 26 cancers worldwide. They estimated 10.9 million new cases, 6.7 million deaths and 24.6 million people alive within three years of diagnosis. Lung cancer was the most common cancer and the leading cause of cancer death, followed by breast and colorectal cancers for incidence, and the paper documented the contrasting patterns of developed and developing regions, including the large burden of stomach, liver and cervical cancers in the latter.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/canjclin.55.2.74"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-jemal-global-cancer-statistics-2011-cacancer"],"cancers":["nsclc","breast-hr-positive","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":["bray-freddie"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2005,"doi":"10.3322/canjclin.55.2.74","authors":"Parkin DM, Bray F, Ferlay J, Pisani P.","paperType":"observational","findings":["About 10.9 million new cancer cases, 6.7 million cancer deaths and 24.6 million people living with cancer within three years of diagnosis in 2002.","Lung cancer the most common cancer (about 1.35 million cases) and leading cause of cancer death; breast (1.15 million) and colorectal (1 million) cancers next.","Stomach, liver and cervical cancers made up a much larger share of the burden in developing countries."],"whatItMeans":"The first of the modern GLOBOCAN summaries in CA, it set the template that Jemal, Torre, Bray and Sung later followed and provides the 2002 baseline for tracking how the global burden has grown and shifted.","caveats":["Registry coverage in 2002 was far thinner than today, so many estimates were rough.","Superseded by later GLOBOCAN releases."],"changedPractice":false},{"id":"paper-pathfinder-lancet-2023","kind":"paper","name":"PATHFINDER: the first prospective test of a multi-cancer blood test in people without symptoms","aka":[],"tldr":"In 6,621 adults over 50, the Galleri test flagged a cancer signal in 1.4%, of whom 38% turned out to have cancer; diagnostic work-up took about two months for true positives and over five months for false positives.","summary":"PATHFINDER was a single-arm prospective study in which 6,621 adults aged 50 or over at seven US health systems had the Galleri methylation-based multi-cancer early detection (MCED) test in addition to standard screening. A cancer signal triggered clinician-directed diagnostic evaluation guided by the predicted cancer signal origin.\n\nA signal was detected in 92 participants (1.4%); 35 had cancer confirmed, giving a positive predictive value of 38%. Specificity was 99.1% and the cancer signal origin prediction was correct in the large majority of true positives. Median time to diagnostic resolution was 79 days: 57 days for true positives and 162 days for false positives. Almost half of the cancers detected were early stage, and several were in organs without standard screening.\n\nThe study established feasibility and the diagnostic pathway and set the stage for the randomised NHS-Galleri trial and the larger PATHFINDER 2.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S0140-6736(23)01700-2"},{"label":"ClinicalTrials.gov NCT04241796","url":"https://clinicaltrials.gov/study/NCT04241796"}],"tags":[],"related":["idea-prev-mced-positive-resolution-pathway","idea-prev-mced-pretest-decision-aid"],"cancers":[],"sections":["early-detection"],"technologies":["mced","liquid-biopsy","methylation-profiling"],"targets":[],"drugs":["galleri"],"companies":[],"institutions":["dana-farber"],"pathways":[],"terms":["ppv","stage-shift"],"trials":["pathfinder-2","nhs-galleri"],"people":[],"bottlenecks":["b-early-detection","b-overdiagnosis","b-biomarker-validation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"doi":"10.1016/S0140-6736(23)01700-2","pmid":"37805216","authors":"Schrag D, Beer TM, McDonnell CH, et al.","paperType":"observational","findings":["Cancer signal detected in 92 of 6,621 (1.4%); 35 true positives, PPV 38%","Specificity 99.1%; negative predictive value 98.6%","Median time to diagnostic resolution 79 days (57 for true positives, 162 for false positives)","Most participants with a false-positive signal underwent imaging and a substantial minority an invasive procedure"],"whatItMeans":"A multi-cancer blood test can be run in ordinary clinics, and most positive results can be resolved with imaging. But six in ten positives are false alarms that take months to resolve, and the test misses most cancers. Whether it reduces late-stage cancer or deaths is unknown; that requires randomised trials.","caveats":["Single-arm; no control group and no mortality or stage-shift endpoint","Sensitivity for incident cancers was low because many cancers arose after a negative test","Participants were largely white, insured and health-literate","Harm from false positives (anxiety, procedures, cost) was documented but not weighed against benefit"],"changedPractice":false,"participants":6621},{"id":"paper-empower-cscc-1-cemiplimab-migden-nejm-2018","kind":"paper","name":"PD-1 blockade with cemiplimab in advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1)","aka":[],"tldr":"Cemiplimab shrank tumours in about half of patients with metastatic or locally advanced cutaneous squamous cell carcinoma, a highly mutated skin cancer with almost no previous treatment options, leading to the first approval for the disease.","summary":"Phase 1 expansion cohort (26 patients) and phase 2 study (59 patients) of cemiplimab in patients with metastatic or locally advanced cutaneous squamous cell carcinoma not amenable to curative surgery or radiotherapy.\n\nObjective response was 50 percent in the phase 1 cohort and 47 percent in the phase 2 metastatic cohort, with most responses durable beyond six months and typical immune-related toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1805131"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29863979/"}],"tags":[],"related":[],"cancers":["lip-cancer","advanced-cutaneous-scc"],"sections":[],"technologies":[],"targets":[],"drugs":["cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["empower-cscc-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1805131","pmid":"29863979","authors":"Migden MR, Rischin D, Schmults CD, et al.","paperType":"observational","findings":["Objective response 50 percent (phase 1) and 47 percent (phase 2 metastatic cohort).","Durable responses exceeding six months in the majority of responders."],"whatItMeans":"PD-1 blockade is the first-line systemic treatment for advanced cutaneous squamous cell carcinoma, including on the lip, and cemiplimab has since moved into neoadjuvant and adjuvant use.","caveats":["Single-arm; transplant recipients and immunosuppressed patients were excluded."],"changedPractice":true,"participants":85},{"id":"paper-heinrich-pdgfra-gist-science-2003","kind":"paper","name":"PDGFRA activating mutations in gastrointestinal stromal tumours","aka":[],"tldr":"This study found that most gastrointestinal stromal tumours without KIT mutations instead carry activating mutations in the related receptor PDGFRA, including the D842V mutation that resists imatinib, completing the genetic definition of the disease.","summary":"Mutation analysis of KIT-wild-type gastrointestinal stromal tumours identifying activating PDGFRA mutations in about a third, mutually exclusive with KIT mutations, with the mutant receptors showing constitutive activation and, for D842V, resistance to imatinib in vitro, while other PDGFRA mutants were sensitive.","asOf":"2026-09-17","links":[{"label":"Science 2003","url":"https://doi.org/10.1126/science.1079666"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12522257/"}],"tags":[],"related":[],"cancers":["gist-pdgfra-d842v"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2003,"doi":"10.1126/science.1079666","pmid":"12522257","authors":"Heinrich MC, Corless CL, Duensing A, et al.","paperType":"basic","findings":["PDGFRA mutations in about 35 percent of KIT wild-type GISTs.","D842V mutant resistant to imatinib; other PDGFRA mutants sensitive."],"whatItMeans":"PDGFRA testing is part of standard GIST genotyping, and the imatinib resistance of D842V predicted here led to the development of avapritinib.","caveats":["Discovery study; clinical resistance of D842V was confirmed in later trials."],"changedPractice":true},{"id":"paper-perseus-dara-vrd-transplant-nejm-2024","kind":"paper","name":"PERSEUS: daratumumab added to bortezomib-lenalidomide-dexamethasone around autologous transplant in newly diagnosed myeloma","aka":[],"tldr":"Adding daratumumab to the standard three-drug induction, transplant and maintenance cut progression or death by 58% and pushed MRD-negativity to three-quarters of patients.","summary":"PERSEUS randomised 709 transplant-eligible patients with newly diagnosed multiple myeloma to daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRd) induction and consolidation with daratumumab-lenalidomide maintenance, or VRd with lenalidomide maintenance. The primary endpoint was PFS. At 48 months PFS was 84.3% versus 67.7% (hazard ratio 0.42); complete response or better was 87.9% versus 70.1% and MRD-negativity at 10^-5 was 75.2% versus 47.5%. Daratumumab could be stopped after two years of maintenance in patients with sustained MRD-negativity. Grade 3-4 neutropenia, thrombocytopenia and infections were more frequent with daratumumab.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2312054"},{"label":"ClinicalTrials.gov NCT03710603","url":"https://clinicaltrials.gov/study/NCT03710603"}],"tags":[],"related":["cd38-plus-triplet"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["autologous-stem-cell-transplant","mrd-testing"],"targets":["cd38"],"drugs":["daratumumab","bortezomib","lenalidomide"],"companies":["johnson-johnson"],"institutions":[],"pathways":[],"terms":["pfs","mrd-negativity-myeloma"],"trials":["perseus"],"people":[],"bottlenecks":["b-dormancy-mrd","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2312054","authors":"Sonneveld P, Dimopoulos MA, Boccadoro M, et al.","paperType":"rct","findings":["709 transplant-eligible patients; D-VRd + D-R maintenance vs VRd + R maintenance.","48-month PFS 84.3% vs 67.7%; hazard ratio 0.42.","Complete response or better 87.9% vs 70.1%.","MRD-negativity (10^-5) 75.2% vs 47.5%; sustained MRD-negativity over 12 months 64.8% vs 29.7%.","More grade 3-4 neutropenia (62.1% vs 51.0%) and infections with daratumumab."],"whatItMeans":"PERSEUS, with the earlier GRIFFIN and CASSIOPEIA trials, made a four-drug daratumumab quadruplet the standard for fit patients heading to transplant. It also introduced MRD-directed stopping of the antibody, a step towards treatment that is deep but not indefinite. Whether transplant itself remains necessary on top of a quadruplet is now the open question.","caveats":["PFS, not overall survival, was the primary endpoint; OS follow-up is immature.","Both arms had autologous transplant, so it does not test transplant versus no transplant.","MRD-guided discontinuation applied only to daratumumab, not lenalidomide.","Younger, fitter patients than typical clinic populations."],"changedPractice":true,"participants":709},{"id":"paper-pharos-encorafenib-binimetinib-riely-jco-2023","kind":"paper","name":"PHAROS: encorafenib plus binimetinib in BRAF V600E-mutant metastatic non-small-cell lung cancer","aka":[],"tldr":"A second BRAF and MEK inhibitor pair, encorafenib plus binimetinib, shrank tumours in three quarters of untreated and nearly half of previously treated patients with BRAF V600E lung cancer, giving a better-tolerated alternative to dabrafenib-trametinib.","summary":"Phase 2 study of 98 patients with BRAF V600E-mutant metastatic non-small-cell lung cancer, 59 treatment-naive and 39 previously treated, given encorafenib plus binimetinib.\n\nObjective response was 75 percent in treatment-naive and 46 percent in previously treated patients, with median duration of response not reached and 16.7 months respectively; pyrexia was less common than with dabrafenib-trametinib.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2023","url":"https://doi.org/10.1200/JCO.23.00774"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37270692/"}],"tags":[],"related":[],"cancers":["braf-v600e-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["binimetinib","encorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["pharos"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2023,"doi":"10.1200/JCO.23.00774","pmid":"37270692","authors":"Riely GJ, Smit EF, Ahn MJ, et al.","paperType":"observational","findings":["Objective response 75 percent (treatment-naive) and 46 percent (previously treated).","Median duration of response 16.7 months in previously treated patients."],"whatItMeans":"Encorafenib-binimetinib is approved for BRAF V600E lung cancer and offers a second targeted option, particularly for patients troubled by fever on dabrafenib-trametinib.","caveats":["Single-arm; no head-to-head comparison with dabrafenib-trametinib."],"changedPractice":true,"participants":98},{"id":"paper-tchekmedyian-lenvatinib-adenoid-cystic-jco-2019","kind":"paper","name":"Phase 2 study of lenvatinib in progressive, recurrent or metastatic adenoid cystic carcinoma","aka":[],"tldr":"The multikinase inhibitor lenvatinib shrank tumours in about one in six patients with progressing adenoid cystic carcinoma and stabilised most of the rest, making it one of the few active drugs for this slow but relentless salivary cancer.","summary":"Single-arm phase 2 study of 32 patients with progressive recurrent or metastatic adenoid cystic carcinoma treated with lenvatinib 24 mg daily.\n\nPartial response occurred in 15.6 percent and stable disease in 75 percent, with a median progression-free survival of 17.5 months; most patients required dose reductions for hypertension, fatigue and oral pain.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.18.01859"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30939095/"}],"tags":[],"related":[],"cancers":["adenoid-cystic-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["lenvatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.18.01859","pmid":"30939095","authors":"Tchekmedyian V, Sherman EJ, Dunn L, et al.","paperType":"observational","findings":["Partial response 15.6 percent; stable disease 75 percent.","Median progression-free survival 17.5 months."],"whatItMeans":"Lenvatinib (like axitinib) is a guideline option for progressing adenoid cystic carcinoma; responses are uncommon, so it is reserved for documented progression rather than indolent disease.","caveats":["Small single-arm study in a slow-growing disease, where stable disease may reflect natural history.","Dose reductions were needed in most patients."],"changedPractice":true,"participants":32},{"id":"paper-takahashi-trastuzumab-docetaxel-salivary-duct-jco-2019","kind":"paper","name":"Phase 2 trial of trastuzumab and docetaxel in HER2-positive salivary duct carcinoma","aka":[],"tldr":"In HER2-positive salivary duct carcinoma, an aggressive salivary cancer resembling breast cancer, trastuzumab plus docetaxel shrank tumours in 70 percent of patients, establishing HER2 testing and targeting in the disease.","summary":"Single-arm phase 2 study of 57 patients with HER2-positive locally advanced, recurrent or metastatic salivary duct carcinoma treated with trastuzumab and docetaxel.\n\nObjective response was 70.2 percent with a median progression-free survival of 8.9 months and median overall survival of 39.7 months, with toxicity similar to the regimen's use in breast cancer.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2019","url":"https://doi.org/10.1200/JCO.18.00545"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30452336/"}],"tags":[],"related":[],"cancers":["salivary-duct-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["docetaxel","trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.18.00545","pmid":"30452336","authors":"Takahashi H, Tada Y, Saotome T, et al.","paperType":"observational","findings":["Objective response 70.2 percent.","Median progression-free survival 8.9 months; median overall survival 39.7 months."],"whatItMeans":"HER2 testing is standard in salivary duct carcinoma and trastuzumab-docetaxel a first-line option for HER2-positive advanced disease, with trastuzumab deruxtecan available at progression.","caveats":["Single-arm study in a rare disease.","About 30 to 40 percent of salivary duct carcinomas are HER2-positive."],"changedPractice":true,"participants":57},{"id":"paper-vogelzang-pemetrexed-mesothelioma-jco-2003","kind":"paper","name":"Phase 3 trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma","aka":[],"tldr":"Adding pemetrexed to cisplatin lengthened survival by almost three months in pleural mesothelioma, making platinum-pemetrexed the first, and for many years the only, standard chemotherapy for the disease.","summary":"Phase 3 trial of 456 chemotherapy-naive patients with malignant pleural mesothelioma randomised to pemetrexed plus cisplatin or cisplatin alone, with folic acid and vitamin B12 supplementation introduced part-way through to reduce toxicity.\n\nMedian overall survival was 12.1 versus 9.3 months, response rate 41.3 versus 16.7 percent, and lung function and symptoms were better with the combination; vitamin supplementation markedly reduced severe toxicity.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2003","url":"https://doi.org/10.1200/JCO.2003.11.136"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12860938/"}],"tags":[],"related":[],"cancers":["pleural-mesothelioma","peritoneal-mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","pemetrexed"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2003,"doi":"10.1200/JCO.2003.11.136","pmid":"12860938","authors":"Vogelzang NJ, Rusthoven JJ, Symanowski J, et al.","paperType":"rct","findings":["Median overall survival 12.1 vs 9.3 months.","Objective response 41.3 percent vs 16.7 percent."],"whatItMeans":"Platinum-pemetrexed remains the chemotherapy backbone in mesothelioma, now combined with pembrolizumab or bevacizumab, or replaced by dual immunotherapy in non-epithelioid disease.","caveats":["Single-agent cisplatin comparator.","Vitamin supplementation changed mid-trial."],"changedPractice":true,"participants":456},{"id":"paper-tan-phyllodes-consensus-histopathology-2016","kind":"paper","name":"Phyllodes tumours of the breast: a consensus review","aka":[],"tldr":"This international consensus review sets out how pathologists grade phyllodes tumours as benign, borderline or malignant and how those grades should guide surgery and follow-up.","summary":"Consensus review by an international group of breast pathologists on the diagnosis, grading criteria (stromal cellularity, atypia, mitoses, overgrowth and margins), differential diagnosis from fibroadenoma, molecular findings including MED12 mutations, and management implications for phyllodes tumours.","asOf":"2026-09-17","links":[{"label":"Histopathology 2016","url":"https://doi.org/10.1111/his.12876"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26768026/"}],"tags":[],"related":[],"cancers":["phyllodes-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Histopathology","year":2016,"doi":"10.1111/his.12876","pmid":"26768026","authors":"Tan BY, Acs G, Apple SK, et al.","paperType":"review","findings":[],"whatItMeans":"The three-tier grading on a phyllodes pathology report and the margin recommendations for each grade follow this review and the WHO classification it informed.","caveats":["Grading remains partly subjective and inter-observer variation persists."],"changedPractice":true},{"id":"paper-aparicio-aggressive-variant-ccr-2013","kind":"paper","name":"Platinum-based chemotherapy for variant castration-resistant prostate cancer (aggressive variant criteria)","aka":[],"tldr":"This trial defined clinical criteria for aggressive variant prostate cancer, such as visceral spread, low PSA relative to tumour burden and neuroendocrine features, and showed that these men respond to carboplatin-docetaxel followed by etoposide-cisplatin.","summary":"Phase 2 study of 120 men with castration-resistant prostate cancer meeting proposed anaplastic (aggressive variant) criteria treated with first-line carboplatin and docetaxel followed at progression by etoposide and cisplatin.\n\nResponse to first-line therapy occurred in the majority, median overall survival was 16 months, and the clinical criteria identified a group behaving like small-cell carcinoma even when histology showed adenocarcinoma.","asOf":"2026-09-17","links":[{"label":"Clin Cancer Res 2013","url":"https://doi.org/10.1158/1078-0432.CCR-12-3791"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23649003/"}],"tags":[],"related":[],"cancers":["prostate-nepc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2013,"doi":"10.1158/1078-0432.CCR-12-3791","pmid":"23649003","authors":"Aparicio AM, Harzstark AL, Corn PG, et al.","paperType":"observational","findings":["Aggressive variant criteria defined: visceral metastases, lytic bone metastases, bulky nodes, low PSA relative to burden, neuroendocrine markers, short response to hormonal therapy.","Median overall survival 16 months with platinum-based sequential therapy."],"whatItMeans":"The aggressive variant criteria are used to select men for platinum-based chemotherapy without needing neuroendocrine histology, and underpin trials of platinum combinations and PARP inhibitors in this group.","caveats":["Single-arm phase 2; criteria were subsequently linked to combined RB1, TP53 and PTEN loss."],"changedPractice":true,"participants":120},{"id":"paper-polarix-polatuzumab-rchp-nejm-2022","kind":"paper","name":"POLARIX: swapping vincristine for the antibody-drug conjugate polatuzumab vedotin in first-line treatment of diffuse large B-cell lymphoma","aka":[],"tldr":"Replacing one chemotherapy drug in R-CHOP with a CD79b antibody-drug conjugate modestly reduced progression (2-year PFS 76.7% versus 70.2%) without changing survival or side effects.","summary":"POLARIX randomised 879 previously untreated patients with diffuse large B-cell lymphoma (IPI 2-5, age 18-80) to pola-R-CHP (polatuzumab vedotin replacing vincristine) or standard R-CHOP for six cycles plus two rituximab doses. The primary endpoint was investigator-assessed PFS. At two years PFS was 76.7% versus 70.2% (hazard ratio 0.73) while overall survival was identical (88.7% versus 88.6%) and the safety profiles were similar. Exploratory subgroups suggested most benefit in activated B-cell-like subtype, older patients and higher IPI, with little or no benefit in germinal-centre subtype. It was the first regimen to beat R-CHOP in two decades of trials.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2115304"},{"label":"ClinicalTrials.gov NCT03274492","url":"https://clinicaltrials.gov/study/NCT03274492"}],"tags":[],"related":[],"cancers":["dlbcl"],"sections":[],"technologies":["adc"],"targets":["cd79b","cd20"],"drugs":["polatuzumab-vedotin","rituximab","doxorubicin","vincristine"],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["pfs","os"],"trials":["polarix"],"people":[],"bottlenecks":["b-drug-pricing","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2115304","authors":"Tilly H, Morschhauser F, Sehn LH, et al.","paperType":"rct","findings":["879 untreated DLBCL patients, IPI 2-5; pola-R-CHP vs R-CHOP.","2-year PFS 76.7% vs 70.2%; hazard ratio 0.73 (about 6.5 percentage points absolute).","2-year overall survival 88.7% vs 88.6%; no difference.","Grade 3-4 adverse events 57.7% vs 57.5%; peripheral neuropathy rates similar.","Exploratory: benefit concentrated in ABC subtype, IPI 3-5 and age over 60; GCB subtype showed none."],"whatItMeans":"POLARIX gave the first new first-line standard for DLBCL since rituximab was added to CHOP, and pola-R-CHP is now approved and widely used, especially in higher-risk or ABC-type disease. The gain is modest and survival is unchanged, so many clinicians still use R-CHOP in lower-risk or GCB-type patients. Cost and subgroup uncertainty drive ongoing debate.","caveats":["No overall survival benefit; the PFS gain is modest in absolute terms.","Subgroup effects are exploratory and hypothesis-generating, yet influence practice.","Excluded very low IPI (0-1) and age over 80.","High cost relative to a generic-based regimen."],"changedPractice":true,"participants":879},{"id":"paper-portec-2-lancet-2010","kind":"paper","name":"PORTEC-2: vaginal brachytherapy versus pelvic external beam radiotherapy for high-intermediate-risk endometrial cancer","aka":[],"tldr":"For endometrial cancer of high-intermediate risk, brachytherapy to the top of the vagina alone controlled the disease as well as radiotherapy to the whole pelvis, with fewer bowel side effects and better quality of life.","summary":"Phase 3 trial of 427 women with stage I to IIA endometrial carcinoma with high-intermediate-risk features randomised to vaginal brachytherapy or external beam pelvic radiotherapy.\n\nFive-year vaginal recurrence was 1.8 versus 1.6 percent, locoregional relapse 5.1 versus 2.1 percent (not significant), and overall survival 84.8 versus 79.6 percent, with markedly less gastrointestinal toxicity after brachytherapy.","asOf":"2026-09-17","links":[{"label":"Lancet 2010","url":"https://doi.org/10.1016/S0140-6736(09)62163-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/20206777/"}],"tags":[],"related":[],"cancers":["endometrial-nsmp"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["portec-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2010,"doi":"10.1016/S0140-6736(09)62163-2","pmid":"20206777","authors":"Nout RA, Smit VT, Putter H, et al.","paperType":"rct","findings":["Five-year vaginal recurrence 1.8 percent vs 1.6 percent.","Five-year overall survival 84.8 percent vs 79.6 percent (not significant)."],"whatItMeans":"Vaginal brachytherapy is the standard adjuvant treatment for high-intermediate-risk endometrial cancer, with pelvic radiotherapy reserved for higher-risk features such as substantial lymphovascular invasion or p53 abnormality.","caveats":["Pelvic recurrences were slightly more frequent after brachytherapy alone.","Molecular classification was not available; later analysis shows p53-abnormal tumours do poorly with either."],"changedPractice":true,"participants":427},{"id":"paper-portec-3-lancet-oncol-2018","kind":"paper","name":"PORTEC-3: adjuvant chemoradiotherapy versus radiotherapy alone for high-risk endometrial cancer","aka":[],"tldr":"Adding cisplatin during pelvic radiotherapy and four cycles of carboplatin-paclitaxel afterwards improved failure-free survival in high-risk endometrial cancer, most clearly in stage III and serous cancers, at the cost of more toxicity.","summary":"Phase 3 trial of 686 women with high-risk endometrial cancer (stage I grade 3 with deep invasion or lymphovascular invasion, stage II to III, or serous or clear cell histology) randomised to pelvic radiotherapy alone or radiotherapy with concurrent cisplatin followed by four cycles of carboplatin-paclitaxel.\n\nFive-year failure-free survival was 75.5 versus 68.6 percent (hazard ratio 0.71); overall survival was 81.4 versus 76.1 percent, significant only on longer follow-up, with the largest benefit in stage III and serous disease.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2018","url":"https://doi.org/10.1016/S1470-2045(18)30079-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29449189/"}],"tags":[],"related":[],"cancers":["endometrial-p53-abnormal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["portec-3"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2018,"doi":"10.1016/S1470-2045(18)30079-2","pmid":"29449189","authors":"de Boer SM, Powell ME, Mileshkin L, et al.","paperType":"rct","findings":["Five-year failure-free survival 75.5 percent vs 68.6 percent; hazard ratio 0.71.","Updated five-year overall survival 81.4 percent vs 76.1 percent."],"whatItMeans":"Chemoradiotherapy is the standard for stage III and for p53-abnormal or serous endometrial cancer; for other stage I to II tumours radiotherapy alone or brachytherapy suffices.","caveats":["Grade 3 or worse adverse events 60 percent vs 12 percent during treatment; persistent neuropathy.","The molecular sub-analysis shows benefit is concentrated in p53-abnormal tumours."],"changedPractice":true,"participants":686},{"id":"paper-prasad-surrogate-endpoints-jama-im-2015","kind":"paper","name":"Prasad: most surrogate endpoints in cancer trials correlate poorly with survival","aka":[],"tldr":"A systematic review of 36 trial-level meta-analyses found that in over half the surrogate endpoint (response rate, progression-free survival) had a low correlation with overall survival, and only about a quarter showed a strong correlation.","summary":"Prasad and colleagues searched for trial-level meta-analyses that quantified the correlation between a surrogate endpoint and overall survival across randomised oncology trials. They identified 36 articles covering 65 surrogate-survival associations in many tumour types and settings.\n\nUsing a conventional threshold, 52% of reported correlations were low (r below 0.7), 25% medium (0.7 to 0.85) and 23% high (0.85 or more). Correlations were weakest in the metastatic setting and for response rate. A companion analysis by the same group (Kim and Prasad, JAMA Internal Medicine 2015) showed that of 54 FDA cancer drug approvals in 2008-2012, 36 were based on surrogates, and after a median 4.4 years only 5 had demonstrated an overall survival benefit.\n\nThe work catalysed the debate over accelerated approval, the FDA's 2023-2025 reforms requiring confirmatory trials to be under way at approval, and the growing use of quality-of-life and patient-reported endpoints.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1001/jamainternmed.2015.2829"},{"label":"Kim and Prasad: FDA approvals on surrogates (2015)","url":"https://doi.org/10.1001/jamainternmed.2015.5868"}],"tags":[],"related":["idea-tr1-surrogate-validation-programme","idea-tr1-power-for-meaningful-benefit","idea-prev-mced-stage-endpoint-surrogate","idea-tr1-win-ratio-net-benefit-endpoint"],"cancers":[],"sections":["drug-discovery"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["pfs","os","orr","accelerated-approval","hazard-ratio","recist"],"trials":[],"people":[],"bottlenecks":["b-trial-design","b-regulatory-fragmentation","b-drug-pricing","b-patient-voice"],"keyPapers":[],"journals":["jama-internal-medicine"],"dependsOn":[],"notes":[],"journal":"JAMA Internal Medicine","year":2015,"doi":"10.1001/jamainternmed.2015.2829","pmid":"26098871","authors":"Prasad V, Kim C, Burotto M, Vandross A","paperType":"meta-analysis","findings":["36 trial-level meta-analyses covering 65 surrogate-OS associations reviewed","52% of surrogate-survival correlations were low (r below 0.7), 25% medium, 23% high","Response rate and PFS in the metastatic setting were the weakest surrogates","Companion analysis: of 36 approvals on surrogates (2008-2012), 5 later showed an OS benefit, 18 failed to or were not tested, and 13 remained unknown"],"whatItMeans":"A drug that shrinks tumours or delays progression on scans has not necessarily been shown to help patients live longer or better. Patients and clinicians should ask what the endpoint was; regulators should insist on timely confirmatory trials; and trialists should validate surrogates before relying on them.","caveats":["Trial-level correlation is only one way to validate a surrogate; some settings (adjuvant DFS in colon cancer) have well-validated surrogates","Low correlation may reflect crossover and post-progression therapy diluting the OS signal rather than a useless surrogate","The review depended on published meta-analyses and their heterogeneous methods","PFS can be a meaningful endpoint in itself when progression is symptomatic and treatment is tolerable"],"changedPractice":false},{"id":"paper-lee-prc2-mpnst-nat-genet-2014","kind":"paper","name":"PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumours","aka":[],"tldr":"Sequencing showed that most malignant peripheral nerve sheath tumours lose the polycomb repressive complex 2 through EED or SUZ12 mutations, on top of NF1 and CDKN2A loss, explaining their biology and giving pathologists the H3K27me3 stain that diagnoses them.","summary":"Genomic analysis of malignant peripheral nerve sheath tumours identifying loss-of-function alterations in EED or SUZ12, components of PRC2, in 70 percent of sporadic and 90 percent of radiotherapy-associated tumours, co-occurring with NF1 and CDKN2A inactivation, leading to loss of H3K27 trimethylation and amplified Ras signalling.","asOf":"2026-09-17","links":[{"label":"Nat Genet 2014","url":"https://doi.org/10.1038/ng.3095"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25240281/"}],"tags":[],"related":[],"cancers":["malignant-peripheral-nerve-sheath-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2014,"doi":"10.1038/ng.3095","pmid":"25240281","authors":"Lee W, Teckie S, Wiesner T, et al.","paperType":"translational","findings":["PRC2 component loss (EED or SUZ12) in 70 to 90 percent of MPNST.","Complete loss of H3K27me3 in PRC2-deficient tumours."],"whatItMeans":"Loss of H3K27me3 immunostaining is now a diagnostic marker for MPNST, and PRC2 loss is a target for epigenetic and combination therapies under investigation.","caveats":["Therapeutic exploitation of PRC2 loss remains experimental."],"changedPractice":true},{"id":"paper-precision-mri-targeted-biopsy-nejm-2018","kind":"paper","name":"PRECISION: MRI-targeted or standard biopsy for prostate cancer diagnosis","aka":[],"tldr":"Doing an MRI first and biopsying only suspicious areas found more clinically significant prostate cancers and fewer harmless ones than standard biopsy, while sparing a quarter of men any biopsy at all.","summary":"Multicentre randomised non-inferiority trial of 500 biopsy-naive men with suspected prostate cancer randomised to MRI with targeted biopsy of suspicious lesions only (no biopsy if MRI was negative) or standard transrectal ultrasound-guided 10 to 12 core biopsy.\n\nClinically significant cancer was detected in 38 percent of the MRI group against 26 percent with standard biopsy, clinically insignificant cancer in 9 versus 22 percent, and 28 percent of MRI-group men avoided biopsy.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1801993"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29552975/"}],"tags":[],"related":[],"cancers":["prostate-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["precision-mri"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1801993","pmid":"29552975","authors":"Kasivisvanathan V, Rannikko AS, Borghi M, et al.","paperType":"rct","findings":["Clinically significant cancer detected in 38 percent vs 26 percent.","Clinically insignificant cancer in 9 percent vs 22 percent; 28 percent of MRI arm avoided biopsy."],"whatItMeans":"Pre-biopsy MRI with targeted sampling is now the standard diagnostic pathway for suspected prostate cancer, reducing overdiagnosis of low-risk disease.","caveats":["Targeted biopsy alone may miss some significant cancers; many centres combine targeted and systematic cores.","Depends on MRI quality and reader expertise."],"changedPractice":true,"participants":500},{"id":"paper-predimed-breast-jama-im-2015","kind":"paper","name":"PREDIMED: a Mediterranean diet with extra-virgin olive oil and fewer breast cancers","aka":[],"tldr":"In a Spanish cardiovascular prevention trial, women assigned to a Mediterranean diet supplemented with extra-virgin olive oil had about two-thirds fewer invasive breast cancers than a low-fat control group, although the number of cases was small.","summary":"PREDIMED randomised older Spanish adults at high cardiovascular risk to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts, or advice to follow a low-fat diet. This secondary analysis examined invasive breast cancer in the 4,282 women over a median 4.8 years.\n\nThirty-five incident breast cancers occurred. The olive-oil group had a hazard ratio of 0.32 versus control; the nut group's reduction was not statistically significant. The original 2018 retraction and republication of PREDIMED (for randomisation irregularities at some sites) led to a re-analysis with similar estimates.\n\nIt is the only randomised trial evidence that a whole-diet intervention reduces cancer incidence, but it rests on very few events.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1001/jamainternmed.2015.4838"},{"label":"ClinicalTrials.gov ISRCTN35739639","url":"https://clinicaltrials.gov/study/ISRCTN35739639"}],"tags":[],"related":["paper-body-fatness-iarc-nejm-2016","idea-prev-chemoprevention-master-protocol"],"cancers":["breast-hr-positive"],"sections":["nutrition-lifestyle","prevention"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-trial-design"],"keyPapers":[],"journals":["jama-internal-medicine"],"dependsOn":[],"notes":[],"journal":"JAMA Internal Medicine","year":2015,"doi":"10.1001/jamainternmed.2015.4838","authors":"Toledo E, Salas-Salvadó J, Donat-Vargas C, et al.","paperType":"rct","findings":["Invasive breast cancer HR 0.32 (95% CI 0.13-0.79) for Mediterranean diet plus extra-virgin olive oil vs control","Mediterranean diet plus nuts: HR 0.59 (95% CI 0.26-1.35), not significant","Only 35 breast cancers occurred among 4,282 women over about 5 years","Effect estimates were similar after the 2018 re-analysis excluding sites with randomisation problems"],"whatItMeans":"A Mediterranean dietary pattern rich in olive oil may lower breast cancer risk, and it is safe and good for the heart anyway. The evidence is suggestive, not definitive, because of the small number of cancers; it should not be presented as proven cancer prevention.","caveats":["Breast cancer was not a pre-specified primary endpoint and cases were few","Randomisation irregularities at some sites forced a retraction and republication of the parent trial","Older Spanish women at high cardiovascular risk; not generalisable to younger or other populations","No mammographic screening protocol, so ascertainment could differ between arms"],"changedPractice":false,"participants":4282},{"id":"paper-prima-niraparib-nejm-2019","kind":"paper","name":"PRIMA: niraparib maintenance in newly diagnosed advanced ovarian cancer","aka":[],"tldr":"Niraparib maintenance after first-line chemotherapy delayed progression in newly diagnosed advanced ovarian cancer whether or not the tumour had a homologous recombination deficiency, though the gain was much larger when it did.","summary":"Phase 3 placebo-controlled trial of 733 patients with newly diagnosed advanced high-grade ovarian cancer at high risk of relapse who had responded to platinum chemotherapy, randomised to niraparib or placebo maintenance.\n\nIn homologous recombination-deficient tumours median progression-free survival was 21.9 versus 10.4 months (hazard ratio 0.43); in the overall population it was 13.8 versus 8.2 months (hazard ratio 0.62), with a smaller benefit in homologous recombination-proficient disease (hazard ratio 0.68).","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2019","url":"https://doi.org/10.1056/NEJMoa1910962"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31562799/"}],"tags":[],"related":[],"cancers":["platinum-sensitive-ovarian-cancer","high-grade-serous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["niraparib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["prima"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1910962","pmid":"31562799","authors":"González-Martín A, Pothuri B, Vergote I, et al.","paperType":"rct","findings":["Homologous recombination-deficient: median progression-free survival 21.9 vs 10.4 months; hazard ratio 0.43.","Overall population: 13.8 vs 8.2 months; hazard ratio 0.62."],"whatItMeans":"Niraparib is approved as first-line maintenance for all comers, making PARP inhibitor maintenance available beyond BRCA-mutated disease, though the benefit in proficient tumours is modest and long-term survival data are neutral.","caveats":["No overall survival benefit at final analysis.","Haematological toxicity requires individualised starting doses."],"changedPractice":true,"participants":733},{"id":"paper-bonvalot-retroperitoneal-sarcoma-compartmental-jco-2009","kind":"paper","name":"Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control","aka":[],"tldr":"This French multicentre study showed that resecting a retroperitoneal sarcoma together with the adjacent organs, even when not obviously involved, reduced local recurrence more than threefold, establishing the compartmental surgical approach.","summary":"Retrospective analysis of 382 patients with primary retroperitoneal sarcoma from French Sarcoma Group centres examining surgical technique, margins and outcomes.\n\nSystematic en bloc resection of adjacent organs (compartmental resection) was associated with a 3.29-fold lower risk of abdominal recurrence compared with simple complete resection, without higher mortality, while incomplete resection and high grade predicted recurrence.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2009","url":"https://doi.org/10.1200/JCO.2008.18.0802"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19047280/"}],"tags":[],"related":[],"cancers":["retroperitoneal-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2009,"doi":"10.1200/JCO.2008.18.0802","pmid":"19047280","authors":"Bonvalot S, Rivoire M, Castaing M, et al.","paperType":"observational","findings":["Abdominal recurrence risk reduced 3.29-fold with compartmental resection.","Postoperative mortality 3 percent."],"whatItMeans":"Extended en bloc resection in a sarcoma reference centre is the standard operation for retroperitoneal sarcoma.","caveats":["Retrospective; extended resection carries morbidity and remains debated for low-grade liposarcoma."],"changedPractice":true,"participants":382},{"id":"paper-prodige-23-lancet-oncol-2021","kind":"paper","name":"PRODIGE 23: induction FOLFIRINOX before chemoradiotherapy and surgery for locally advanced rectal cancer","aka":[],"tldr":"Six cycles of FOLFIRINOX chemotherapy before standard chemoradiation and surgery reduced metastases and improved disease-free survival in locally advanced rectal cancer, and longer follow-up showed a survival benefit.","summary":"Phase 3 trial of 461 patients with cT3 or cT4 rectal adenocarcinoma randomised to induction mFOLFIRINOX followed by chemoradiotherapy, surgery and three months of adjuvant chemotherapy, or chemoradiotherapy, surgery and six months of adjuvant chemotherapy.\n\nThree-year disease-free survival was 76 versus 69 percent (hazard ratio 0.69), pathological complete response 28 versus 12 percent, and the seven-year update showed improved overall survival (81.9 versus 76.1 percent).","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(21)00079-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33862000/"}],"tags":[],"related":[],"cancers":["rectal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["prodige-23"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00079-6","pmid":"33862000","authors":"Conroy T, Bosset JF, Etienne PL, et al.","paperType":"rct","findings":["Three-year disease-free survival 76 percent vs 69 percent; hazard ratio 0.69.","Seven-year overall survival 81.9 percent vs 76.1 percent."],"whatItMeans":"Induction FOLFIRINOX-based total neoadjuvant therapy is a preferred strategy for locally advanced rectal cancer, and the first to show a survival gain.","caveats":["Total treatment burden is high; FOLFIRINOX toxicity requires fit patients.","Compared against a control arm receiving six months of adjuvant chemotherapy, which many patients do not complete."],"changedPractice":true,"participants":461},{"id":"paper-profound-nejm-2020","kind":"paper","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","aka":[],"tldr":"In men with metastatic castration-resistant prostate cancer carrying BRCA1, BRCA2 or ATM alterations who had progressed on hormonal therapy, the PARP inhibitor olaparib delayed progression and lengthened survival compared with another hormonal agent.","summary":"Phase 3 trial of 387 men with metastatic castration-resistant prostate cancer progressing on enzalutamide or abiraterone, with alterations in BRCA1, BRCA2 or ATM (cohort A) or 12 other homologous recombination genes (cohort B), randomised 2:1 to olaparib or physician's choice of enzalutamide or abiraterone.\n\nIn cohort A median progression-free survival was 7.4 versus 3.6 months (hazard ratio 0.34) and median overall survival 19.1 versus 14.7 months (hazard ratio 0.69 despite crossover); benefit was driven mainly by BRCA2.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa1911440"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32343890/"}],"tags":[],"related":[],"cancers":["prostate-mcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["olaparib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["profound"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa1911440","pmid":"32343890","authors":"de Bono J, Mateo J, Fizazi K, et al.","paperType":"rct","findings":["Cohort A: median progression-free survival 7.4 vs 3.6 months; hazard ratio 0.34.","Cohort A: median overall survival 19.1 vs 14.7 months; hazard ratio 0.69."],"whatItMeans":"Germline and tumour testing for homologous recombination repair genes is now standard in metastatic prostate cancer, and olaparib is approved for BRCA-mutated disease after a hormonal agent.","caveats":["Benefit in ATM and the cohort B genes was weak or absent.","The comparator, a second hormonal agent, has limited activity after progression on the first."],"changedPractice":true,"participants":387},{"id":"paper-church-pole-endometrial-jnci-2015","kind":"paper","name":"Prognostic significance of POLE proofreading mutations in endometrial cancer","aka":[],"tldr":"Endometrial cancers with mutations in the proofreading domain of POLE, though hypermutated and often high grade, almost never recur, identifying a group of women who can be spared adjuvant treatment.","summary":"Analysis of 788 endometrial cancers from the PORTEC-1 and PORTEC-2 trials for POLE exonuclease domain mutations, found in 6.1 percent, with survival analysis and a meta-analysis of published series.\n\nPOLE-mutant tumours were more often high grade yet had excellent recurrence-free survival (hazard ratio 0.14) and cancer-specific survival, independent of other prognostic factors.","asOf":"2026-09-17","links":[{"label":"J Natl Cancer Inst 2015","url":"https://doi.org/10.1093/jnci/dju402"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25505230/"}],"tags":[],"related":[],"cancers":["endometrial-pole-ultramutated"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jnci"],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":2015,"doi":"10.1093/jnci/dju402","pmid":"25505230","authors":"Church DN, Stelloo E, Nout RA, et al.","paperType":"translational","findings":["POLE exonuclease domain mutations in 6.1 percent of tumours.","Recurrence-free survival hazard ratio 0.14 for POLE-mutant tumours."],"whatItMeans":"POLE sequencing is now part of endometrial cancer classification, and guidelines allow omission of adjuvant therapy for stage I to II POLE-mutated tumours.","caveats":["Retrospective analysis of trial cohorts; only pathogenic hotspot mutations carry the favourable prognosis."],"changedPractice":true,"participants":788},{"id":"paper-promid-rinke-jco-2009","kind":"paper","name":"PROMID: octreotide LAR in the control of tumour growth in metastatic midgut neuroendocrine tumours","aka":[],"tldr":"The PROMID trial was the first to show that a somatostatin analogue, octreotide, slows tumour growth in midgut neuroendocrine tumours, more than doubling the time to progression compared with placebo.","summary":"Phase 3 placebo-controlled trial of 85 treatment-naive patients with well-differentiated metastatic midgut neuroendocrine tumours randomised to octreotide LAR 30 mg monthly or placebo.\n\nMedian time to tumour progression was 14.3 versus 6.0 months (hazard ratio 0.34), with the greatest benefit in patients with low hepatic tumour load and resected primary tumours.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2009","url":"https://doi.org/10.1200/JCO.2009.22.8510"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19704057/"}],"tags":[],"related":[],"cancers":["small-intestinal-net"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["promid"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2009,"doi":"10.1200/JCO.2009.22.8510","pmid":"19704057","authors":"Rinke A, Müller HH, Schade-Brittinger C, et al.","paperType":"rct","findings":["Median time to progression 14.3 vs 6.0 months; hazard ratio 0.34.","Benefit largest with hepatic tumour load of 10 percent or less."],"whatItMeans":"Octreotide LAR became a standard first-line antiproliferative therapy for small intestinal neuroendocrine tumours, later joined by lanreotide after CLARINET.","caveats":["Small trial that closed early for slow accrual.","No overall survival benefit because of crossover."],"changedPractice":true,"participants":85},{"id":"paper-propsma-hofman-lancet-2020","kind":"paper","name":"proPSMA: PSMA PET-CT versus conventional imaging for staging high-risk prostate cancer","aka":[],"tldr":"PSMA PET-CT was 27 percentage points more accurate than CT and bone scan for finding spread in men with high-risk prostate cancer before treatment, with less radiation and more influence on management, and it has replaced conventional imaging where available.","summary":"Randomised multicentre trial of 302 men with high-risk localised prostate cancer randomised to conventional imaging (CT and bone scan) or gallium-68 PSMA PET-CT for staging, with crossover imaging to define a reference standard.\n\nAccuracy was 92 percent for PSMA PET-CT against 65 percent for conventional imaging, with higher sensitivity (85 versus 38 percent) and specificity, fewer equivocal results, lower radiation dose and more frequent management change.","asOf":"2026-09-17","links":[{"label":"Lancet 2020","url":"https://doi.org/10.1016/S0140-6736(20)30314-7"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32209449/"}],"tags":[],"related":[],"cancers":["prostate-bcr","prostate-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["propsma"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2020,"doi":"10.1016/S0140-6736(20)30314-7","pmid":"32209449","authors":"Hofman MS, Lawrentschuk N, Francis RJ, et al.","paperType":"rct","findings":["Accuracy 92 percent vs 65 percent (27 percent absolute difference).","Sensitivity 85 percent vs 38 percent; specificity 98 percent vs 91 percent."],"whatItMeans":"PSMA PET-CT is the preferred staging investigation for high-risk prostate cancer and for biochemical recurrence, though most treatment trials were designed with conventional imaging.","caveats":["Reference standard relied partly on imaging follow-up rather than histology.","Detecting more disease does not by itself prove better outcomes."],"changedPractice":true,"participants":302},{"id":"paper-brca-risk-reducing-surgery-jama-2010","kind":"paper","name":"PROSE consortium: preventive surgery lowers cancer and death in BRCA1 and BRCA2 carriers","aka":[],"tldr":"Among 2,482 women with BRCA1 or BRCA2 mutations, removing the ovaries and fallopian tubes was associated with 60% lower all-cause mortality, and no breast cancers occurred in the women who had preventive mastectomy.","summary":"The PROSE consortium followed 2,482 women with a BRCA1 or BRCA2 mutation at 22 centres in Europe and North America from 1974 to 2008, comparing outcomes in those who did and did not undergo risk-reducing mastectomy (RRM) or risk-reducing salpingo-oophorectomy (RRSO).\n\nNo breast cancers were diagnosed in the 247 women who had RRM over 3 years of follow-up, compared with 98 in the 1,372 who did not. RRSO was associated with lower risk of ovarian cancer, of first breast cancer in BRCA1 carriers, and with reduced all-cause mortality (10% vs 3%), breast cancer-specific mortality and ovarian cancer-specific mortality.\n\nIt was the first study to link risk-reducing surgery to a survival advantage and cemented RRSO as the standard recommendation for carriers by age 35-40 (BRCA1) or 40-45 (BRCA2).","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1001/jama.2010.1237"}],"tags":[],"related":["idea-moon-population-germline-screening","idea-prev-population-germline-screening-at-30","idea-prev-brca1-denosumab-prevention"],"cancers":["ovarian","breast-hr-positive","tnbc"],"sections":["prevention","surgery"],"technologies":["germline-testing"],"targets":["brca"],"drugs":[],"companies":[],"institutions":["penn-abramson"],"pathways":[],"terms":["germline-vs-somatic"],"trials":[],"people":["susan-domchek"],"bottlenecks":["b-hereditary-risk","b-prevention-adoption"],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2010,"doi":"10.1001/jama.2010.1237","pmid":"20810374","authors":"Domchek SM, Friebel TM, Singer CF, et al.","paperType":"observational","findings":["Risk-reducing mastectomy: 0 breast cancers in 247 women vs 98 in 1,372 without surgery","RRSO associated with lower all-cause mortality: 3% vs 10% (HR 0.40, 95% CI 0.26-0.61)","RRSO associated with lower breast cancer-specific mortality (HR 0.44) and ovarian cancer-specific mortality (HR 0.21)","RRSO reduced ovarian cancer risk in women with no prior breast cancer (HR 0.28 in BRCA1 carriers)"],"whatItMeans":"For women who carry a BRCA mutation, preventive removal of the ovaries and tubes saves lives, and preventive mastectomy almost eliminates breast cancer. These are the strongest prevention effects in oncology, which is why finding carriers before they develop cancer matters so much.","caveats":["Observational; women choosing surgery may differ from those who do not (healthy-adopter bias)","Follow-up after RRM was short (about 3 years)","Surgical menopause has cardiovascular, bone and quality-of-life costs not captured here","Later analyses questioned whether RRSO reduces breast cancer risk once ascertainment bias is addressed"],"changedPractice":true,"participants":2482},{"id":"paper-prospect-nejm-2023","kind":"paper","name":"PROSPECT: neoadjuvant FOLFOX with selective use of chemoradiotherapy for locally advanced rectal cancer","aka":[],"tldr":"For rectal cancers of intermediate risk suitable for sphincter-sparing surgery, six cycles of FOLFOX chemotherapy, with radiotherapy only if the tumour did not shrink, was as effective as routine chemoradiation and spared nine in ten patients pelvic radiotherapy.","summary":"Phase 3 non-inferiority trial of 1,194 patients with cT2 node-positive, cT3 node-negative or cT3 node-positive rectal cancer candidates for sphincter-sparing surgery, randomised to neoadjuvant FOLFOX with chemoradiotherapy only for poor response, or standard pelvic chemoradiotherapy.\n\nFive-year disease-free survival was 80.8 versus 78.6 percent (non-inferior), local recurrence 1.8 versus 1.6 percent, and only 9 percent of FOLFOX patients needed chemoradiotherapy; quality of life differed in bowel, sexual and neuropathy domains by arm.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2303269"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37272534/"}],"tags":[],"related":[],"cancers":["rectal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["prospect"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2303269","pmid":"37272534","authors":"Schrag D, Shi Q, Weiser MR, et al.","paperType":"rct","findings":["Five-year disease-free survival 80.8 percent vs 78.6 percent (non-inferior).","Chemoradiotherapy avoided in 91 percent of the FOLFOX arm."],"whatItMeans":"Selected patients with intermediate-risk rectal cancer can avoid radiotherapy altogether, with chemotherapy alone before surgery, trading neuropathy for better long-term bowel and sexual function.","caveats":["Excluded T4 tumours, threatened mesorectal fascia and low tumours needing abdominoperineal resection.","Non-inferiority margin allowed a modest loss of efficacy."],"changedPractice":true,"participants":1194},{"id":"paper-barth-phyllodes-adjuvant-radiotherapy-ann-surg-oncol-2009","kind":"paper","name":"Prospective multi-institutional study of adjuvant radiotherapy after resection of borderline and malignant phyllodes tumours","aka":[],"tldr":"In a prospective study, no woman whose borderline or malignant phyllodes tumour was excised with clear margins and then given radiotherapy had a local recurrence, supporting radiotherapy after breast-conserving surgery for these tumours.","summary":"Prospective study of 46 women with borderline or malignant phyllodes tumours treated with margin-negative breast-conserving resection followed by adjuvant radiotherapy.\n\nWith a median follow-up of 56 months there were no local recurrences, compared with historical local recurrence rates of 15 to 30 percent after surgery alone, though distant metastases occurred in a small number of malignant cases.","asOf":"2026-09-17","links":[{"label":"Ann Surg Oncol 2009","url":"https://doi.org/10.1245/s10434-009-0489-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19424757/"}],"tags":[],"related":[],"cancers":["phyllodes-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-surgical-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of surgical oncology","year":2009,"doi":"10.1245/s10434-009-0489-2","pmid":"19424757","authors":"Barth RJ, Wells WA, Mitchell SE, et al.","paperType":"observational","findings":["Local recurrence 0 percent at a median of 56 months after resection plus radiotherapy."],"whatItMeans":"Adjuvant radiotherapy is considered after breast conservation for borderline and malignant phyllodes tumours; it does not address the risk of distant spread.","caveats":["Small, non-randomised study with a historical comparison."],"changedPractice":true,"participants":46},{"id":"paper-prosper-nejm-2018","kind":"paper","name":"PROSPER: enzalutamide in men with non-metastatic castration-resistant prostate cancer","aka":[],"tldr":"Enzalutamide delayed metastases by almost two years in men with rapidly rising PSA on hormone therapy and no visible spread, and longer follow-up showed it also lengthened survival.","summary":"Phase 3 placebo-controlled trial of 1,401 men with non-metastatic castration-resistant prostate cancer and PSA doubling time of ten months or less randomised 2:1 to enzalutamide or placebo with continued androgen deprivation.\n\nMedian metastasis-free survival was 36.6 versus 14.7 months (hazard ratio 0.29), and the final analysis showed median overall survival of 67.0 versus 56.3 months (hazard ratio 0.73); fatigue, hypertension and falls were more common.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1800536"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29949494/"}],"tags":[],"related":[],"cancers":["prostate-nmcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["enzalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["prosper"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1800536","pmid":"29949494","authors":"Hussain M, Fizazi K, Saad F, et al.","paperType":"rct","findings":["Median metastasis-free survival 36.6 vs 14.7 months; hazard ratio 0.29.","Median overall survival 67.0 vs 56.3 months; hazard ratio 0.73."],"whatItMeans":"Enzalutamide is one of three androgen receptor inhibitors standard for high-risk non-metastatic castration-resistant prostate cancer.","caveats":["Fatigue and cognitive effects are more prominent than with darolutamide.","Conventional imaging defined non-metastatic status."],"changedPractice":true,"participants":1401},{"id":"paper-protect-nejm-2016","kind":"paper","name":"ProtecT: 10-year outcomes after monitoring, surgery or radiotherapy for localised prostate cancer","aka":[],"tldr":"In the only randomised trial to compare active monitoring, surgery and radiotherapy for PSA-detected localised prostate cancer, deaths from prostate cancer were rare and equal at ten years in all three groups, though monitoring led to more metastases and progression.","summary":"Phase 3 trial of 1,643 men with PSA-detected localised prostate cancer randomised to active monitoring, radical prostatectomy or radiotherapy with six months of androgen deprivation.\n\nProstate cancer-specific mortality at ten years was about 1 percent in every group (17 deaths in total), while metastases (6.3 versus 2.4 and 3.0 per 1,000 person-years) and clinical progression were more frequent with monitoring; patient-reported outcomes showed distinct side-effect patterns for each treatment.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2016","url":"https://doi.org/10.1056/NEJMoa1606220"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27626136/"}],"tags":[],"related":[],"cancers":["prostate-intermediate-risk","prostate-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["protect"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1606220","pmid":"27626136","authors":"Hamdy FC, Donovan JL, Lane JA, et al.","paperType":"rct","findings":["Prostate cancer-specific mortality about 1 percent at ten years in all groups.","Metastases 6.3 per 1,000 person-years with monitoring vs 2.4 (surgery) and 3.0 (radiotherapy)."],"whatItMeans":"Most men with low- and favourable intermediate-risk prostate cancer can safely choose monitoring, and treatment choice should weigh urinary, sexual and bowel side effects against a small difference in progression.","caveats":["Most men had low-risk disease; about 20 percent were intermediate or high risk.","Active monitoring was less intensive than modern active surveillance with MRI."],"changedPractice":true,"participants":1643},{"id":"paper-protect-15-year-nejm-2023","kind":"paper","name":"ProtecT: fifteen-year outcomes after monitoring, surgery or radiotherapy for prostate cancer","aka":[],"tldr":"Fifteen years on, ProtecT still found no difference in prostate cancer deaths between monitoring, surgery and radiotherapy, with about 97 percent of men alive from their cancer in every group, confirming that many men can defer or avoid treatment.","summary":"Fifteen-year follow-up of the 1,643 men randomised in ProtecT to active monitoring, prostatectomy or radiotherapy.\n\nProstate cancer-specific mortality was 3.1 percent with monitoring, 2.2 percent with surgery and 2.9 percent with radiotherapy (no significant difference); metastases occurred in 9.4, 4.7 and 5.0 percent respectively; about a quarter of men in the monitoring group remained untreated at 15 years.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2214122"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36912538/"}],"tags":[],"related":[],"cancers":["prostate-low-risk","prostate-intermediate-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["protect"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2214122","pmid":"36912538","authors":"Hamdy FC, Donovan JL, Lane JA, et al.","paperType":"rct","findings":["Fifteen-year prostate cancer mortality 3.1 percent (monitoring), 2.2 percent (surgery), 2.9 percent (radiotherapy).","Metastatic disease 9.4 percent vs 4.7 percent vs 5.0 percent."],"whatItMeans":"Long-term data support active surveillance as a safe choice for low and much intermediate-risk disease, while the lower metastasis rate with treatment informs the discussion for men with longer life expectancy.","caveats":["Trial design predates MRI-based diagnosis and modern surveillance protocols."],"changedPractice":true,"participants":1643},{"id":"paper-quail-joyce-microenvironment-metastasis-natmed-2013","kind":"paper","name":"Quail and Joyce 2013: microenvironmental regulation of tumour progression and metastasis","aka":[],"tldr":"A review of how the normal cells around a tumour, including fibroblasts, immune cells and blood vessels, are recruited to help it grow and spread, and how distant organs are prepared to receive metastases before the cancer cells arrive.","summary":"Quail and Joyce surveyed the tumour microenvironment at each step of progression and metastasis: how cancer-associated fibroblasts, tumour-associated macrophages, other myeloid and lymphoid cells and the vasculature support primary tumour growth, invasion and intravasation; how bone marrow-derived cells and tumour-secreted factors establish a pre-metastatic niche in distant organs; and how the microenvironment at secondary sites governs dormancy and outgrowth. They discussed therapies aimed at these host cells, including macrophage-targeting and anti-angiogenic drugs, as complements to treatments aimed at the cancer cell.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nm.3394"}],"tags":[],"related":["paper-coussens-werb-inflammation-cancer-nature-2002"],"cancers":[],"sections":[],"technologies":["antiangiogenic"],"targets":["csf1r"],"drugs":[],"companies":[],"institutions":["mskcc"],"pathways":["metastatic-cascade","pre-metastatic-niche"],"terms":["metastasis","cancer-associated-fibroblasts","tumor-associated-macrophages","angiogenesis"],"trials":[],"people":["johanna-joyce"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2013,"doi":"10.1038/nm.3394","authors":"Quail DF, Joyce JA.","paperType":"review","findings":["Stromal, immune and vascular cells are co-opted at every stage from primary growth to metastatic colonisation.","Tumour-derived factors and bone marrow-derived cells prepare pre-metastatic niches in distant organs before cancer cells arrive.","The microenvironment at secondary sites controls whether disseminated cells stay dormant or grow out."],"whatItMeans":"This review is the standard map of the tumour microenvironment and the reason microenvironment-directed drugs, from anti-angiogenics to macrophage and fibroblast targeting agents, are developed alongside tumour-cell-directed ones.","caveats":["A review; many mechanisms rest on mouse models.","Microenvironment-targeted therapies have had mixed clinical success so far."],"changedPractice":false},{"id":"paper-quantum-first-quizartinib-lancet-2023","kind":"paper","name":"QuANTUM-First: quizartinib added to intensive chemotherapy and continued as maintenance in newly diagnosed FLT3-ITD AML","aka":[],"tldr":"Adding the FLT3 inhibitor quizartinib to standard chemotherapy, and continuing it for up to three years, roughly doubled median survival in FLT3-ITD acute myeloid leukaemia.","summary":"QuANTUM-First randomised 539 adults aged 18-75 with newly diagnosed FLT3-ITD-positive AML to quizartinib or placebo added to standard 7+3 induction and consolidation, continued after allogeneic transplant where performed, and then as maintenance for up to 36 cycles. The primary endpoint was overall survival. Median OS was 31.9 versus 15.1 months (hazard ratio 0.78), with similar remission rates but lower relapse in the quizartinib arm. QT prolongation and cytopenias were more frequent with quizartinib. It followed RATIFY (midostaurin) as the second phase 3 trial to show a survival benefit from a FLT3 inhibitor in front-line therapy, and the first with a selective type II inhibitor.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=QuANTUM-First%20quizartinib%20FLT3-ITD%20Erba%20Lancet%202023"},{"label":"ClinicalTrials.gov NCT02668653","url":"https://clinicaltrials.gov/study/NCT02668653"}],"tags":[],"related":["flt3i-plus-7-3","paper-admiral-gilteritinib-flt3-nejm-2019"],"cancers":["aml"],"sections":[],"technologies":["allogeneic-hsct"],"targets":["flt3"],"drugs":["quizartinib","midostaurin","gilteritinib","cytarabine-7-3"],"companies":["daiichi-sankyo"],"institutions":[],"pathways":[],"terms":["os"],"trials":["quantum-first"],"people":[],"bottlenecks":["b-resistance","b-dose-optimisation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"authors":"Erba HP, Montesinos P, Kim HJ, et al.","paperType":"rct","findings":["539 patients aged 18-75 with FLT3-ITD AML; quizartinib vs placebo with 7+3, consolidation and up to 3 years of maintenance.","Median OS 31.9 vs 15.1 months; hazard ratio 0.78.","Complete remission rates were similar (around 55%), so benefit came from deeper remissions and fewer relapses.","Benefit maintained in patients who proceeded to allogeneic transplant with post-transplant quizartinib.","More grade 3 QT prolongation, neutropenia and infections with quizartinib."],"whatItMeans":"QuANTUM-First gave FLT3-ITD AML patients a second front-line targeted option and showed that continuing a FLT3 inhibitor as long-term maintenance, including after transplant, pays off. Quizartinib was approved for this indication in 2023. Head-to-head data against midostaurin are lacking, and the design leaves open how much of the benefit came from maintenance.","caveats":["Applies only to FLT3-ITD, not FLT3-TKD mutations.","Contribution of maintenance versus induction-phase quizartinib cannot be separated.","Placebo, rather than midostaurin, was the comparator.","Cardiac monitoring for QT prolongation is required; older patients gained less."],"changedPractice":true,"participants":539},{"id":"paper-quartz-lancet-2016","kind":"paper","name":"QUARTZ: whole-brain radiotherapy versus supportive care alone for brain metastases from non-small-cell lung cancer","aka":[],"tldr":"For patients with lung cancer brain metastases unsuitable for surgery or radiosurgery, whole-brain radiotherapy added no meaningful survival or quality of life compared with steroids and supportive care alone.","summary":"Non-inferiority phase 3 trial of 538 patients with brain metastases from non-small-cell lung cancer unsuitable for resection or stereotactic radiotherapy, randomised to optimal supportive care with dexamethasone with or without whole-brain radiotherapy (20 Gy in five fractions).\n\nQuality-adjusted life years were 46.4 days with radiotherapy and 41.7 days without, a difference within the non-inferiority margin, and overall survival was about nine weeks in both arms.","asOf":"2026-09-17","links":[{"label":"Lancet 2016","url":"https://doi.org/10.1016/S0140-6736(16)30825-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27604504/"}],"tags":[],"related":[],"cancers":["secondary-brain-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":["dexamethasone"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["quartz"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2016,"doi":"10.1016/S0140-6736(16)30825-X","pmid":"27604504","authors":"Mulvenna P, Nankivell M, Barton R, et al.","paperType":"rct","findings":["Quality-adjusted life years 46.4 vs 41.7 days (non-inferior).","Median overall survival about 9 weeks in both arms."],"whatItMeans":"Whole-brain radiotherapy is not a default for poor-prognosis brain metastases; supportive care alone is an acceptable choice, with radiotherapy reserved for selected younger, fitter patients.","caveats":["Population had a very poor prognosis; subgroups such as those under 60 may benefit.","Predates targeted therapy for driver-mutated lung cancer with brain penetration."],"changedPractice":true,"participants":538},{"id":"paper-radiant-3-everolimus-pnet-yao-nejm-2011","kind":"paper","name":"RADIANT-3: everolimus for advanced pancreatic neuroendocrine tumours","aka":[],"tldr":"The mTOR inhibitor everolimus more than doubled the time to progression in advanced pancreatic neuroendocrine tumours, becoming one of the first two targeted drugs approved for the disease in 2011.","summary":"Phase 3 placebo-controlled trial of 410 patients with advanced, low- or intermediate-grade, progressive pancreatic neuroendocrine tumours randomised to everolimus 10 mg daily or placebo.\n\nMedian progression-free survival was 11.0 versus 4.6 months (hazard ratio 0.35), with stomatitis, rash, diarrhoea and hyperglycaemia as the characteristic toxicities; overall survival was similar because of crossover.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2011","url":"https://doi.org/10.1056/NEJMoa1009290"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21306238/"}],"tags":[],"related":[],"cancers":["pancreatic-net"],"sections":[],"technologies":[],"targets":[],"drugs":["everolimus"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1009290","pmid":"21306238","authors":"Yao JC, Shah MH, Ito T, et al.","paperType":"rct","findings":["Median progression-free survival 11.0 vs 4.6 months; hazard ratio 0.35.","Objective response 5 percent; benefit was disease stabilisation."],"whatItMeans":"Everolimus is a standard option for progressive pancreatic neuroendocrine tumours, alongside sunitinib, chemotherapy and radioligand therapy.","caveats":["Crossover obscured any survival benefit.","Hyperglycaemia is a particular concern in this population."],"changedPractice":true,"participants":410},{"id":"paper-radiant-4-everolimus-lancet-2016","kind":"paper","name":"RADIANT-4: everolimus for advanced non-functional neuroendocrine tumours of the lung or gastrointestinal tract","aka":[],"tldr":"Everolimus more than doubled the time to progression in advanced non-functioning neuroendocrine tumours of the lung and gut, the first drug with randomised evidence in lung carcinoids.","summary":"Phase 3 placebo-controlled trial of 302 patients with advanced progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin randomised 2:1 to everolimus 10 mg daily or placebo.\n\nMedian progression-free survival was 11.0 versus 3.9 months (hazard ratio 0.48), with consistent benefit in lung and gastrointestinal subgroups; stomatitis, diarrhoea and infections were the main toxicities.","asOf":"2026-09-17","links":[{"label":"Lancet 2016","url":"https://doi.org/10.1016/S0140-6736(15)00817-X"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26703889/"}],"tags":[],"related":[],"cancers":["lung-net","small-intestinal-net"],"sections":[],"technologies":[],"targets":[],"drugs":["everolimus"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2016,"doi":"10.1016/S0140-6736(15)00817-X","pmid":"26703889","authors":"Yao JC, Fazio N, Singh S, et al.","paperType":"rct","findings":["Median progression-free survival 11.0 vs 3.9 months; hazard ratio 0.48.","Lung subgroup: 9.2 vs 3.6 months."],"whatItMeans":"Everolimus is approved for progressive lung and gastrointestinal neuroendocrine tumours and is a standard option after somatostatin analogues, particularly in lung carcinoids where radioligand therapy is off label.","caveats":["No overall survival benefit shown.","Response rates were low; benefit is disease stabilisation."],"changedPractice":true,"participants":302},{"id":"paper-radicals-rt-lancet-2020","kind":"paper","name":"RADICALS-RT: timing of radiotherapy after radical prostatectomy","aka":[],"tldr":"Giving radiotherapy to every man with risk factors immediately after prostatectomy was no better than waiting and treating only those whose PSA rose, so early salvage radiotherapy became the standard and spared many men unnecessary treatment.","summary":"Phase 3 trial of 1,396 men after radical prostatectomy with at least one risk factor (pT3/4, Gleason 7 to 10, positive margins or preoperative PSA of 10 or more) randomised to adjuvant radiotherapy within six months or an observation policy with early salvage radiotherapy at biochemical failure.\n\nFive-year biochemical progression-free survival was 85 percent with adjuvant and 88 percent with salvage policy (hazard ratio 1.10, no difference), with only a third of the salvage group receiving radiotherapy by five years and more urinary and bowel toxicity in the adjuvant group; a meta-analysis with two similar trials (ARTISTIC) confirmed the result.","asOf":"2026-09-17","links":[{"label":"Lancet 2020","url":"https://doi.org/10.1016/S0140-6736(20)31553-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33002429/"}],"tags":[],"related":[],"cancers":["prostate-bcr"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2020,"doi":"10.1016/S0140-6736(20)31553-1","pmid":"33002429","authors":"Parker CC, Clarke NW, Cook AD, et al.","paperType":"rct","findings":["Five-year biochemical progression-free survival 85 percent (adjuvant) vs 88 percent (salvage policy).","Only 33 percent of the salvage-policy group had received radiotherapy at five years."],"whatItMeans":"Observation with early salvage radiotherapy at PSA recurrence is standard after prostatectomy, avoiding radiotherapy in most men who would never have needed it.","caveats":["Men with the highest-risk features (multiple adverse factors) were under-represented.","Longer follow-up for metastasis-free survival is pending."],"changedPractice":true,"participants":1396},{"id":"paper-bonner-cetuximab-radiotherapy-nejm-2006","kind":"paper","name":"Radiotherapy plus cetuximab for locoregionally advanced squamous cell carcinoma of the head and neck","aka":[],"tldr":"Adding the EGFR antibody cetuximab to radiotherapy lengthened survival in locally advanced head and neck cancer by about 20 months without increasing the mucosal toxicity of radiotherapy, giving patients unfit for cisplatin an alternative.","summary":"Phase 3 trial of 424 patients with stage III to IV squamous cell carcinoma of the oropharynx, hypopharynx or larynx randomised to high-dose radiotherapy alone or with weekly cetuximab.\n\nMedian overall survival was 49.0 versus 29.3 months (hazard ratio 0.74) and locoregional control 24.4 versus 14.9 months; apart from acneiform rash and infusion reactions, toxicity was not increased. Later analyses suggested the benefit was concentrated in oropharyngeal cancer.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2006","url":"https://doi.org/10.1056/NEJMoa053422"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16467544/"}],"tags":[],"related":[],"cancers":["hpv-negative-head-and-neck-cancer","hypopharyngeal-cancer","lip-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["cetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2006,"doi":"10.1056/NEJMoa053422","pmid":"16467544","authors":"Bonner JA, Harari PM, Giralt J, et al.","paperType":"rct","findings":["Median overall survival 49.0 vs 29.3 months; hazard ratio 0.74.","Median locoregional control 24.4 vs 14.9 months."],"whatItMeans":"Cetuximab-radiotherapy is the standard for patients who cannot receive cisplatin; head-to-head trials in HPV-positive disease (RTOG 1016, De-ESCALaTE) later showed it inferior to cisplatin where cisplatin is possible.","caveats":["Never compared directly with cisplatin chemoradiation in this trial.","HPV status was not known."],"changedPractice":true,"participants":424},{"id":"paper-rahib-projecting-cancer-deaths-2030-cancerres-2014","kind":"paper","name":"Rahib 2014: projecting US cancer incidence and deaths to 2030","aka":[],"tldr":"A projection that by 2030 pancreatic and liver cancers would overtake breast, prostate and colorectal cancers to become the second and third leading causes of cancer death in the United States, because progress against the common cancers was not being matched in these two.","summary":"Rahib and colleagues at the Pancreatic Cancer Action Network combined US population projections with registry trends in incidence and mortality to project cancer cases and deaths to 2030. They forecast that lung cancer would remain the leading cause of cancer death, that pancreatic and liver cancers would rise to second and third place, and that thyroid, melanoma and uterine cancers would be among the fastest-growing in incidence, while colorectal cancer would fall in rank. The paper was widely used to argue for research funding directed at cancers with stagnant outcomes.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1158/0008-5472.CAN-14-0155"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":["pancreatic","hcc","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Cancer Research","year":2014,"doi":"10.1158/0008-5472.CAN-14-0155","authors":"Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM.","paperType":"observational","findings":["Projected that pancreatic and liver cancers would become the second and third leading causes of US cancer death by 2030, after lung cancer.","Breast, prostate and lung cancers projected to remain the most commonly diagnosed; thyroid, melanoma and uterine cancers among the fastest rising in incidence.","Projections driven by an ageing population combined with flat or rising death rates for pancreatic and liver cancer."],"whatItMeans":"This paper reframed pancreatic and liver cancer as the coming burden and is cited in most arguments for investing in them. Its pancreatic cancer projection has been tracking close to reality in the years since.","caveats":["Projections assume that recent trends continue and cannot anticipate new treatments or screening.","US-specific."],"changedPractice":false},{"id":"paper-rainbow-ramucirumab-paclitaxel-lancet-oncol-2014","kind":"paper","name":"RAINBOW: ramucirumab plus paclitaxel versus placebo plus paclitaxel in previously treated advanced gastric cancer","aka":[],"tldr":"Adding the anti-VEGFR2 antibody ramucirumab to weekly paclitaxel lengthened survival by over two months in gastric cancer that had progressed after first-line chemotherapy, establishing the standard second-line regimen.","summary":"Phase 3 placebo-controlled trial of 665 patients with advanced gastric or junctional adenocarcinoma progressing after first-line platinum-fluoropyrimidine chemotherapy randomised to ramucirumab or placebo with weekly paclitaxel.\n\nMedian overall survival was 9.6 versus 7.4 months (hazard ratio 0.81), progression-free survival 4.4 versus 2.9 months and response 28 versus 16 percent; neutropenia, hypertension and fatigue were more frequent with ramucirumab.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2014","url":"https://doi.org/10.1016/S1470-2045(14)70420-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25240821/"}],"tags":[],"related":[],"cancers":["gastric-pdl1-high","gastric-cldn18-2-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["ramucirumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rainbow"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2014,"doi":"10.1016/S1470-2045(14)70420-6","pmid":"25240821","authors":"Wilke H, Muro K, Van Cutsem E, et al.","paperType":"rct","findings":["Median overall survival 9.6 vs 7.4 months; hazard ratio 0.81.","Median progression-free survival 4.4 vs 2.9 months."],"whatItMeans":"Ramucirumab-paclitaxel is the second-line standard for HER2-negative gastric cancer after chemo-immunotherapy, and the comparator for newer agents.","caveats":["Regional differences: benefit was smaller in Asian patients, partly because of more third-line therapy."],"changedPractice":true,"participants":665},{"id":"paper-ramp-201-avutometinib-defactinib-lgsoc-jco-2025","kind":"paper","name":"RAMP 201: avutometinib with or without defactinib in recurrent low-grade serous ovarian cancer","aka":[],"tldr":"The combination of the RAF/MEK clamp avutometinib and the FAK inhibitor defactinib shrank tumours in about a third of women with recurrent low-grade serous ovarian cancer and in 44 percent of those with KRAS mutations, leading to the first approval specific to this disease.","summary":"Phase 2 study of 115 patients with recurrent low-grade serous ovarian cancer treated with avutometinib alone or with defactinib; the combination was selected for expansion.\n\nIn the combination arm, objective response was 31 percent overall and 44 percent in KRAS-mutant tumours (17 percent in KRAS wild-type), with median duration of response of 31 months and median progression-free survival of 12.9 months overall; toxicity included creatine kinase elevation, nausea and rash.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2025","url":"https://doi.org/10.1200/JCO-25-00112"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/40644648/"}],"tags":[],"related":[],"cancers":["low-grade-serous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ramp-201"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2025,"doi":"10.1200/JCO-25-00112","pmid":"40644648","authors":"Banerjee SN, Van Nieuwenhuysen E, Aghajanian C, et al.","paperType":"observational","findings":["Objective response 31 percent overall; 44 percent in KRAS-mutant and 17 percent in KRAS wild-type tumours.","Median duration of response 31.1 months."],"whatItMeans":"Avutometinib plus defactinib is approved for KRAS-mutant recurrent low-grade serous ovarian cancer, making KRAS testing a routine part of managing the disease; RAMP 301 is comparing it with standard therapy.","caveats":["Single-arm; approval was accelerated pending the randomised RAMP 301 trial."],"changedPractice":true,"participants":115},{"id":"paper-rapido-lancet-oncol-2021","kind":"paper","name":"RAPIDO: short-course radiotherapy followed by chemotherapy before surgery for high-risk locally advanced rectal cancer","aka":[],"tldr":"Giving all treatment before surgery, with a week of radiotherapy followed by four to five months of chemotherapy, halved distant metastases and doubled the complete response rate compared with standard chemoradiation in high-risk rectal cancer.","summary":"Phase 3 trial of 912 patients with high-risk locally advanced rectal adenocarcinoma randomised to short-course radiotherapy (5 x 5 Gy) followed by six cycles of CAPOX or nine of FOLFOX then total mesorectal excision, or standard long-course chemoradiotherapy, surgery and optional adjuvant chemotherapy.\n\nDisease-related treatment failure at three years was 23.7 versus 30.4 percent, distant metastases 20.0 versus 26.8 percent and pathological complete response 28 versus 14 percent; longer follow-up showed more locoregional failures in the experimental arm.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(20)30555-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33301740/"}],"tags":[],"related":[],"cancers":["rectal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rapido"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(20)30555-6","pmid":"33301740","authors":"Bahadoer RR, Dijkstra EA, van Etten B, et al.","paperType":"rct","findings":["Three-year disease-related treatment failure 23.7 percent vs 30.4 percent; hazard ratio 0.75.","Pathological complete response 28 percent vs 14 percent."],"whatItMeans":"Total neoadjuvant therapy is now a standard for high-risk rectal cancer, improving compliance with chemotherapy and enabling organ preservation, though the locoregional recurrence signal favours long-course chemoradiation in some patients.","caveats":["Five-year locoregional failure was higher with the experimental arm (10 vs 6 percent).","No overall survival difference."],"changedPractice":true,"participants":912},{"id":"paper-ratify-midostaurin-nejm-2017","kind":"paper","name":"RATIFY: midostaurin added to chemotherapy for acute myeloid leukaemia with a FLT3 mutation","aka":[],"tldr":"Adding the FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy, then as maintenance, lengthened survival in adults under 60 with FLT3-mutated acute myeloid leukaemia, the first targeted drug to do so.","summary":"Phase 3 placebo-controlled trial of 717 patients aged 18 to 59 with newly diagnosed FLT3-mutated AML (ITD or TKD) randomised to midostaurin or placebo with daunorubicin-cytarabine induction, high-dose cytarabine consolidation and a year of maintenance.\n\nMedian overall survival was 74.7 months with midostaurin against 25.6 months with placebo (hazard ratio 0.78), with benefit across FLT3 subtypes and in patients who went on to transplant.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2017","url":"https://doi.org/10.1056/NEJMoa1614359"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28644114/"}],"tags":[],"related":[],"cancers":["aml-flt3"],"sections":[],"technologies":[],"targets":[],"drugs":["midostaurin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ratify"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1614359","pmid":"28644114","authors":"Stone RM, Mandrekar SJ, Sanford BL, et al.","paperType":"rct","findings":["Median overall survival 74.7 vs 25.6 months; hazard ratio for death 0.78.","Four-year overall survival 51.4 percent vs 44.3 percent."],"whatItMeans":"FLT3 testing at diagnosis and a FLT3 inhibitor during chemotherapy became standard. Quizartinib (QuANTUM-First) is an alternative for FLT3-ITD, and the approach extended FLT3 inhibitors into maintenance and relapse.","caveats":["Patients over 60 were excluded.","The contribution of maintenance midostaurin could not be isolated."],"changedPractice":true,"participants":717},{"id":"paper-persson-myb-nfib-pnas-2009","kind":"paper","name":"Recurrent fusion of MYB and NFIB transcription factor genes in adenoid cystic carcinoma","aka":[],"tldr":"This study discovered that adenoid cystic carcinomas of the salivary gland and breast are driven by a fusion of the MYB and NFIB genes, providing the defining molecular feature of the tumour and a diagnostic marker.","summary":"Molecular study identifying a recurrent t(6;9) translocation in adenoid cystic carcinoma that fuses the MYB oncogene to NFIB, leading to MYB overexpression by loss of microRNA-mediated repression, present in the majority of tumours of both head and neck and breast origin.","asOf":"2026-09-17","links":[{"label":"Proc Natl Acad Sci U S A 2009","url":"https://doi.org/10.1073/pnas.0909114106"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19841262/"}],"tags":[],"related":[],"cancers":["adenoid-cystic-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"Proceedings of the National Academy of Sciences","year":2009,"doi":"10.1073/pnas.0909114106","pmid":"19841262","authors":"Persson M, Andrén Y, Mark J, et al.","paperType":"basic","findings":["MYB-NFIB fusion detected in the majority of adenoid cystic carcinomas.","Fusion leads to MYB overexpression through loss of 3' untranslated region regulation."],"whatItMeans":"MYB immunostaining and MYB-NFIB fusion testing are now diagnostic tools for adenoid cystic carcinoma, and MYB is the principal target of therapeutic research in the disease.","caveats":["No approved MYB-directed therapy has yet followed."],"changedPractice":true},{"id":"paper-reflect-lenvatinib-lancet-2018","kind":"paper","name":"REFLECT: lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma","aka":[],"tldr":"Lenvatinib matched sorafenib for survival in advanced liver cancer while shrinking tumours far more often and delaying progression longer, making it the first new first-line option in ten years.","summary":"Phase 3 non-inferiority trial of 954 patients with unresectable hepatocellular carcinoma randomised to lenvatinib (weight-based 8 or 12 mg) or sorafenib.\n\nMedian overall survival was 13.6 versus 12.3 months (hazard ratio 0.92, non-inferior), progression-free survival 7.4 versus 3.7 months, and response 24.1 versus 9.2 percent; hypertension, proteinuria and decreased appetite were more frequent with lenvatinib.","asOf":"2026-09-17","links":[{"label":"Lancet 2018","url":"https://doi.org/10.1016/S0140-6736(18)30207-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29433850/"}],"tags":[],"related":[],"cancers":["hcc-advanced"],"sections":[],"technologies":[],"targets":[],"drugs":["lenvatinib","sorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["reflect"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2018,"doi":"10.1016/S0140-6736(18)30207-1","pmid":"29433850","authors":"Kudo M, Finn RS, Qin S, et al.","paperType":"rct","findings":["Median overall survival 13.6 vs 12.3 months; hazard ratio 0.92 (non-inferior).","Objective response 24.1 percent vs 9.2 percent."],"whatItMeans":"Lenvatinib is a first-line alternative to sorafenib and the preferred kinase inhibitor when immunotherapy is contraindicated, such as after liver transplantation.","caveats":["Excluded main portal vein invasion and over 50 percent liver involvement.","Non-inferiority rather than superiority."],"changedPractice":true,"participants":954},{"id":"paper-wotherspoon-h-pylori-malt-lancet-1993","kind":"paper","name":"Regression of primary low-grade gastric MALT lymphoma after eradication of Helicobacter pylori","aka":[],"tldr":"In six patients, eradicating the stomach bacterium Helicobacter pylori with antibiotics made low-grade gastric lymphoma regress, proving that a cancer could be caused by, and treated through, a chronic infection.","summary":"Case series of six patients with primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type and Helicobacter pylori infection treated with antibiotics to eradicate the organism.\n\nIn five patients the lymphoma regressed histologically and endoscopically after eradication, supporting the hypothesis that the lymphoma is driven by antigenic stimulation from the infection.","asOf":"2026-09-17","links":[{"label":"Lancet 1993","url":"https://doi.org/10.1016/0140-6736(93)91409-F"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/8102719/"}],"tags":[],"related":[],"cancers":["marginal-zone-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":1993,"doi":"10.1016/0140-6736(93)91409-F","pmid":"8102719","authors":"Wotherspoon AC, Doglioni C, Diss TC, et al.","paperType":"observational","findings":["Lymphoma regression in five of six patients after Helicobacter pylori eradication."],"whatItMeans":"Antibiotic eradication is the first-line treatment for Helicobacter pylori-positive gastric MALT lymphoma, curing most patients without chemotherapy or radiotherapy.","caveats":["Six patients; lymphomas with t(11;18) or deep invasion often do not respond and need radiotherapy."],"changedPractice":true,"participants":6},{"id":"paper-relativity-047-nejm-2022","kind":"paper","name":"RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma","aka":[],"tldr":"Adding an antibody against a second immune brake, LAG-3, to nivolumab delayed progression in advanced melanoma compared with nivolumab alone, with far fewer serious side effects than the ipilimumab combination.","summary":"Double-blind phase 3 trial of 714 patients with untreated advanced melanoma randomised to a fixed-dose combination of relatlimab (anti-LAG-3) and nivolumab or nivolumab alone. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 10.1 vs 4.6 months (HR 0.75). Grade 3-4 treatment-related adverse events were 18.9% vs 9.7%, much lower than the roughly 55-59% seen with nivolumab plus ipilimumab. It validated LAG-3 as the third checkpoint target after CTLA-4 and PD-1, led to FDA approval of the combination (Opdualag) in 2022, and provided a gentler dual-checkpoint option.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2109970"},{"label":"ClinicalTrials.gov NCT03470922","url":"https://clinicaltrials.gov/study/NCT03470922"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["lag3","pd1"],"drugs":["relatlimab-nivolumab","nivolumab"],"companies":["bms"],"institutions":["md-anderson"],"pathways":[],"terms":["pfs","os","irae","first-line"],"trials":["checkmate-067"],"people":[],"bottlenecks":["b-immunotherapy-response","b-toxicity-qol","b-combination-space"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2109970","authors":"Tawbi HA, Schadendorf D, Lipson EJ, et al.","paperType":"rct","findings":["Median PFS 10.1 vs 4.6 months; HR 0.75 (95% CI 0.62-0.92); 12-month PFS 47.7% vs 36.0%.","Benefit consistent across LAG-3 and PD-L1 expression subgroups, so neither is used for selection.","Grade 3-4 treatment-related adverse events 18.9% vs 9.7%; discontinuation for toxicity 14.6% vs 6.7%.","Overall survival (updated analysis): median 51.0 vs 34.1 months, HR 0.80, not meeting the prespecified significance threshold.","Objective response 43.1% vs 32.6% in later analyses."],"whatItMeans":"Patients with newly diagnosed advanced melanoma have a dual-checkpoint option that improves on nivolumab alone with only a modest increase in serious side effects, making it attractive for those unable to tolerate or unwilling to risk the toxicity of ipilimumab. It did not prove superior survival, and it has not been compared with nivolumab plus ipilimumab, which remains preferred for patients with brain metastases or other high-risk features. LAG-3 is now an established target under study in many other cancers.","caveats":["Overall survival improvement did not reach statistical significance.","No head-to-head comparison with nivolumab plus ipilimumab; indirect comparisons suggest the ipilimumab combination may be more active in poor-prognosis subgroups.","Patients with active brain metastases were excluded.","Whether relatlimab adds benefit in other tumours is not yet demonstrated in phase 3."],"changedPractice":true,"participants":714},{"id":"paper-reproducibility-project-cancer-biology-elife-2021","kind":"paper","name":"Reproducibility Project: Cancer Biology found that landmark preclinical results mostly shrank or vanished on replication","aka":[],"tldr":"An eight-year effort to repeat 50 experiments from 23 high-impact cancer biology papers found that replication effect sizes were on average 85% smaller than the originals, and fewer than half of the effects replicated by most criteria.","summary":"The Center for Open Science and Science Exchange set out in 2013 to replicate selected experiments from 53 high-impact cancer biology papers published 2010-2012, with registered reports and original-author consultation. Only 50 experiments from 23 papers could be completed; the companion paper (Errington et al., eLife 2021, 'Challenges for assessing replicability') documents that no original paper contained enough methodological detail to design a replication without contacting the authors, and that about a third of authors were unhelpful or unresponsive.\n\nAcross 158 measured effects, the median replication effect size was 85% smaller than the original; 92% of replication effects were smaller than the originals. Using five criteria, 46% of effects replicated on more criteria than they failed; for original positive results, about 40% replicated, while null results replicated at 80%.\n\nThe project quantified the preclinical reproducibility problem that pharmaceutical groups (Begley and Ellis 2012; Prinz 2011) had reported anecdotally, and shaped funder requirements for rigour and data sharing.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.7554/eLife.71601"},{"label":"Companion paper: challenges for assessing replicability","url":"https://doi.org/10.7554/eLife.67995"}],"tags":[],"related":["idea-tr1-surrogate-validation-programme","idea-fund-public-nonprofit-cro"],"cancers":[],"sections":["drug-discovery"],"technologies":["pdx-models","organoids"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-reproducibility","b-translational-valley","b-preclinical-models","b-negative-results"],"keyPapers":[],"journals":["elife"],"dependsOn":[],"notes":[],"journal":"eLife","year":2021,"doi":"10.7554/eLife.71601","pmid":"34874005","authors":"Errington TM, Mathur M, Soderberg CK, et al.","paperType":"meta-analysis","findings":["50 experiments from 23 papers completed out of 193 planned from 53 papers","Median replication effect size 85% smaller than original; 92% of replication effects smaller than originals","46% of 158 effects replicated on more criteria than they failed; original positive results replicated about 40% of the time, null results 80%","No original paper described methods in enough detail to replicate without author contact; 32% of authors were minimally helpful or unresponsive"],"whatItMeans":"Many exciting laboratory findings that motivate drug programmes are weaker or less reliable than published, which helps explain the high failure rate of drugs entering clinical trials. It argues for pre-registration, detailed methods, data sharing and independent replication before major translational investment.","caveats":["Replications used the original protocols where possible, but reagents, animals and laboratories differ; some failures may reflect context sensitivity rather than error","Selection of high-impact papers may not represent the field","Under-powered replications could miss true effects; effect-size shrinkage is the more robust finding","Only about a quarter of planned experiments were completed, which limits generalisation"],"changedPractice":false},{"id":"paper-ata-medullary-thyroid-guideline-wells-thyroid-2015","kind":"paper","name":"Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma","aka":[],"tldr":"The American Thyroid Association guideline for medullary thyroid cancer sets out RET germline testing for every patient, the timing of prophylactic thyroidectomy in hereditary carriers by mutation risk, surgical extent, and systemic therapy for advanced disease.","summary":"Comprehensive guideline covering diagnosis and genetic testing, risk categories for RET mutations (highest, high, moderate) with recommended ages for prophylactic surgery, initial surgical management, postoperative calcitonin surveillance, management of persistent or recurrent disease, external radiotherapy and kinase inhibitors.","asOf":"2026-09-17","links":[{"label":"Thyroid 2015","url":"https://doi.org/10.1089/thy.2014.0335"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25810047/"}],"tags":[],"related":[],"cancers":["medullary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Thyroid","year":2015,"doi":"10.1089/thy.2014.0335","pmid":"25810047","authors":"Wells SA, Asa SL, Dralle H, et al.","paperType":"guideline","findings":[],"whatItMeans":"The medullary thyroid cancer page's approach to hereditary carriers and to surgery without radioactive iodine follows this guideline.","caveats":["Predates selpercatinib and pralsetinib; systemic therapy recommendations are outdated."],"changedPractice":true},{"id":"paper-r-iss-palumbo-jco-2015","kind":"paper","name":"Revised International Staging System (R-ISS) for multiple myeloma","aka":[],"tldr":"The revised staging system for myeloma combines the older albumin and beta-2 microglobulin stage with high-risk chromosome changes and a raised lactate dehydrogenase, giving three groups with very different survival.","summary":"Analysis of 3,060 patients from eleven international trials to build a staging system combining ISS stage, chromosomal abnormalities detected by fluorescence in situ hybridisation (del(17p), t(4;14), t(14;16)) and serum lactate dehydrogenase.\n\nFive-year overall survival was 82 percent in R-ISS stage I, 62 percent in stage II and 40 percent in stage III. The R-ISS became the standard prognostic framework and the basis for trial stratification.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2015","url":"https://doi.org/10.1200/JCO.2015.61.2267"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26240224/"}],"tags":[],"related":[],"cancers":["myeloma-transplant-eligible","plasma-cell-leukaemia","myeloma-relapsed-refractory"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2015,"doi":"10.1200/JCO.2015.61.2267","pmid":"26240224","authors":"Palumbo A, Avet-Loiseau H, Oliva S, et al.","paperType":"methods","findings":["Five-year overall survival 82, 62 and 40 percent in stages I, II and III.","Five-year progression-free survival 55, 36 and 24 percent."],"whatItMeans":"The stage on a myeloma report, and the label of high-risk disease that drives intensified treatment and trial choice, comes from the R-ISS; the 2022 R2-ISS adds 1q gain.","caveats":["Stage II is a large heterogeneous group.","Derived from trial patients treated with older regimens."],"changedPractice":true,"participants":3060},{"id":"paper-olsen-mycosis-fungoides-staging-blood-2007","kind":"paper","name":"Revisions to the staging and classification of mycosis fungoides and Sezary syndrome (ISCL/EORTC)","aka":[],"tldr":"The 2007 international revision of the TNMB staging system for mycosis fungoides and Sezary syndrome defined skin, node, visceral and blood classes that remain the basis for staging, treatment choice and trial eligibility.","summary":"Consensus proposal from the International Society for Cutaneous Lymphomas and the EORTC cutaneous lymphoma task force revising the tumour, node, metastasis and blood (TNMB) classification, defining blood involvement classes B0 to B2, patch/plaque/tumour skin classes and clinical stages IA to IVB.","asOf":"2026-09-17","links":[{"label":"Blood 2007","url":"https://doi.org/10.1182/blood-2007-03-055749"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/17540844/"}],"tags":[],"related":[],"cancers":["cutaneous-t-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood"],"dependsOn":[],"notes":[],"journal":"Blood","year":2007,"doi":"10.1182/blood-2007-03-055749","pmid":"17540844","authors":"Olsen E, Vonderheid E, Pimpinelli N, et al.","paperType":"guideline","findings":[],"whatItMeans":"The stages quoted on the cutaneous T-cell lymphoma page and the skin-directed versus systemic treatment split by stage follow this classification.","caveats":["Updated in 2022 to refine blood staging using flow cytometry."],"changedPractice":true},{"id":"paper-reya-cancer-stem-cells-nature-2001","kind":"paper","name":"Reya 2001: stem cells, cancer and cancer stem cells","aka":[],"tldr":"The review that framed the cancer stem cell idea: only a small subset of cells in a tumour may be able to renew it, so treatments that shrink a tumour without removing those cells let it grow back.","summary":"Reya, Morrison, Clarke and Weissman set out the parallels between normal stem cells and cancer. Normal stem cells self-renew and give rise to differentiated progeny, and the same signalling pathways that control self-renewal, including Wnt, Notch and Sonic hedgehog, are recurrently altered in cancers. Drawing on experiments in which only rare, marker-defined cells from human leukaemia could re-establish the disease in mice, they proposed that many cancers are maintained by a minority of cancer stem cells and that these cells, rather than the tumour bulk, should be the target of therapy.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/35102167"}],"tags":[],"related":[],"cancers":["aml"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["stanford"],"pathways":[],"terms":["stem-cell","relapse-recurrence"],"trials":[],"people":["irving-weissman"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2001,"doi":"10.1038/35102167","authors":"Reya T, Morrison SJ, Clarke MF, Weissman IL.","paperType":"review","findings":["Self-renewal pathways of normal stem cells (Wnt, Notch, Sonic hedgehog) are frequently deregulated in cancer.","In acute myeloid leukaemia only a rare, marker-defined subset of cells could transplant the disease into immunodeficient mice, the first experimental cancer stem cells.","Proposed that tumour growth and relapse are driven by cancer stem cells and that therapies should be judged by their effect on that population."],"whatItMeans":"The paper launched two decades of work on tumour-initiating cells in solid cancers, on why relapse follows apparently complete responses, and on measuring residual disease at the level of the cells that can regrow it. It also connected developmental biology pathways to cancer drug discovery.","caveats":["Whether cancer stem cells are a fixed population or a reversible cell state remains debated.","Transplantation assays in mice may select for cells that survive the assay rather than cells that drive the disease in patients."],"changedPractice":false},{"id":"paper-ribas-wolchok-checkpoint-blockade-science-2018","kind":"paper","name":"Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade","aka":[],"tldr":"A review by two of the field's leading trialists, written as checkpoint inhibitors reached a dozen cancers, explaining how CTLA-4 and PD-1 blockade work, why only some patients respond, and how resistance arises.","summary":"Ribas and Wolchok summarised the science and clinical results of checkpoint blockade at the point where PD-1 pathway antibodies had been approved across many cancers. They described CTLA-4 blockade as broadening the T cell repertoire and PD-1 blockade as reinvigorating exhausted T cells already in the tumour; reviewed the features of responding tumours, including mutational burden, pre-existing T cell infiltration and interferon-gamma signalling; and catalogued primary and acquired resistance mechanisms such as loss of antigen presentation and interferon signalling defects. They argued for rational combinations based on these mechanisms.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.aar4060"}],"tags":[],"related":["paper-pardoll-immune-checkpoint-blockade-nrc-2012","paper-tumeh-pd1-adaptive-immune-resistance-nature-2014"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["ctla4","pd1","pdl1"],"drugs":[],"companies":[],"institutions":["ucla-jonsson","mskcc"],"pathways":[],"terms":["immune-checkpoint","tmb","irae"],"trials":[],"people":["antoni-ribas","jedd-wolchok"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":2018,"doi":"10.1126/science.aar4060","authors":"Ribas A, Wolchok JD.","paperType":"review","findings":["CTLA-4 blockade acts mainly at T cell priming and broadens the repertoire; PD-1 blockade reinvigorates antigen-experienced T cells in the tumour.","Response is associated with mutational burden, pre-existing T cell infiltration and intact interferon-gamma signalling.","Resistance arises through loss of antigen presentation (for example beta-2-microglobulin), JAK-STAT defects and immunosuppressive microenvironments."],"whatItMeans":"This is the standard overview of checkpoint immunotherapy for clinicians and scientists, tying together the trial results and the biology of response and resistance that guide today's combination trials.","caveats":["A review; the field has moved on with LAG-3 blockade, neoadjuvant use and new biomarkers.","Both authors led many of the trials discussed."],"changedPractice":false},{"id":"paper-rizvi-mutational-landscape-pd1-science-2015","kind":"paper","name":"Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer","aka":[],"tldr":"Lung cancers with more mutations, typically those caused by smoking, were more likely to respond to pembrolizumab, the study that established tumour mutational burden as a biomarker for immunotherapy.","summary":"Rizvi, Hellmann, Snyder and colleagues at Memorial Sloan Kettering sequenced the exomes of non-small-cell lung cancers from patients treated with pembrolizumab in a discovery cohort of 16 and a validation cohort of 18. A higher number of nonsynonymous mutations was associated with a higher response rate, more durable clinical benefit and longer progression-free survival. A molecular smoking signature, a higher predicted neoantigen burden and mutations in DNA repair genes also tracked with benefit, and in one responder the team detected T cells recognising a specific neoantigen.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.aaa1348"}],"tags":[],"related":["paper-pardoll-immune-checkpoint-blockade-nrc-2012"],"cancers":["nsclc"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":[],"institutions":["mskcc"],"pathways":[],"terms":["tmb","neoantigen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":2015,"doi":"10.1126/science.aaa1348","authors":"Rizvi NA, Hellmann MD, Snyder A, et al.","paperType":"translational","findings":["Whole-exome sequencing of NSCLC from 16 patients (discovery) and 18 (validation) treated with pembrolizumab.","Higher nonsynonymous mutation burden was associated with durable clinical benefit (73% vs 13% in the discovery cohort) and longer progression-free survival.","A transversion-high smoking signature, predicted neoantigen burden and DNA repair pathway mutations were also associated with benefit.","Neoantigen-specific T cells were detected in a responding patient."],"whatItMeans":"This paper turned a hypothesis into a biomarker: tumour mutational burden is now measured by commercial panels and underpins the tissue-agnostic approval of pembrolizumab for TMB-high tumours. It also explains why smokers' lung cancers, long the hardest to treat, respond better to immunotherapy than never-smokers' cancers.","caveats":["Small cohorts; the mutation burden cut-off was set within the study.","TMB has proved a weaker and less consistent predictor in later, larger trials, and panel-based estimates differ between assays."],"changedPractice":true,"participants":34},{"id":"paper-rohaas-til-vs-ipilimumab-nejm-2022","kind":"paper","name":"Rohaas 2022: the first randomised trial of TIL therapy, against ipilimumab, in advanced melanoma","aka":[],"tldr":"In a head-to-head trial, tumour-infiltrating lymphocyte therapy halved the risk of progression compared with ipilimumab in melanoma that had mostly already failed PD-1 blockade.","summary":"This academic phase 3 trial from the Netherlands Cancer Institute and Copenhagen randomised 168 patients with unresectable stage IIIC-IV melanoma, 86% of whom had progressed on anti-PD-1 therapy, to TIL therapy (tumour resection, ex vivo expansion, cyclophosphamide-fludarabine lymphodepletion, infusion and high-dose interleukin-2) or ipilimumab 3 mg/kg. The primary endpoint was progression-free survival. Median PFS was 7.2 versus 3.1 months (hazard ratio 0.50); objective response was 49% versus 21% and complete response 20% versus 7%. Grade 3 or higher adverse events occurred in all TIL patients, driven by chemotherapy and IL-2, and were transient. Median overall survival was 25.8 versus 18.9 months, not statistically significant. It is the first randomised evidence that a cell therapy improves outcomes in a solid tumour.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2210233"},{"label":"ClinicalTrials.gov NCT02278887","url":"https://clinicaltrials.gov/study/NCT02278887"}],"tags":[],"related":["paper-c-144-01-lifileucel-melanoma-jco-2021"],"cancers":["melanoma"],"sections":[],"technologies":["til-therapy"],"targets":["ctla4"],"drugs":["ipilimumab","aldesleukin","cyclophosphamide","lifileucel"],"companies":[],"institutions":["nki"],"pathways":[],"terms":["tils","pfs"],"trials":[],"people":["john-haanen","ton-schumacher"],"bottlenecks":["b-manufacturing-cell-therapy","b-funding-allocation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2210233","authors":"Rohaas MW, Borch TH, van den Berg JH, et al.","paperType":"rct","findings":["168 patients with advanced melanoma (86% anti-PD-1 refractory); TIL therapy vs ipilimumab.","Median PFS 7.2 vs 3.1 months; hazard ratio 0.50.","Objective response 49% vs 21%; complete response 20% vs 7%.","Median OS 25.8 vs 18.9 months (hazard ratio 0.83, not significant).","Grade 3 or higher adverse events 100% vs 57%, mostly lymphodepletion- and IL-2-related and resolving before discharge."],"whatItMeans":"This trial supplied the randomised proof that was missing for TIL therapy and showed academic centres can run cell-therapy phase 3 trials without industry. It supports TIL as a standard option after checkpoint inhibitor failure in melanoma and underpinned reimbursement in the Netherlands. The comparator, ipilimumab, is itself only modestly effective in this setting, and overall survival did not differ significantly.","caveats":["Ipilimumab monotherapy is a weak comparator in PD-1-refractory melanoma.","Overall survival benefit was not statistically significant; crossover was allowed.","Severe but transient toxicity requiring inpatient care.","Academic manufacturing at two centres; scalability and reproducibility outside them are unproven."],"changedPractice":true,"participants":168},{"id":"paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023","kind":"paper","name":"Rojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer","aka":[],"tldr":"Individualised mRNA vaccines encoding up to 20 of each patient's tumour mutations generated strong T-cell responses in half of pancreatic cancer patients after surgery, and those responders had far fewer relapses.","summary":"In this phase 1 study at Memorial Sloan Kettering, 16 patients with resected pancreatic ductal adenocarcinoma received atezolizumab followed by autogene cevumeran, an individualised uridine mRNA-lipoplex vaccine encoding up to 20 predicted neoantigens manufactured within about nine weeks of surgery, and then modified FOLFIRINOX chemotherapy. The vaccine expanded high-magnitude neoantigen-specific T cells in 8 of 16 patients. At a median follow-up of 18 months, responders had not reached median recurrence-free survival whereas non-responders had a median of 13.4 months (hazard ratio 0.08). Vaccine-induced T-cell clones were shown to be newly generated and, in a 2025 follow-up, persisted for years with continued separation of recurrence curves. A randomised phase 2 trial (IMCODE003) in the same setting is under way.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=Personalized%20RNA%20neoantigen%20vaccines%20stimulate%20T%20cells%20in%20pancreatic%20cancer%20Rojas%20Nature%202023"},{"label":"ClinicalTrials.gov NCT04161755","url":"https://clinicaltrials.gov/study/NCT04161755"}],"tags":[],"related":["vaccine-plus-pd1"],"cancers":["pancreatic","melanoma"],"sections":[],"technologies":["neoantigen-mrna-vaccine"],"targets":["pd1"],"drugs":["autogene-cevumeran","atezolizumab","intismeran-autogene"],"companies":["biontech","roche-genentech"],"institutions":["mskcc"],"pathways":[],"terms":["neoantigen","tmb"],"trials":["interpath-001"],"people":[],"bottlenecks":["b-immunotherapy-response","b-manufacturing-cell-therapy","b-tme-immunosuppression"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2023,"authors":"Rojas LA, Sethna Z, Soares KC, et al.","paperType":"translational","findings":["16 patients with resected pancreatic cancer; atezolizumab, then individualised mRNA neoantigen vaccine (up to 20 neoantigens), then mFOLFIRINOX.","Vaccine manufactured and delivered within about 9 weeks of surgery in most patients.","High-magnitude neoantigen-specific T-cell responses in 8 of 16 (50%).","Median recurrence-free survival not reached in responders vs 13.4 months in non-responders; hazard ratio 0.08.","Responding T-cell clones were de novo and persisted for up to several years in the 2025 follow-up."],"whatItMeans":"Pancreatic cancer was thought to be immunologically inert because of its low mutation burden; this study showed that with the right vaccine platform its few neoantigens can still be targeted. It is the strongest human evidence so far that personalised cancer vaccines can generate durable, tumour-specific immunity, and it justifies the randomised trials now running in pancreatic cancer and melanoma. Benefit is not yet proven, because responders may simply have had more immunogenic tumours.","caveats":["Tiny, non-randomised study; the association between immune response and recurrence could reflect confounding.","Half the patients did not mount a response, for reasons that are only partly understood (for example, splenectomy).","Manufacturing an individual vaccine within weeks of surgery is expensive and logistically complex.","Clinical benefit awaits the randomised IMCODE003 result."],"changedPractice":false,"participants":16},{"id":"paper-rosella-relacorilant-lancet-2025","kind":"paper","name":"ROSELLA: relacorilant plus nab-paclitaxel in platinum-resistant ovarian cancer","aka":[],"tldr":"Adding relacorilant, a drug that blocks the cortisol receptor and thereby restores chemotherapy sensitivity, to nab-paclitaxel lengthened progression-free and overall survival in platinum-resistant ovarian cancer regardless of any biomarker.","summary":"Phase 3 trial of 381 patients with platinum-resistant ovarian cancer and one to three prior lines randomised to intermittent relacorilant plus nab-paclitaxel or nab-paclitaxel alone.\n\nMedian progression-free survival was 6.54 versus 5.52 months (hazard ratio 0.70) and interim median overall survival 15.97 versus 11.50 months (hazard ratio 0.69), with a similar safety profile between arms.","asOf":"2026-09-17","links":[{"label":"Lancet 2025","url":"https://doi.org/10.1016/S0140-6736(25)01040-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/40473448/"}],"tags":[],"related":[],"cancers":["platinum-resistant-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["relacorilant"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rosella"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2025,"doi":"10.1016/S0140-6736(25)01040-2","pmid":"40473448","authors":"Olawaiye AB, Gladieff L, O'Malley DM, et al.","paperType":"rct","findings":["Median progression-free survival 6.54 vs 5.52 months; hazard ratio 0.70.","Interim median overall survival 15.97 vs 11.50 months; hazard ratio 0.69."],"whatItMeans":"Relacorilant with nab-paclitaxel is a new option for platinum-resistant disease that does not depend on folate receptor status, with regulatory review following the trial.","caveats":["Open-label design.","Overall survival analysis was interim."],"changedPractice":true,"participants":381},{"id":"paper-rtog-91-11-forastiere-nejm-2003","kind":"paper","name":"RTOG 91-11: concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer","aka":[],"tldr":"Giving cisplatin at the same time as radiotherapy preserved the larynx in more patients with advanced laryngeal cancer than either induction chemotherapy followed by radiotherapy or radiotherapy alone, defining the standard larynx-preserving treatment.","summary":"Phase 3 trial of 547 patients with stage III to IV laryngeal cancer randomised to induction cisplatin-fluorouracil followed by radiotherapy, concurrent cisplatin with radiotherapy, or radiotherapy alone.\n\nLaryngectomy-free survival was similar between the chemotherapy arms, but laryngeal preservation at two years was 88 percent with concurrent chemoradiation against 75 percent with induction and 70 percent with radiotherapy alone, and locoregional control was best with concurrent treatment; overall survival was similar in all arms.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2003","url":"https://doi.org/10.1056/NEJMoa031317"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/14645636/"}],"tags":[],"related":[],"cancers":["laryngeal-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rtog-91-11"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2003,"doi":"10.1056/NEJMoa031317","pmid":"14645636","authors":"Forastiere AA, Goepfert H, Maor M, et al.","paperType":"rct","findings":["Two-year laryngeal preservation 88 percent (concurrent) vs 75 percent (induction) vs 70 percent (radiotherapy alone).","Overall survival similar across arms."],"whatItMeans":"Concurrent cisplatin chemoradiation is the standard larynx-preserving treatment for advanced laryngeal cancer where the larynx is still functioning; laryngectomy is reserved for extensive disease or salvage.","caveats":["Long-term follow-up showed more non-cancer deaths in the concurrent arm.","T4 tumours with cartilage invasion were excluded."],"changedPractice":true,"participants":547},{"id":"paper-rtog-9402-cairncross-jco-2013","kind":"paper","name":"RTOG 9402: PCV chemotherapy before radiotherapy for anaplastic oligodendroglioma, long-term results","aka":[],"tldr":"Long follow-up of this trial showed that adding PCV chemotherapy to radiotherapy roughly doubled survival, from about seven to fourteen years, in anaplastic oligodendroglioma with loss of chromosomes 1p and 19q, while tumours without the codeletion gained nothing.","summary":"Phase 3 trial of 291 patients with anaplastic oligodendroglioma or oligoastrocytoma randomised to intensive PCV followed by radiotherapy or radiotherapy alone, reported at a median follow-up of 11.3 years.\n\nOverall survival did not differ in the whole cohort, but in 1p/19q-codeleted tumours median survival was 14.7 years with PCV against 7.3 years without (hazard ratio 0.59), while non-codeleted tumours had a median of 2.6 versus 2.7 years.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2013","url":"https://doi.org/10.1200/JCO.2012.43.2674"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23071247/"}],"tags":[],"related":[],"cancers":["oligodendroglioma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rtog-9402"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2013,"doi":"10.1200/JCO.2012.43.2674","pmid":"23071247","authors":"Cairncross G, Wang M, Shaw E, et al.","paperType":"rct","findings":["Codeleted tumours: median overall survival 14.7 vs 7.3 years; hazard ratio 0.59.","Non-codeleted tumours: no benefit (2.6 vs 2.7 years)."],"whatItMeans":"1p/19q codeletion is a predictive marker: codeleted oligodendroglioma is treated with radiotherapy plus PCV, and the finding helped make the codeletion part of the tumour's definition.","caveats":["Retrospective molecular subgrouping of a trial designed before codeletion was known to matter.","Intensive PCV schedule was poorly tolerated."],"changedPractice":true,"participants":291},{"id":"paper-rtog-9408-short-term-adt-jones-nejm-2011","kind":"paper","name":"RTOG 9408: radiotherapy with short-term androgen deprivation for localised prostate cancer","aka":[],"tldr":"Four months of hormone therapy around radiotherapy improved survival in men with early prostate cancer, with the benefit confined to intermediate-risk disease, so short-course androgen deprivation became standard for that group.","summary":"Phase 3 trial of 1,979 men with T1b to T2b prostate cancer and PSA of 20 or less randomised to radiotherapy alone or with four months of androgen deprivation beginning two months before radiotherapy.\n\nTen-year overall survival was 62 versus 57 percent and prostate cancer mortality 4 versus 8 percent with androgen deprivation; the benefit was seen in intermediate-risk men (ten-year survival 61 versus 54 percent) and not in low-risk men.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2011","url":"https://doi.org/10.1056/NEJMoa1012348"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21751904/"}],"tags":[],"related":[],"cancers":["prostate-intermediate-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1012348","pmid":"21751904","authors":"Jones CU, Hunt D, McGowan DG, et al.","paperType":"rct","findings":["Ten-year overall survival 62 percent vs 57 percent.","Intermediate risk: ten-year overall survival 61 percent vs 54 percent; no benefit in low risk."],"whatItMeans":"Short-term androgen deprivation with radiotherapy is standard for unfavourable intermediate-risk prostate cancer; low-risk men do not need it.","caveats":["Radiotherapy dose (66.6 Gy) was lower than current practice; whether hormones are needed with dose-escalated radiotherapy is debated."],"changedPractice":true,"participants":1979},{"id":"paper-cooper-rtog-9501-nejm-2004","kind":"paper","name":"RTOG 9501: postoperative concurrent radiotherapy and chemotherapy for high-risk head and neck squamous cell carcinoma","aka":[],"tldr":"In this American trial, adding cisplatin to postoperative radiotherapy for high-risk head and neck cancer improved local control and disease-free survival but not overall survival, and doubled severe toxicity.","summary":"Phase 3 trial of 459 patients with resected high-risk head and neck squamous cell carcinoma (two or more involved nodes, extracapsular extension or positive margins) randomised to postoperative radiotherapy alone or with concurrent cisplatin.\n\nLocoregional control at two years was 82 versus 72 percent (hazard ratio 0.61) and disease-free survival was improved (hazard ratio 0.78), but overall survival did not differ significantly; grade 3 or worse adverse events were 77 versus 34 percent. Long-term follow-up confirmed benefit only in patients with extracapsular extension or positive margins.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2004","url":"https://doi.org/10.1056/NEJMoa032646"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15128893/"}],"tags":[],"related":[],"cancers":["hpv-negative-head-and-neck-cancer","oral-cavity-cancer","buccal-mucosa-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2004,"doi":"10.1056/NEJMoa032646","pmid":"15128893","authors":"Cooper JS, Pajak TF, Forastiere AA, et al.","paperType":"rct","findings":["Two-year locoregional control 82 percent vs 72 percent.","Grade 3 or greater adverse events 77 percent vs 34 percent."],"whatItMeans":"With EORTC 22931, this trial defines who receives postoperative chemoradiation: patients with extranodal extension or positive margins, not those whose only risk factor is multiple nodes.","caveats":["No overall survival benefit in the whole population.","Different high-risk definitions from the EORTC trial."],"changedPractice":true,"participants":459},{"id":"paper-rtog-9802-buckner-nejm-2016","kind":"paper","name":"RTOG 9802: radiation plus procarbazine, lomustine and vincristine in high-risk low-grade glioma","aka":[],"tldr":"Adding PCV chemotherapy after radiotherapy for grade 2 glioma in adults who were over 40 or had residual tumour lengthened median survival from about eight to over thirteen years, one of the largest gains ever seen in neuro-oncology.","summary":"Phase 3 trial of 251 patients with grade 2 astrocytoma, oligodendroglioma or oligoastrocytoma who were either aged 40 or over or had undergone subtotal resection, randomised to radiotherapy alone or radiotherapy followed by six cycles of procarbazine, lomustine and vincristine (PCV).\n\nMedian overall survival was 13.3 years with PCV against 7.8 years with radiotherapy alone (hazard ratio 0.59), with benefit across histologies in later molecular analyses, strongest in IDH-mutant tumours.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2016","url":"https://doi.org/10.1056/NEJMoa1500925"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27050206/"}],"tags":[],"related":[],"cancers":["idh-mutant-astrocytoma","oligodendroglioma"],"sections":[],"technologies":[],"targets":[],"drugs":["procarbazine","vincristine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1500925","pmid":"27050206","authors":"Buckner JC, Shaw EG, Pugh SL, et al.","paperType":"rct","findings":["Median overall survival 13.3 vs 7.8 years; hazard ratio for death 0.59.","Ten-year progression-free survival 51 percent vs 21 percent."],"whatItMeans":"Radiotherapy followed by PCV is the standard for high-risk grade 2 IDH-mutant glioma; whether temozolomide can replace PCV, and whether vorasidenib can defer both, are the current questions.","caveats":["Small trial that took two decades to report.","PCV toxicity limits completion of all six cycles."],"changedPractice":true,"participants":251},{"id":"paper-ruby-nejm-2023","kind":"paper","name":"RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer","aka":[],"tldr":"Adding the PD-1 antibody dostarlimab to first-line chemotherapy for advanced endometrial cancer cut progression by 72% in tumours with defective mismatch repair and by about a third overall, and later improved survival.","summary":"Double-blind, placebo-controlled phase 3 trial of 494 patients with primary advanced (stage III-IV) or first recurrent endometrial cancer randomised to dostarlimab or placebo with carboplatin-paclitaxel for six cycles, then dostarlimab or placebo maintenance for up to three years. Primary endpoints were PFS in the dMMR/MSI-high population and in the overall population, and OS.\n\nIn dMMR tumours (about 24% of patients), 24-month PFS was 61.4% vs 15.7% (HR 0.28); overall, 36.1% vs 18.1% (HR 0.64). Overall survival was improved in the whole population (HR 0.69 in the 2024 analysis). Together with NRG-GY018 (pembrolizumab), it made chemo-immunotherapy the first-line standard for advanced endometrial cancer and mismatch repair testing routine.","asOf":"2026-09-08","links":[{"label":"NEJM 2023","url":"https://doi.org/10.1056/NEJMoa2216334"},{"label":"ClinicalTrials.gov NCT03981796","url":"https://clinicaltrials.gov/study/NCT03981796"}],"tags":[],"related":[],"cancers":["endometrial"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","histopathology-ihc"],"targets":["pd1"],"drugs":["dostarlimab","carboplatin","paclitaxel"],"companies":["gsk"],"institutions":[],"pathways":[],"terms":["msi","pfs","os","first-line"],"trials":[],"people":[],"bottlenecks":["b-immunotherapy-response","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2216334","authors":"Mirza MR, Chase DM, Slomovitz BM, et al.","paperType":"rct","findings":["dMMR/MSI-high: 24-month PFS 61.4% vs 15.7%; HR 0.28 (95% CI 0.16-0.50).","Overall population: 24-month PFS 36.1% vs 18.1%; HR 0.64 (95% CI 0.51-0.80).","Overall survival (Annals of Oncology 2024): HR 0.69 in the overall population; HR 0.32 in dMMR.","Mismatch-repair-proficient tumours had a smaller benefit (PFS HR about 0.76), concentrated in TP53-mutated and PD-L1-positive subgroups in exploratory analyses.","Grade 3 or higher adverse events 70.5% vs 59.8%; immune-related events, mainly hypothyroidism and rash, were more frequent with dostarlimab."],"whatItMeans":"Women with newly diagnosed advanced or recurrent endometrial cancer should receive a PD-1 antibody (dostarlimab or pembrolizumab) with their chemotherapy, and mismatch repair testing is now essential because women with dMMR tumours gain a very large and durable benefit. The gain in mismatch-repair-proficient tumours is real but smaller, and molecular classification (POLE, p53, MMR) is increasingly used to decide who benefits most.","caveats":["The dMMR benefit dominates; the pMMR benefit is modest and debated for the p53-wild-type, non-specific-molecular-profile subgroup.","Up to three years of maintenance immunotherapy adds cost and cumulative immune toxicity.","Recurrent disease after prior adjuvant chemotherapy was included but patients with prior immunotherapy were not.","The parallel DUO-E trial suggests adding olaparib may help pMMR tumours, but the optimal combination is unsettled."],"changedPractice":true,"participants":494},{"id":"paper-sarc028-pembrolizumab-sarcoma-tawbi-lancet-oncol-2017","kind":"paper","name":"SARC028: pembrolizumab in advanced soft tissue and bone sarcoma","aka":[],"tldr":"Pembrolizumab had little effect in most sarcomas, but it shrank tumours in about 40 percent of patients with undifferentiated pleomorphic sarcoma and some with dedifferentiated liposarcoma, singling out these subtypes for immunotherapy.","summary":"Phase 2 study of 86 patients with advanced soft tissue sarcoma (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, synovial sarcoma, leiomyosarcoma) or bone sarcoma treated with pembrolizumab.\n\nObjective response was 18 percent in soft tissue sarcoma, driven by 40 percent in undifferentiated pleomorphic sarcoma and 20 percent in dedifferentiated liposarcoma, with no responses in leiomyosarcoma and one in synovial sarcoma; bone sarcoma response was 5 percent.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2017","url":"https://doi.org/10.1016/S1470-2045(17)30624-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28988646/"}],"tags":[],"related":[],"cancers":["undifferentiated-pleomorphic-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["sarc028"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2017,"doi":"10.1016/S1470-2045(17)30624-1","pmid":"28988646","authors":"Tawbi HA, Burgess M, Bolejack V, et al.","paperType":"observational","findings":["Objective response 40 percent in undifferentiated pleomorphic sarcoma; 20 percent in dedifferentiated liposarcoma.","0 percent in leiomyosarcoma; 5 percent in bone sarcomas."],"whatItMeans":"PD-1 blockade is an off-label or trial option specifically for undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, not for sarcoma in general.","caveats":["Small cohorts of about 10 patients per histology; expansion cohorts confirmed lower rates (about 23 percent) in undifferentiated pleomorphic sarcoma."],"changedPractice":true,"participants":86},{"id":"paper-sato-lgr5-organoids-nature-2009","kind":"paper","name":"Sato 2009: single Lgr5 stem cells build crypt-villus organoids","aka":[],"tldr":"The experiment that invented organoids: a single intestinal stem cell, given three growth factors in a gel, grew into a miniature gut lining that could be kept alive indefinitely, a method since extended to tumours from individual patients.","summary":"Sato, Clevers and colleagues at the Hubrecht Institute showed that single Lgr5-positive stem cells from the mouse small intestine, embedded in Matrigel with EGF, Noggin and R-spondin 1 and no supporting mesenchyme, form self-organising structures with crypt and villus domains containing all the differentiated cell types of the gut. The organoids could be passaged for over eight months without losing their properties. The method was soon adapted to human tissue and to tumours, creating patient-derived organoids for drug testing.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature07935"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["organoids","organoid-guided-therapy-scale"],"targets":[],"drugs":[],"companies":[],"institutions":["umc-utrecht"],"pathways":[],"terms":["stem-cell"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2009,"doi":"10.1038/nature07935","authors":"Sato T, Vries RG, Snippert HJ, et al.","paperType":"methods","findings":["Single Lgr5-positive intestinal stem cells formed crypt-villus organoids in Matrigel with EGF, Noggin and R-spondin 1, without a mesenchymal niche.","Organoids contained all differentiated intestinal cell types and could be maintained for more than eight months.","The defined culture conditions were the basis for later human and tumour organoid systems."],"whatItMeans":"Organoids from patients' tumours are now used to test drugs before treatment, to model rare cancers and to study resistance. Every one of those systems descends from this culture method.","caveats":["Mouse intestine only in this paper; human and tumour organoids came in later work.","Organoids lack blood vessels, immune cells and stroma unless these are added."],"changedPractice":false},{"id":"paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004","kind":"paper","name":"Sauer 2004: chemoradiotherapy before rather than after surgery for rectal cancer (CAO/ARO/AIO-94)","aka":[],"tldr":"Giving chemotherapy and radiotherapy before surgery rather than after halved local recurrences of rectal cancer, caused less toxicity and let more patients keep their anal sphincter, without changing overall survival.","summary":"The German Rectal Cancer Study Group randomised 823 patients with locally advanced rectal cancer (clinical stage T3 or T4 or node-positive) to fluorouracil-based chemoradiotherapy either before or after total mesorectal excision, with both groups receiving further chemotherapy. Preoperative treatment reduced five-year local recurrence, lowered acute and long-term toxicity and increased sphincter-preserving surgery among patients whose tumours had been judged to need an abdominoperineal resection, while overall survival was the same in both arms.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa040694"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["fluorouracil"],"companies":[],"institutions":[],"pathways":[],"terms":["chemoradiation","neoadjuvant-adjuvant","total-neoadjuvant-therapy","organ-preservation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2004,"doi":"10.1056/NEJMoa040694","authors":"Sauer R, Becker H, Hohenberger W, et al.","paperType":"rct","findings":["823 patients with locally advanced rectal cancer; chemoradiotherapy before or after total mesorectal excision.","Five-year local recurrence 6% with preoperative vs 13% with postoperative treatment.","Five-year overall survival 76% vs 74%, not significantly different.","Grade 3 or 4 acute toxicity 27% vs 40%; long-term toxicity 14% vs 24%; sphincter preservation rose in patients initially judged to need an abdominoperineal resection."],"whatItMeans":"This trial made preoperative chemoradiotherapy the standard for locally advanced rectal cancer worldwide and is the foundation on which total neoadjuvant therapy and watch-and-wait organ preservation were later built.","caveats":["Overall survival was unchanged; the gain is in local control, toxicity and function.","Chemotherapy was fluorouracil alone by the standards of 2004.","Staging relied on endorectal ultrasound and CT rather than modern MRI."],"changedPractice":true,"participants":823},{"id":"paper-scalp-trial-jama-2017","kind":"paper","name":"SCALP: scalp cooling to prevent hair loss during chemotherapy for early breast cancer","aka":[],"tldr":"In the first randomised trial of a modern scalp cooling system, half the women who used the Paxman device during taxane or anthracycline chemotherapy for early breast cancer kept most of their hair, compared with none of those who did not.","summary":"SCALP was a multicentre randomised trial at seven US centres of the Paxman Orbis scalp cooling system in women with stage I or II breast cancer receiving at least four cycles of taxane-based, anthracycline-based or combined chemotherapy, randomised 2:1 to cooling or no cooling. The primary endpoint was hair preservation, defined as Dean scale grade 0 or 1 (less than 50 percent hair loss without the need for a wig) after four cycles.\n\nAt the planned interim analysis of 142 evaluable women, 48 of 95 (50.5 percent) in the cooling group preserved their hair compared with 0 of 47 in the control group, and the trial stopped early for efficacy. Preservation was better with taxane-only regimens than with anthracycline-containing regimens. Adverse events were mild (headache, chills, scalp pain) and there were no scalp metastases during follow-up. Quality-of-life measures did not differ significantly at four cycles. A companion single-arm study of the DigniCap system (Rugo et al., same issue) reported hair preservation in 66.3 percent of women on non-anthracycline taxane regimens versus none of 16 concurrent controls. Together the two studies underpinned FDA clearance of both devices for solid tumours.","asOf":"2026-09-10","links":[{"label":"SCALP randomised trial (JAMA 2017)","url":"https://doi.org/10.1001/jama.2016.20939"},{"label":"DigniCap prospective cohort with concurrent controls (JAMA 2017)","url":"https://doi.org/10.1001/jama.2016.21038"},{"label":"Scalp cooling and the risk of scalp metastases: systematic review (Breast Cancer Res Treat 2017)","url":"https://doi.org/10.1007/s10549-017-4185-9"}],"tags":["complementary","hair-loss"],"related":[],"cancers":["breast-hr-positive","tnbc","breast-her2-positive"],"sections":[],"technologies":["scalp-cooling"],"targets":[],"drugs":["docetaxel","paclitaxel","doxorubicin","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol"],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2017,"doi":"10.1001/jama.2016.20939","authors":"Nangia J, Wang T, Osborne C, et al.","paperType":"rct","findings":["182 women randomised; interim analysis of 142 evaluable: hair preservation 50.5% (48/95) with scalp cooling versus 0% (0/47) without.","Preservation higher with taxane-only than anthracycline-containing chemotherapy.","Adverse events limited to grade 1-2 headache, chills and scalp discomfort; no scalp metastases.","Companion DigniCap study: 66.3% hair preservation on non-anthracycline taxane regimens versus 0% in controls."],"whatItMeans":"Scalp cooling works, especially for taxane-based regimens, and is safe. The question moved from whether to how to make it available: device time in the chemotherapy chair, staff training, and who pays.","caveats":["Open-label; the outcome was assessed by clinicians and patients who knew the allocation.","Stopped early at interim analysis, which can overestimate effect size.","Anthracycline-containing regimens, common in breast cancer, had lower preservation rates."],"changedPractice":true,"participants":182},{"id":"paper-schreiber-cancer-immunoediting-science-2011","kind":"paper","name":"Schreiber, Old and Smyth 2011: cancer immunoediting","aka":[],"tldr":"The review that set out the three Es of how the immune system shapes a cancer: elimination of many early tumours, an equilibrium in which growth is held in check, and escape when the tumour evolves ways to evade attack.","summary":"Schreiber, Old and Smyth summarised two decades of evidence, much of it from genetically modified mice, that the immune system both suppresses and sculpts tumours. In the elimination phase innate and adaptive immunity destroy many nascent cancers; in equilibrium, adaptive immunity holds surviving tumour cells dormant while editing their immunogenicity; in escape, variants that have lost antigens, upregulated PD-L1 or recruited suppressive cells grow out. The framework explained why clinically apparent cancers are poorly immunogenic and why checkpoint blockade can work.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.1203486"}],"tags":[],"related":["paper-pardoll-immune-checkpoint-blockade-nrc-2012"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pdl1"],"drugs":[],"companies":[],"institutions":["wustl-siteman"],"pathways":[],"terms":["immune-system","immune-checkpoint"],"trials":[],"people":["robert-schreiber"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":2011,"doi":"10.1126/science.1203486","authors":"Schreiber RD, Old LJ, Smyth MJ.","paperType":"review","findings":["Immune-deficient mice develop more spontaneous and carcinogen-induced cancers, showing immune surveillance is real.","Tumours can persist in an equilibrium state controlled by adaptive immunity, as shown by outgrowth when T cells are depleted.","Escape occurs through loss of antigen presentation, immunosuppressive cytokines and ligands such as PD-L1, and recruitment of regulatory cells."],"whatItMeans":"Immunoediting is the conceptual backbone of modern immuno-oncology: it explains tumour heterogeneity, dormancy and late relapse, and why immunotherapy works by releasing pre-existing but suppressed immunity.","caveats":["Largely based on mouse models; human equilibrium is inferred rather than observed.","A review, so it synthesises rather than tests."],"changedPractice":false},{"id":"paper-select-lenvatinib-nejm-2015","kind":"paper","name":"SELECT: lenvatinib versus placebo in radioiodine-refractory differentiated thyroid cancer","aka":[],"tldr":"The multikinase inhibitor lenvatinib delayed progression by almost fifteen months compared with placebo in iodine-refractory differentiated thyroid cancer and shrank tumours in two thirds of patients, becoming the preferred drug for this disease.","summary":"Phase 3 placebo-controlled trial of 392 patients with progressive radioiodine-refractory differentiated thyroid cancer randomised 2:1 to lenvatinib 24 mg daily or placebo.\n\nMedian progression-free survival was 18.3 versus 3.6 months (hazard ratio 0.21) and response 64.8 versus 1.5 percent; hypertension, diarrhoea, fatigue and proteinuria led to dose reductions in most patients, and there were six treatment-related deaths.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2015","url":"https://doi.org/10.1056/NEJMoa1406470"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25671254/"}],"tags":[],"related":[],"cancers":["follicular-thyroid-cancer","papillary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["lenvatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["select-lenvatinib"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1406470","pmid":"25671254","authors":"Schlumberger M, Tahara M, Wirth LJ, et al.","paperType":"rct","findings":["Median progression-free survival 18.3 vs 3.6 months; hazard ratio 0.21.","Objective response 64.8 percent vs 1.5 percent."],"whatItMeans":"Lenvatinib is the first-choice kinase inhibitor for progressive iodine-refractory papillary and follicular thyroid cancer, reserved for symptomatic or rapidly progressing disease because of its toxicity.","caveats":["No overall survival benefit because of crossover.","Starting dose debate; 18 mg was not non-inferior in a later study."],"changedPractice":true,"participants":392},{"id":"paper-hpv-self-sampling-bmj-2018","kind":"paper","name":"Self-collected HPV samples are as accurate as clinician samples and reach women who never attend screening","aka":[],"tldr":"A meta-analysis of 56 accuracy studies and 25 randomised trials found that self-sampled swabs tested with PCR detect precancer as well as clinician-taken samples, and mailing kits to under-screened women roughly doubles participation.","summary":"Arbyn and colleagues pooled diagnostic accuracy studies comparing HPV testing on self-collected versus clinician-collected samples, and randomised trials comparing strategies to reach under-screened women.\n\nWith PCR-based assays, sensitivity for CIN2+ and CIN3+ on self samples was equivalent to clinician samples (relative sensitivity 0.99) and specificity was marginally lower (0.98). Signal-amplification assays performed worse on self samples. Mailing self-sampling kits to all under-screened women increased participation more than twofold compared with an invitation letter, as did door-to-door offers; opt-in kits produced smaller gains.\n\nThe findings underpin WHO and national guidance that self-sampling is an acceptable primary screening method.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1136/bmj.k4823"}],"tags":[],"related":["idea-prev-hpv-self-sampling-mailed-default","idea-prev-hpv-same-day-screen-and-treat","idea-acc-hpv-self-sample-same-day-ablation"],"cancers":["cervical"],"sections":["early-detection","prevention"],"technologies":["hpv-testing","hpv-vaccine"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-global-access","b-early-detection"],"keyPapers":[],"journals":["bmj"],"dependsOn":[],"notes":[],"journal":"BMJ","year":2018,"doi":"10.1136/bmj.k4823","pmid":"30518635","authors":"Arbyn M, Smith SB, Temin S, Sultana F, Castle P","paperType":"meta-analysis","findings":["PCR-based assays: pooled relative sensitivity of self vs clinician samples 0.99 for CIN2+, relative specificity 0.98","Signal-amplification assays were less sensitive on self samples (relative sensitivity 0.85 for CIN2+)","Mailing kits to under-screened women increased participation about 2.3-fold versus invitation letters","Opt-in approaches (women must request a kit) gave only modest participation gains"],"whatItMeans":"Women can collect their own screening sample at home with no loss of accuracy if the laboratory uses a PCR test. Sending kits directly is the most effective way to reach women who do not attend, which matters because most cervical cancers occur in under-screened women.","caveats":["Accuracy equivalence holds only for PCR-based assays validated for self samples","Triage of positive self-samples still requires a clinic visit; follow-up completion is the weak point","Participation trials were heterogeneous in setting and delivery","Self-sampling for cytology (rather than HPV) is not supported"],"changedPractice":true},{"id":"paper-sempet-de-santis-jco-2004","kind":"paper","name":"SEMPET: FDG-PET as a predictor of viable tumour in post-chemotherapy seminoma residuals","aka":[],"tldr":"A PET scan reliably told apart residual masses that still contained living seminoma from scar tissue after chemotherapy, allowing surgeons to leave PET-negative masses alone rather than operating on all masses over 3 cm.","summary":"Prospective multicentre study of 51 patients with metastatic seminoma and residual masses after chemotherapy who underwent FDG-PET, with results validated against histology or clinical follow-up.\n\nPET had a sensitivity of 80 percent and specificity of 100 percent for viable tumour, and for residual lesions over 3 cm specificity and sensitivity were both 100 percent, outperforming CT size criteria.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2004","url":"https://doi.org/10.1200/JCO.2004.07.188"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15020605/"}],"tags":[],"related":[],"cancers":["seminoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2004,"doi":"10.1200/JCO.2004.07.188","pmid":"15020605","authors":"De Santis M, Becherer A, Bokemeyer C, et al.","paperType":"observational","findings":["Specificity 100 percent, sensitivity 80 percent for viable residual seminoma.","Sensitivity and specificity 100 percent for lesions over 3 cm."],"whatItMeans":"FDG-PET is standard for residual seminoma masses larger than 3 cm after chemotherapy, sparing most men surgery.","caveats":["Small study; false positives occur when PET is done too soon after chemotherapy, so scans are delayed at least six weeks."],"changedPractice":true,"participants":51},{"id":"paper-shape-nejm-2024","kind":"paper","name":"SHAPE: simple versus radical hysterectomy in low-risk early cervical cancer","aka":[],"tldr":"For small, low-risk cervical cancers, a simple hysterectomy gave the same very low pelvic recurrence rate as a radical hysterectomy with fewer urinary and sexual complications, so less extensive surgery is now acceptable.","summary":"Phase 3 non-inferiority trial of 700 women with low-risk cervical cancer (up to 2 cm, limited stromal invasion) randomised to simple hysterectomy or radical hysterectomy, both with pelvic node assessment.\n\nThree-year pelvic recurrence was 2.52 percent with simple hysterectomy and 2.17 percent with radical hysterectomy, within the non-inferiority margin, with fewer urinary incontinence and retention problems and better sexual health after simple hysterectomy.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2024","url":"https://doi.org/10.1056/NEJMoa2308900"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38416430/"}],"tags":[],"related":[],"cancers":["early-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["shape"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2308900","pmid":"38416430","authors":"Plante M, Kwon JS, Ferguson S, et al.","paperType":"rct","findings":["Three-year pelvic recurrence 2.52 percent vs 2.17 percent (non-inferior).","Urinary incontinence 2.4 percent vs 5.5 percent within four weeks; urinary retention 0.6 percent vs 11.0 percent."],"whatItMeans":"Women with low-risk early cervical cancer can be offered simple hysterectomy, sparing them the bladder and sexual morbidity of parametrectomy, provided strict eligibility criteria are applied.","caveats":["Strict imaging and pathology criteria define low risk; misapplication to larger tumours would be unsafe.","Longer follow-up is pending."],"changedPractice":true,"participants":700},{"id":"paper-sharp-sorafenib-nejm-2008","kind":"paper","name":"SHARP: sorafenib in advanced hepatocellular carcinoma","aka":[],"tldr":"Sorafenib was the first systemic drug to lengthen survival in advanced liver cancer, adding almost three months compared with placebo, and remained the only option for a decade.","summary":"Phase 3 placebo-controlled trial of 602 patients with advanced hepatocellular carcinoma and preserved liver function (Child-Pugh A) randomised to sorafenib 400 mg twice daily or placebo.\n\nMedian overall survival was 10.7 versus 7.9 months (hazard ratio 0.69), time to radiological progression 5.5 versus 2.8 months, with response in only 2 percent; diarrhoea, weight loss and hand-foot skin reaction were the main toxicities.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2008","url":"https://doi.org/10.1056/NEJMoa0708857"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/18650514/"}],"tags":[],"related":[],"cancers":["hcc-advanced"],"sections":[],"technologies":[],"targets":[],"drugs":["sorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["sharp"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2008,"doi":"10.1056/NEJMoa0708857","pmid":"18650514","authors":"Llovet JM, Ricci S, Mazzaferro V, et al.","paperType":"rct","findings":["Median overall survival 10.7 vs 7.9 months; hazard ratio 0.69.","Time to radiological progression 5.5 vs 2.8 months."],"whatItMeans":"Sorafenib became the reference standard against which lenvatinib, atezolizumab-bevacizumab and durvalumab-tremelimumab were tested, and remains an option where immunotherapy is unsuitable.","caveats":["Benefit confined to patients with good liver function.","Very low response rate; benefit is disease stabilisation."],"changedPractice":true,"participants":602},{"id":"paper-sherr-roberts-cdk-inhibitors-genesdev-1999","kind":"paper","name":"Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase","aka":[],"tldr":"The classic review of the brakes on the cell cycle, the proteins that hold back the cyclin-dependent kinases which commit a cell to dividing, and how cancers lose them, the biology behind today's CDK4/6 inhibitors.","summary":"Sherr and Roberts described the two families of cyclin-dependent kinase inhibitors that govern passage through G1: the INK4 proteins (p16, p15, p18 and p19), which specifically block cyclin D-CDK4 and CDK6, and the Cip/Kip proteins (p21, p27 and p57), which act on a broader range of cyclin-CDK complexes. They explained how these inhibitors integrate mitogenic and anti-proliferative signals to control the restriction point, how p21 links p53 to arrest and p27 mediates contact inhibition and TGF-beta responses, and how loss of p16 or p27 and overexpression of cyclin D contribute to cancer.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1101/gad.13.12.1501"}],"tags":[],"related":["paper-el-deiry-waf1-p21-cell-1993"],"cancers":[],"sections":[],"technologies":["cdk46-inhibitor"],"targets":["cdk4-6"],"drugs":[],"companies":[],"institutions":["st-jude"],"pathways":["cell-cycle-engine-cdks","p53-cell-cycle"],"terms":["cell-cycle","tumour-suppressor-gene"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Genes and Development","year":1999,"doi":"10.1101/gad.13.12.1501","authors":"Sherr CJ, Roberts JM.","paperType":"review","findings":["INK4 inhibitors (p16, p15, p18, p19) specifically restrain cyclin D-dependent CDK4 and CDK6; Cip/Kip inhibitors (p21, p27, p57) act more broadly.","These inhibitors integrate growth-promoting and growth-inhibitory signals at the G1 restriction point.","Loss of p16 (CDKN2A) or p27 and cyclin D overexpression are common in cancer and remove the G1 brake."],"whatItMeans":"This review is the textbook basis for the cyclin D-CDK4/6-RB axis that palbociclib, ribociclib and abemaciclib target in breast cancer, and for reading CDKN2A loss and cyclin D1 amplification in tumour genomes.","caveats":["Written before the clinical development of CDK4/6 inhibitors.","Later work showed CDK2 and cyclin E can bypass the CDK4/6 brake, which underlies resistance."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2012-cacancer-2012","kind":"paper","name":"Siegel 2012: Cancer statistics, 2012","aka":[],"tldr":"The American Cancer Society's annual US report for 2012 projected about 1.64 million new cancer cases and reported that death rates had fallen steadily since the early 1990s in both men and women, sparing more than a million lives.","summary":"Siegel, Naishadham and Jemal projected 1,638,910 new cancer cases and 577,190 cancer deaths in the United States for 2012. Cancer death rates had declined from their peaks by 22.9% in men (from 1990) and 15.3% in women (from 1991) to 2008, which the authors estimated had averted more than a million cancer deaths. The report noted the largest declines in lung, colorectal, breast and prostate cancer mortality and highlighted persistent differences by race and education.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.20138"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2012,"doi":"10.3322/caac.20138","authors":"Siegel R, Naishadham D, Jemal A.","paperType":"observational","findings":["Projected 1,638,910 new cancer cases and 577,190 cancer deaths in the United States in 2012.","Death rates down 22.9% in men and 15.3% in women from their early-1990s peaks to 2008, more than a million deaths averted.","Largest mortality declines in lung, colorectal, breast and prostate cancers."],"whatItMeans":"An early edition of the series that established the now-standard framing of deaths averted since the 1991 peak.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2013-cacancer-2013","kind":"paper","name":"Siegel 2013: Cancer statistics, 2013","aka":[],"tldr":"The American Cancer Society's 2013 report projected about 1.66 million new US cancer cases and put the overall cancer death rate 20 percent below its 1991 peak, with chronic myeloid leukaemia showing the fastest fall in deaths of any cancer.","summary":"Siegel, Naishadham and Jemal projected 1,660,290 new cancer cases and 580,350 cancer deaths in the United States for 2013. Over 2005 to 2009 incidence declined slightly in men (0.6 percent a year) and was stable in women, while death rates fell 1.8 percent a year in men and 1.5 percent a year in women. The overall cancer death rate had dropped 20 percent from its 1991 peak of 215.1 per 100,000 to 173.1 in 2009, with continuing declines in lung, colorectal, breast and prostate cancer. Over 2000 to 2009 the largest annual falls in death rates were for chronic myeloid leukaemia (8.4 percent, the imatinib era), stomach cancer (3.1 percent), colorectal cancer (3.0 percent) and non-Hodgkin lymphoma (3.0 percent).","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21166"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2023-cacancer-2023","paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2013,"doi":"10.3322/caac.21166","authors":"Siegel R, Naishadham D, Jemal A.","paperType":"observational","findings":["Projected 1,660,290 new cancer cases and 580,350 cancer deaths in the United States in 2013.","Overall cancer death rate down 20 percent from 215.1 per 100,000 in 1991 to 173.1 in 2009.","Fastest annual falls in death rates for chronic myeloid leukaemia (8.4 percent), stomach cancer, colorectal cancer and non-Hodgkin lymphoma."],"whatItMeans":"The clearest population-level signature of a targeted drug: the fall in chronic myeloid leukaemia deaths after imatinib.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2014-cacancer-2014","kind":"paper","name":"Siegel 2014: Cancer statistics, 2014","aka":[],"tldr":"The American Cancer Society's 2014 report projected about 1.67 million new US cancer cases and estimated that two decades of falling death rates had avoided about 1.34 million cancer deaths, with the gains very unevenly spread by age, race and sex.","summary":"Siegel, Ma, Zou and Jemal projected 1,665,540 new cancer cases and 585,720 cancer deaths in the United States for 2014. Over 2006 to 2010 incidence declined slightly in men (0.6 percent a year) and was stable in women, while death rates fell 1.8 percent a year in men and 1.4 percent a year in women. The combined death rate had fallen for two decades, from 215.1 per 100,000 in 1991 to 171.8 in 2010, a 20 percent decline that translated into about 1,340,400 deaths avoided (952,700 in men and 387,700 in women). The size of the decline ranged from none among white women aged 80 and over to 55 percent among black men aged 40 to 49.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21208"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2023-cacancer-2023","paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2014,"doi":"10.3322/caac.21208","authors":"Siegel R, Ma J, Zou Z, Jemal A.","paperType":"observational","findings":["Projected 1,665,540 new cancer cases and 585,720 cancer deaths in the United States in 2014.","Combined death rate down from 215.1 per 100,000 in 1991 to 171.8 in 2010, about 1,340,400 deaths avoided.","Decline ranged from none in white women aged 80 and over to 55 percent in black men aged 40 to 49."],"whatItMeans":"Introduced the breakdown of progress by age, race and sex that exposed how unequally the decline in cancer deaths had been shared.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2015-cacancer-2015","kind":"paper","name":"Siegel 2015: Cancer statistics, 2015","aka":[],"tldr":"The American Cancer Society's annual US report for 2015 projected about 1.66 million new cancer cases and recorded a cancer death rate 22% below its 1991 peak, the year the series began reporting deaths averted in the millions.","summary":"Siegel and colleagues projected 1,658,370 new cancer cases and 589,430 cancer deaths in the United States for 2015. The cancer death rate had fallen 22% from its 1991 peak to 2011, which the authors translated into about 1.5 million fewer cancer deaths than if rates had stayed at the peak.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21254"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2015,"doi":"10.3322/caac.21254","authors":"Siegel RL, Miller KD, Jemal A.","paperType":"observational","findings":["Projected 1,658,370 new cancer cases and 589,430 cancer deaths in the United States in 2015.","Cancer death rate down 22% from 1991 to 2011, about 1.5 million deaths averted."],"whatItMeans":"This edition marked twenty years of falling US cancer mortality and is cited for the estimate that more than 1.5 million deaths had been averted.","caveats":["Projections rather than counts; registrations arrive years later.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2016-cacancer-2016","kind":"paper","name":"Siegel 2016: Cancer statistics, 2016","aka":[],"tldr":"The American Cancer Society's annual US report for 2016 projected about 1.69 million new cancer cases and recorded a cancer death rate 23% below its 1991 peak, with the report noting that cancer had overtaken heart disease as the leading cause of death in many US states.","summary":"Siegel and colleagues projected 1,685,210 new cancer cases and 595,690 cancer deaths in the United States for 2016. The cancer death rate had fallen 23% from its 1991 peak to 2012, which the authors translated into about 1.7 million fewer cancer deaths than if rates had stayed at the peak. The report noted that cancer had become the leading cause of death in 21 states and among Hispanic and Asian Americans, and it documented persistent racial gaps in mortality.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21332"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2016,"doi":"10.3322/caac.21332","authors":"Siegel RL, Miller KD, Jemal A.","paperType":"observational","findings":["Projected 1,685,210 new cancer cases and 595,690 cancer deaths in the United States in 2016.","Cancer death rate down 23% from 1991 to 2012, about 1.7 million deaths averted.","Cancer was the leading cause of death in 21 states and among Hispanic and Asian American populations."],"whatItMeans":"This edition is cited for the shift of cancer to the leading cause of death in a large part of the United States as heart disease mortality fell faster.","caveats":["Projections rather than counts; registrations arrive years later.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2017-cacancer-2017","kind":"paper","name":"Siegel 2017: Cancer statistics, 2017","aka":[],"tldr":"The American Cancer Society's annual US report for 2017 projected about 1.69 million new cancer cases and recorded a cancer death rate 25% below its 1991 peak.","summary":"Siegel and colleagues projected 1,688,780 new cancer cases and 600,920 cancer deaths in the United States for 2017. The cancer death rate had fallen 25% from its 1991 peak to 2014, which the authors translated into about 2.1 million fewer cancer deaths than if rates had stayed at the peak. The report highlighted that the gender gap in cancer incidence had narrowed and that the racial gap in mortality had shrunk substantially since the early 1990s.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21387"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2017,"doi":"10.3322/caac.21387","authors":"Siegel RL, Miller KD, Jemal A.","paperType":"observational","findings":["Projected 1,688,780 new cancer cases and 600,920 cancer deaths in the United States in 2017.","Cancer death rate down 25% from 1991 to 2014, about 2.1 million deaths averted."],"whatItMeans":"One of the most cited editions of the series, used as the reference for US cancer numbers in the mid-2010s.","caveats":["Projections rather than counts; registrations arrive years later.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2018-cacancer-2018","kind":"paper","name":"Siegel 2018: Cancer statistics, 2018","aka":[],"tldr":"The American Cancer Society's annual US report for 2018 projected about 1.74 million new cancer cases and recorded a cancer death rate 26% below its 1991 peak.","summary":"Siegel and colleagues projected 1,735,350 new cancer cases and 609,640 cancer deaths in the United States for 2018. The cancer death rate had fallen 26% from its 1991 peak to 2015, which the authors translated into about 2.4 million fewer cancer deaths than if rates had stayed at the peak. The report documented declining incidence in men, stable incidence in women, and a narrowing racial gap in mortality, while flagging rising incidence of liver cancer and of colorectal cancer in younger adults.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21442"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2018,"doi":"10.3322/caac.21442","authors":"Siegel RL, Miller KD, Jemal A.","paperType":"observational","findings":["Projected 1,735,350 new cancer cases and 609,640 cancer deaths in the United States in 2018.","Cancer death rate down 26% from 1991 to 2015, about 2.4 million deaths averted.","Rising incidence of liver cancer and of colorectal cancer in adults under 55 were flagged as concerns."],"whatItMeans":"This edition is widely cited for the early warning about colorectal cancer in younger adults, which later editions confirmed.","caveats":["Projections rather than counts; registrations arrive years later.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2019-cacancer-2019","kind":"paper","name":"Siegel 2019: Cancer statistics, 2019","aka":[],"tldr":"The American Cancer Society's annual US report for 2019 projected about 1.76 million new cancer cases, recorded a quarter-century of falling cancer death rates, and drew attention to widening gaps between rich and poor counties.","summary":"Siegel, Miller and Jemal projected 1,762,450 new cancer cases and 606,880 cancer deaths in the United States for 2019. The cancer death rate had fallen continuously since 1991, by 27% to 2016, which the authors translated into about 2.6 million fewer cancer deaths than if rates had stayed at their peak. The report highlighted that the racial gap in cancer mortality was narrowing while the socioeconomic gap was widening, with the poorest counties carrying the highest death rates for the most preventable cancers.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21551"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2019,"doi":"10.3322/caac.21551","authors":"Siegel RL, Miller KD, Jemal A.","paperType":"observational","findings":["Projected 1,762,450 new cancer cases and 606,880 cancer deaths in the United States in 2019.","Cancer death rate down 27% from 1991 to 2016, about 2.6 million deaths averted.","Socioeconomic disparities in cancer mortality were widening even as racial disparities narrowed."],"whatItMeans":"This edition is often cited for the disparities finding: progress against cancer in the United States was reaching some communities much more than others.","caveats":["Projections rather than counts.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2021-cacancer-2021","kind":"paper","name":"Siegel 2021: Cancer statistics, 2021","aka":[],"tldr":"The American Cancer Society's annual US report for 2021 projected about 1.9 million new cancer cases and recorded a cancer death rate 31% below its 1991 peak, with the largest single-year drop yet recorded, driven by lung cancer.","summary":"Siegel and colleagues projected 1,898,160 new cancer cases and 608,570 cancer deaths in the United States for 2021. The cancer death rate had fallen 31% from its 1991 peak to 2018, which the authors translated into about 3.2 million fewer cancer deaths than if rates had stayed at the peak. The decline from 2017 to 2018 was 2.4%, the largest single-year drop recorded, driven by accelerating falls in lung cancer mortality attributed to reduced smoking and to new treatments, and the report noted that the pandemic's effect on diagnoses would only appear in later data.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21654"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2021,"doi":"10.3322/caac.21654","authors":"Siegel RL, Miller KD, Fuchs HE, Jemal A.","paperType":"observational","findings":["Projected 1,898,160 new cancer cases and 608,570 cancer deaths in the United States in 2021.","Cancer death rate down 31% from 1991 to 2018, about 3.2 million deaths averted.","A 2.4% fall in the death rate from 2017 to 2018, the largest single-year drop recorded, driven by lung cancer."],"whatItMeans":"This edition documented the fastest ever annual fall in US cancer mortality and attributed it in part to targeted therapy and immunotherapy for lung cancer, one of the clearest links between new drugs and national statistics.","caveats":["Projections rather than counts; registrations arrive years later.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2022-cacancer-2022","kind":"paper","name":"Siegel 2022: Cancer statistics, 2022","aka":[],"tldr":"The American Cancer Society's annual US report for 2022 projected about 1.9 million new cancer cases and reported that the cancer death rate had fallen by about a third since 1991, with declines in lung cancer deaths accelerating as treatment improved.","summary":"Siegel, Miller, Fuchs and Jemal projected 1,918,030 new cancer cases and 609,360 cancer deaths in the United States for 2022. The cancer death rate had fallen 32% from 1991 to 2019, an estimated 3.5 million deaths averted. The report attributed the accelerating decline in lung cancer mortality to falling smoking, earlier diagnosis and better treatment, and it noted that the pandemic's effect on diagnoses was not yet visible in the data.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21708"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2022,"doi":"10.3322/caac.21708","authors":"Siegel RL, Miller KD, Fuchs HE, Jemal A.","paperType":"observational","findings":["Projected 1,918,030 new cancer cases and 609,360 cancer deaths in the United States in 2022.","Cancer death rate down 32% from 1991 to 2019, about 3.5 million deaths averted.","Lung cancer mortality declines were accelerating, reflecting reduced smoking and advances in treatment."],"whatItMeans":"This edition documented the treatment-driven fall in lung cancer deaths that followed targeted therapy and immunotherapy, a rare case of new drugs visibly moving national mortality statistics.","caveats":["Projections rather than counts, based on data through 2018 and 2019.","US-specific."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2023-cacancer-2023","kind":"paper","name":"Siegel 2023: Cancer statistics, 2023","aka":[],"tldr":"The American Cancer Society's annual US report for 2023 projected about 1.96 million new cancer cases, reported a continued fall in the cancer death rate, and flagged rising prostate cancer diagnoses at advanced stage alongside a steep fall in cervical cancer among young women vaccinated against HPV.","summary":"Siegel, Miller, Wagle and Jemal projected 1,958,310 new cancer cases and 609,820 cancer deaths in the United States for 2023. The cancer death rate had fallen 33% since 1991, an estimated 3.8 million deaths averted. The report noted that prostate cancer incidence had risen by about 3% a year from 2014 to 2019 after a decade of decline, driven by advanced-stage disease, and that cervical cancer incidence in women aged 20 to 24 had fallen by 65% from 2012 to 2019, consistent with HPV vaccination.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21763"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-siegel-cancer-statistics-2024-cacancer-2024"],"cancers":["prostate","cervical"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2023,"doi":"10.3322/caac.21763","authors":"Siegel RL, Miller KD, Wagle NS, Jemal A.","paperType":"observational","findings":["Projected 1,958,310 new cancer cases and 609,820 cancer deaths in the United States in 2023.","Cancer death rate down 33% since 1991, about 3.8 million deaths averted.","Prostate cancer incidence rising about 3% a year from 2014 to 2019, mostly advanced-stage disease.","Cervical cancer incidence in women aged 20 to 24 down 65% from 2012 to 2019."],"whatItMeans":"This edition supplied two widely quoted signals: the first population-level evidence of HPV vaccination preventing cervical cancer in the United States, and the warning that reduced PSA screening was shifting prostate cancer towards later diagnosis.","caveats":["Projections rather than counts.","US-specific; the prostate finding relates to US screening practice."],"changedPractice":false},{"id":"paper-siegel-cancer-statistics-2024-cacancer-2024","kind":"paper","name":"Siegel 2024: Cancer statistics, 2024, the American Cancer Society's annual US report","aka":[],"tldr":"The American Cancer Society's yearly count projected that the United States would pass two million new cancer diagnoses in 2024 for the first time, while the cancer death rate kept falling and colorectal cancer rose to become the leading cause of cancer death in men under 50.","summary":"Each January the American Cancer Society projects the number of new cancer cases and deaths in the United States and reviews trends in incidence, mortality and survival from national registries. The 2024 report projected 2,001,140 new cancer cases and 611,720 cancer deaths. It reported that the cancer mortality rate had fallen by a third since 1991, averting more than four million deaths, but that incidence was rising for six of the ten most common cancers and shifting towards younger adults, with colorectal cancer now the leading cause of cancer death in men under 50 and the second in women under 50.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21820"},{"label":"ACS Cancer Facts and Figures","url":"https://www.cancer.org/research/cancer-facts-statistics.html"}],"tags":[],"related":["paper-bray-globocan-2022-cacancer-2024"],"cancers":["colorectal","prostate","breast-hr-positive","pancreatic","endometrial","melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2024,"doi":"10.3322/caac.21820","authors":"Siegel RL, Giaquinto AN, Jemal A.","paperType":"observational","findings":["Projected 2,001,140 new cancer cases and 611,720 cancer deaths in the United States in 2024, the first year above two million cases.","Cancer mortality down by about a third since 1991, an estimated 4.1 million deaths averted.","Incidence rising for six of the ten most common cancers, including breast, prostate, endometrial, pancreatic, kidney and melanoma.","Colorectal cancer the leading cause of cancer death in men under 50 and the second in women under 50."],"whatItMeans":"This series is the standard reference for US cancer numbers and the source of most headlines about cancer in younger adults. The gap between falling mortality and rising incidence is the argument for both continued treatment advances and stronger prevention and screening.","caveats":["Projections, not counts; actual registrations arrive years later.","US-specific patterns do not transfer directly to other countries."],"changedPractice":false},{"id":"paper-singh-brain-tumour-initiating-cells-nature-2004","kind":"paper","name":"Singh 2004: identification of human brain tumour initiating cells","aka":[],"tldr":"The first proof that human brain tumours are driven by a small population of stem-like cells: a hundred cells carrying the CD133 marker could regrow a patient's tumour in a mouse brain while a hundred thousand cells without it could not.","summary":"Singh, Dirks and colleagues at the Hospital for Sick Children in Toronto isolated CD133-positive cells from human medulloblastomas and glioblastomas and transplanted them into the brains of immunodeficient mice. As few as 100 CD133-positive cells produced tumours that reproduced the histology of the patient's original cancer and could be serially transplanted, whereas up to 100,000 CD133-negative cells did not form tumours. The paper established the brain tumour initiating cell and made CD133 the working marker for glioma stem cells.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature03128"}],"tags":[],"related":["paper-bao-glioma-stem-cells-radioresistance-nature-2006","paper-reya-cancer-stem-cells-nature-2001"],"cancers":["glioblastoma","medulloblastoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["sickkids"],"pathways":[],"terms":["stem-cell"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2004,"doi":"10.1038/nature03128","authors":"Singh SK, Hawkins C, Clarke ID, et al.","paperType":"basic","findings":["CD133-positive cells from human medulloblastoma and glioblastoma initiated tumours in mouse brains from as few as 100 cells.","CD133-negative cells did not form tumours even at 100,000 cells.","Xenografts reproduced the original tumour's phenotype and could be passaged serially."],"whatItMeans":"This paper extended the cancer stem cell model to brain tumours and set up the later finding that these cells resist radiotherapy. It is the basis for treatment strategies aimed at the cells that regrow glioblastoma after surgery and chemoradiation.","caveats":["CD133-negative cells were later shown to initiate tumours in some gliomas, so the marker is imperfect.","Transplantation assays in mice may select for cells that survive the assay."],"changedPractice":false},{"id":"paper-badwe-progesterone-jco-2011","kind":"paper","name":"Single-injection depot progesterone before surgery and survival in operable breast cancer","aka":[],"tldr":"A single cheap hormone injection given days before breast surgery did not help every patient, but among women whose cancer had spread to lymph nodes it improved five-year survival, a result that seeded twenty years of low-cost perioperative trials in India.","summary":"976 women with operable breast cancer at Tata Memorial were randomised to one intramuscular injection of depot hydroxyprogesterone 5 to 14 days before surgery or to surgery alone, with a median follow-up of 65 months. Disease-free and overall survival were not significantly different overall. In node-positive women, 5-year disease-free survival was 65.3% versus 54.7% (hazard ratio 0.72; 95% CI 0.54-0.97; P=0.02) and overall survival 75.7% versus 66.8% (hazard ratio 0.70; 95% CI 0.49-0.99; P=0.04).","asOf":"2026-09-10","links":[{"label":"JCO 2011","url":"https://doi.org/10.1200/JCO.2010.33.0738"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":["tata-memorial"],"pathways":[],"terms":[],"trials":["progesterone-preop-tmh","lidocaine-peritumoral-tmh"],"people":["badwe-rajendra"],"bottlenecks":["b-generic-repurposing"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2011,"doi":"10.1200/JCO.2010.33.0738","authors":"Badwe R, Hawaldar R, Parmar V, et al.","paperType":"rct","findings":["No significant overall improvement in disease-free or overall survival.","Node-positive subgroup: 5-year disease-free survival 65.3% versus 54.7% (HR 0.72).","Node-positive subgroup: 5-year overall survival 75.7% versus 66.8% (HR 0.70).","Intervention cost is a single injection of a generic hormone."],"whatItMeans":"The trial did not change practice, but it established the idea that the days around surgery are a window in which cheap interventions might reduce metastasis, a line the same group pursued to a positive result with peritumoral lidocaine in 2023. It is a reminder that subgroup findings need confirmation, which is still awaited.","caveats":["The benefit is a subgroup finding in a trial whose primary analysis was negative.","Mechanism (progesterone-driven changes in tumour gene expression) is plausible but unproven in humans.","No confirmatory trial has yet reported."],"changedPractice":false,"participants":976},{"id":"paper-siop-cns-gct-96-calaminus-neuro-oncology-2013","kind":"paper","name":"SIOP CNS GCT 96: outcomes for children and adults with intracranial germinoma treated with radiotherapy alone or chemotherapy plus reduced radiotherapy","aka":[],"tldr":"This large European trial showed that localised intracranial germinoma can be cured in almost every patient either with craniospinal radiotherapy or with chemotherapy followed by smaller-field radiotherapy, but that the reduced field must cover the ventricles to avoid relapse.","summary":"Prospective non-randomised trial of 235 patients with intracranial germinoma treated by choice with craniospinal irradiation (24 Gy plus boost) or two cycles of carboplatin, etoposide and ifosfamide followed by focal radiotherapy (40 Gy); metastatic disease received craniospinal irradiation.\n\nFive-year event-free survival was 97 percent with craniospinal irradiation and 88 percent with the combined approach; relapses after focal radiotherapy occurred mainly in the ventricles, prompting whole-ventricular irradiation in the successor trial.","asOf":"2026-09-17","links":[{"label":"Neuro Oncol 2013","url":"https://doi.org/10.1093/neuonc/not019"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23460321/"}],"tags":[],"related":[],"cancers":["cns-germ-cell-tumours"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["neuro-oncology"],"dependsOn":[],"notes":[],"journal":"Neuro-Oncology","year":2013,"doi":"10.1093/neuonc/not019","pmid":"23460321","authors":"Calaminus G, Kortmann R, Worch J, et al.","paperType":"observational","findings":["Five-year event-free survival 97 percent with craniospinal irradiation vs 88 percent with chemotherapy and focal radiotherapy.","Ventricular relapses after focal fields led to adoption of whole-ventricular irradiation."],"whatItMeans":"Chemotherapy followed by whole-ventricular irradiation with a tumour boost, rather than craniospinal irradiation, is the standard for localised germinoma, sparing children the neurocognitive and endocrine cost of wider fields.","caveats":["Treatment was allocated by institutional preference rather than randomisation."],"changedPractice":true,"participants":235},{"id":"paper-slamon-her2-amplification-science-1987","kind":"paper","name":"Slamon 1987: HER2 gene amplification marks an aggressive form of breast cancer","aka":[],"tldr":"Extra copies of the HER2 gene were found in about a quarter to a third of breast cancers and picked out the patients most likely to relapse, the discovery that made HER2 a drug target and a test.","summary":"Slamon and colleagues measured copies of the HER2/neu gene in 189 primary human breast cancers and found amplification in 53 of them, about 28%, with amplification ranging from 2- to more than 20-fold. In node-positive patients, amplification was a strong and independent predictor of both time to relapse and survival, stronger than most conventional factors. The paper established HER2 as a marker of aggressive disease and, with later work showing the receptor's role in growth signalling, as the target that trastuzumab would hit a decade later.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.3798106"}],"tags":[],"related":["paper-slamon-trastuzumab-nejm-2001"],"cancers":["breast-her2-positive"],"sections":[],"technologies":[],"targets":["her2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":["dennis-slamon"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":1987,"doi":"10.1126/science.3798106","authors":"Slamon DJ, Clark GM, Wong SG, et al.","paperType":"translational","findings":["HER2/neu amplification in 53 of 189 primary breast cancers (about 28%).","Amplification correlated with the number of positive lymph nodes and, in node-positive patients, with shorter time to relapse and shorter survival.","Amplification was an independent prognostic factor in multivariate analysis, stronger than tumour size or hormone receptor status."],"whatItMeans":"Every HER2 test, every trastuzumab prescription and the whole HER2-positive breast cancer category trace back to this observation. It is the model for how a genomic marker of bad prognosis became a drug target and then the basis for one of the largest survival gains in solid tumour oncology.","caveats":["Prognostic effect was clearest in node-positive disease; the node-negative signal was weaker in this dataset.","Measured gene copies by Southern blot; clinical testing later moved to immunohistochemistry and in situ hybridisation with their own cut-offs."],"changedPractice":true},{"id":"paper-slamon-her2-breast-ovarian-science-1989","kind":"paper","name":"Slamon 1989: HER2/neu in human breast and ovarian cancer","aka":[],"tldr":"The follow-up to the 1987 discovery: extra copies of the HER2 gene were found in about a quarter to a third of breast cancers and also in ovarian cancers, they led to overproduction of the HER2 protein, and they marked patients with worse outcomes in both diseases.","summary":"Slamon and colleagues examined HER2/neu gene amplification and expression in 526 breast cancers and 120 ovarian cancers. Amplification was present in about a quarter to a third of the breast tumours and was tightly linked to overexpression of HER2 messenger RNA and protein, so measuring the protein could stand in for measuring the gene. Amplification and overexpression were associated with poorer survival in breast cancer and, for the first time, were shown in ovarian cancer with a similar prognostic effect.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.2470152"}],"tags":[],"related":["paper-slamon-her2-amplification-science-1987","paper-slamon-trastuzumab-nejm-2001"],"cancers":["breast-her2-positive","ovarian"],"sections":[],"technologies":[],"targets":["her2"],"drugs":[],"companies":[],"institutions":["ucla-jonsson"],"pathways":[],"terms":[],"trials":[],"people":["dennis-slamon"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":1989,"doi":"10.1126/science.2470152","authors":"Slamon DJ, Godolphin W, Jones LA, et al.","paperType":"translational","findings":["HER2/neu amplification in about 25 to 30% of 526 breast cancers, correlating with mRNA and protein overexpression.","HER2 amplification and overexpression also found in ovarian cancers, associated with poorer survival.","Protein overexpression by immunohistochemistry tracked gene amplification, supporting a tissue test."],"whatItMeans":"This study confirmed HER2 as a prognostic marker and a therapeutic target, showed that immunohistochemistry could identify the patients, and extended the target to ovarian cancer. It set up the clinical development of trastuzumab and the HER2 testing that every breast cancer now receives.","caveats":["Retrospective tumour bank study.","Ovarian findings were smaller in scale and HER2-directed therapy has had less success in ovarian cancer than in breast cancer."],"changedPractice":true},{"id":"paper-slamon-trastuzumab-nejm-2001","kind":"paper","name":"Slamon 2001: adding trastuzumab to chemotherapy for HER2-positive metastatic breast cancer","aka":[],"tldr":"The trial that made trastuzumab standard: adding the HER2 antibody to chemotherapy slowed progression and prolonged life in women whose breast cancers overexpressed HER2, at the cost of heart weakening when it was paired with anthracyclines.","summary":"This phase 3 trial randomised 469 women with previously untreated HER2-overexpressing metastatic breast cancer to chemotherapy (an anthracycline plus cyclophosphamide, or paclitaxel for those who had received adjuvant anthracycline) with or without trastuzumab. Adding trastuzumab lengthened the time to progression and raised the response rate, and it improved overall survival despite two thirds of the chemotherapy-alone group receiving trastuzumab after progression. Cardiac dysfunction was markedly more frequent when trastuzumab was combined with the anthracycline, which is why the two are not given together today.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJM200103153441101"}],"tags":[],"related":["paper-slamon-her2-amplification-science-1987"],"cancers":["breast-her2-positive"],"sections":[],"technologies":[],"targets":["her2"],"drugs":["trastuzumab","paclitaxel"],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["os","orr"],"trials":[],"people":["dennis-slamon"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2001,"doi":"10.1056/NEJM200103153441101","authors":"Slamon DJ, Leyland-Jones B, Shak S, et al.","paperType":"rct","findings":["469 women with HER2-overexpressing metastatic breast cancer; chemotherapy with or without trastuzumab.","Time to progression 7.4 vs 4.6 months; objective response 50% vs 32%.","Median overall survival 25.1 vs 20.3 months, hazard ratio for death 0.80.","Cardiac dysfunction in 27% of patients given anthracycline plus trastuzumab versus 8% with anthracycline alone, and 13% with paclitaxel plus trastuzumab."],"whatItMeans":"This was the first proof that a monoclonal antibody against a growth receptor could extend life in a common solid tumour, and it created HER2-positive breast cancer as a disease treated differently from the rest. Its cardiac finding shaped every later HER2 regimen, which pair trastuzumab with taxanes rather than anthracyclines.","caveats":["Crossover to trastuzumab after progression diluted the survival difference.","HER2 positivity was defined by immunohistochemistry 2+ or 3+, broader than the 3+ or amplified definition used now.","Open-label design."],"changedPractice":true,"participants":469},{"id":"paper-esmo-sts-guideline-gronchi-ann-oncol-2021","kind":"paper","name":"Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guideline","aka":[],"tldr":"The European sarcoma guideline sets out referral to reference centres, biopsy and molecular diagnosis, surgery with radiotherapy for localised disease, the selective use of chemotherapy, and histology-driven treatment of advanced disease.","summary":"Joint European guideline covering the diagnosis, staging, multidisciplinary management and follow-up of soft tissue and visceral sarcomas in adults, including limb and trunk sarcomas, retroperitoneal sarcoma, gastrointestinal stromal tumour, desmoid tumours and subtype-specific systemic therapy recommendations.","asOf":"2026-09-17","links":[{"label":"Ann Oncol 2021","url":"https://doi.org/10.1016/j.annonc.2021.07.006"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34303806/"}],"tags":[],"related":[],"cancers":["myxofibrosarcoma","undifferentiated-pleomorphic-sarcoma","extremity-soft-tissue-sarcoma","retroperitoneal-sarcoma","leiomyosarcoma","liposarcoma","pecoma","malignant-peripheral-nerve-sheath-tumour"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2021,"doi":"10.1016/j.annonc.2021.07.006","pmid":"34303806","authors":"Gronchi A, Miah AB, Dei Tos AP, et al.","paperType":"guideline","findings":[],"whatItMeans":"The general principles on the sarcoma subtype pages (reference centre surgery, radiotherapy for high-grade deep tumours, doxorubicin first line, histology-directed later lines) follow this guideline.","caveats":["Updated periodically; drug approvals since 2021 (for example nab-sirolimus, afamitresgene) are not covered."],"changedPractice":true},{"id":"paper-solar-1-alpelisib-nejm-2019","kind":"paper","name":"SOLAR-1: alpelisib plus fulvestrant for PIK3CA-mutated hormone receptor-positive advanced breast cancer","aka":[],"tldr":"Alpelisib, a pill blocking the mutated PI3K-alpha enzyme, nearly doubled the time to progression when added to fulvestrant in advanced breast cancer carrying a PIK3CA mutation, at the cost of high blood sugar and rash.","summary":"Phase 3 placebo-controlled trial of 572 patients with hormone receptor-positive, HER2-negative advanced breast cancer after an aromatase inhibitor, randomised to alpelisib or placebo with fulvestrant, stratified by PIK3CA mutation status.\n\nIn the 341 patients with PIK3CA-mutated tumours, median progression-free survival was 11.0 versus 5.7 months (hazard ratio 0.65); no benefit was seen without the mutation. Hyperglycaemia, rash and diarrhoea led to frequent dose changes.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2019","url":"https://doi.org/10.1056/NEJMoa1813904"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31091374/"}],"tags":[],"related":[],"cancers":["hr-positive-metastatic-post-cdk46"],"sections":[],"technologies":[],"targets":[],"drugs":["alpelisib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["solar-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2019,"doi":"10.1056/NEJMoa1813904","pmid":"31091374","authors":"André F, Ciruelos E, Rubovszky G, et al.","paperType":"rct","findings":["Median progression-free survival 11.0 vs 5.7 months in PIK3CA-mutated disease; hazard ratio 0.65.","Grade 3 or worse hyperglycaemia in 36.6 percent of alpelisib patients."],"whatItMeans":"PIK3CA testing became routine in advanced hormone receptor-positive breast cancer, with alpelisib-fulvestrant the first approved PI3K-targeted regimen; capivasertib and inavolisib now offer alternatives.","caveats":["Few patients had received a prior CDK4/6 inhibitor.","Toxicity leads to discontinuation in a meaningful minority."],"changedPractice":true,"participants":572},{"id":"paper-solo-1-nejm-2018","kind":"paper","name":"SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer","aka":[],"tldr":"In women with newly diagnosed advanced BRCA-mutated ovarian cancer who had responded to chemotherapy, two years of the PARP inhibitor olaparib kept far more of them free of progression than placebo, and the effect persisted for years after the tablets stopped. It moved PARP inhibitors into first-line maintenance and made BRCA testing at diagnosis routine.","summary":"Double-blind, placebo-controlled phase 3 trial of 391 patients with newly diagnosed advanced high-grade ovarian cancer and a BRCA1/2 mutation who had responded to platinum-based chemotherapy, randomised 2:1 to two years of olaparib or placebo maintenance. Primary endpoint was investigator-assessed PFS.\n\nPFS HR was 0.30, with 3-year PFS 60% vs 27%. Long-term follow-up showed a durable effect after treatment stopped: 7-year OS 67% vs 46.5% (HR 0.55) and about 45% of olaparib patients progression-free at seven years, suggesting a fraction were cured. It moved PARP inhibitors from recurrent disease to first-line maintenance and made BRCA testing at diagnosis mandatory.","asOf":"2026-09-08","links":[{"label":"NEJM 2018","url":"https://doi.org/10.1056/NEJMoa1810858"},{"label":"ClinicalTrials.gov NCT01844986","url":"https://clinicaltrials.gov/study/NCT01844986"}],"tags":[],"related":[],"cancers":["ovarian"],"sections":[],"technologies":["parp-inhibitor","germline-testing","synthetic-lethality-approaches"],"targets":["parp","brca"],"drugs":["olaparib"],"companies":["astrazeneca","merck"],"institutions":[],"pathways":[],"terms":["synthetic-lethality","pfs","os","germline-vs-somatic","hrd"],"trials":[],"people":["giovanni-scambia","amit-oza"],"bottlenecks":["b-hereditary-risk","b-dormancy-mrd","b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1810858","authors":"Moore K, Colombo N, Scambia G, et al.","paperType":"rct","findings":["Progression-free survival HR 0.30 (95% CI 0.23-0.41); 3-year PFS 60% vs 27%.","Median PFS 56.0 vs 13.8 months at five-year follow-up (Lancet Oncology 2021); 5-year PFS 48% vs 21%.","Overall survival at seven years (JCO 2023): 67.0% vs 46.5%; HR 0.55 (95% CI 0.40-0.76), despite 44% of placebo patients later receiving a PARP inhibitor.","Grade 3 or higher adverse events 39% vs 18%, mainly anaemia; 12% discontinued olaparib for toxicity.","Myelodysplastic syndrome or acute myeloid leukaemia in about 1.5% of olaparib patients at long follow-up, similar to placebo."],"whatItMeans":"Every woman diagnosed with advanced high-grade ovarian cancer should be tested for BRCA mutations at diagnosis, because those who carry one should receive two years of olaparib after chemotherapy, which greatly extends the time in remission and improves long-term survival. The plateau in the survival curves suggests some patients are cured by this approach. Toxicity is mostly anaemia, fatigue and nausea, and the two-year limit appears sufficient.","caveats":["The OS analysis did not formally meet its stringent statistical threshold (p<0.0001) though the effect is large and consistent.","Only BRCA-mutated patients; PRIMA and PAOLA-1 extended maintenance PARP inhibition to HRD-positive non-BRCA tumours.","Long-term surveillance for secondary leukaemia is warranted.","Patients who progress on a PARP inhibitor respond poorly to subsequent platinum, complicating later treatment."],"changedPractice":true,"participants":391},{"id":"paper-curtin-kit-melanoma-jco-2006","kind":"paper","name":"Somatic activation of KIT in distinct subtypes of melanoma","aka":[],"tldr":"This study found KIT mutations and amplifications in a substantial minority of mucosal, acral and chronically sun-damaged skin melanomas but almost never in ordinary skin melanoma, identifying a targetable driver for these rarer subtypes.","summary":"Analysis of 102 primary melanomas from mucosal, acral, chronically sun-damaged and non-sun-damaged sites for KIT copy number and mutations, finding KIT alterations in 39 percent of mucosal, 36 percent of acral and 28 percent of chronically sun-damaged melanomas, and none in non-sun-damaged skin melanomas.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2006","url":"https://doi.org/10.1200/JCO.2006.06.2984"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16908931/"}],"tags":[],"related":[],"cancers":["mucosal-melanoma","acral-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2006,"doi":"10.1200/JCO.2006.06.2984","pmid":"16908931","authors":"Curtin JA, Busam K, Pinkel D, et al.","paperType":"translational","findings":["KIT aberrations in 39 percent of mucosal, 36 percent of acral and 28 percent of chronically sun-damaged melanomas.","Absent in melanomas on skin without chronic sun damage."],"whatItMeans":"KIT joined BRAF and NRAS as a melanoma driver and became the rationale for imatinib and nilotinib in mucosal and acral melanoma.","caveats":["Later series found lower mutation frequencies (about 10 to 15 percent) in mucosal and acral melanoma."],"changedPractice":true,"participants":102},{"id":"paper-spartan-nejm-2018","kind":"paper","name":"SPARTAN: apalutamide for non-metastatic castration-resistant prostate cancer","aka":[],"tldr":"In men whose PSA was rising rapidly on hormone therapy but who had no visible metastases, apalutamide delayed the appearance of metastases by two years and later showed a survival benefit.","summary":"Phase 3 placebo-controlled trial of 1,207 men with non-metastatic castration-resistant prostate cancer and PSA doubling time of ten months or less randomised 2:1 to apalutamide or placebo with continued androgen deprivation.\n\nMedian metastasis-free survival was 40.5 versus 16.2 months (hazard ratio 0.28), and the final analysis showed median overall survival of 73.9 versus 59.9 months (hazard ratio 0.78); rash, fracture and hypothyroidism were more common with apalutamide.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1715546"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29420164/"}],"tags":[],"related":[],"cancers":["prostate-nmcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["apalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1715546","pmid":"29420164","authors":"Smith MR, Saad F, Chowdhury S, et al.","paperType":"rct","findings":["Median metastasis-free survival 40.5 vs 16.2 months; hazard ratio 0.28.","Median overall survival 73.9 vs 59.9 months; hazard ratio 0.78."],"whatItMeans":"Apalutamide, enzalutamide or darolutamide are standard for high-risk non-metastatic castration-resistant prostate cancer, a setting largely defined by conventional imaging.","caveats":["Most of these men would show metastases on PSMA PET.","Rash in about a quarter of patients."],"changedPractice":true,"participants":1207},{"id":"paper-spearhead-1-afami-cel-sarcoma-lancet-2024","kind":"paper","name":"SPEARHEAD-1: afami-cel, the first engineered T-cell receptor therapy approved for a solid tumour, in synovial sarcoma","aka":[],"tldr":"T cells engineered with a receptor recognising the MAGE-A4 cancer antigen shrank tumours in 37% of patients with advanced synovial sarcoma or myxoid liposarcoma, leading to the first approval of a TCR-T therapy.","summary":"SPEARHEAD-1 was a single-arm phase 2 trial of afamitresgene autoleucel (afami-cel), autologous T cells transduced with an affinity-enhanced T-cell receptor recognising a MAGE-A4 peptide presented by HLA-A*02, in 52 patients with advanced synovial sarcoma (44) or myxoid round cell liposarcoma (8) after prior anthracycline or ifosfamide. Patients were screened for HLA-A*02 and MAGE-A4 expression, received cyclophosphamide-fludarabine lymphodepletion and a single infusion. The overall response rate was 37% (39% in synovial sarcoma) with a median duration of response of about 12 months. Cytokine release syndrome occurred in 71% (grade 3 in a small minority) and prolonged cytopenias were common. The FDA granted accelerated approval in August 2024, the first TCR-T therapy and the first engineered T-cell therapy for a solid tumour.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=SPEARHEAD-1%20afamitresgene%20autoleucel%20synovial%20sarcoma%20D'Angelo%20Lancet%202024"},{"label":"ClinicalTrials.gov NCT04044768","url":"https://clinicaltrials.gov/study/NCT04044768"}],"tags":[],"related":["paper-c-144-01-lifileucel-melanoma-jco-2021"],"cancers":["sarcoma"],"sections":[],"technologies":["tcr-t"],"targets":[],"drugs":["afamitresgene-autoleucel","letetresgene-autoleucel"],"companies":["adaptimmune"],"institutions":[],"pathways":[],"terms":["orr","crs"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-manufacturing-cell-therapy"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"authors":"D'Angelo SP, Araujo DM, Abdul Razak AR, et al.","paperType":"translational","findings":["52 patients (44 synovial sarcoma, 8 myxoid round cell liposarcoma); HLA-A*02-positive and MAGE-A4-positive.","Overall response 37% overall; 39% in synovial sarcoma; 25% in MRCLS.","Median duration of response about 12 months; some responses lasting beyond 2 years.","CRS 71%, mostly grade 1-2; prolonged grade 3-4 cytopenias frequent.","Roughly a third of screened patients were eligible after HLA and antigen testing."],"whatItMeans":"Afami-cel showed that T cells can be redirected against an intracellular cancer antigen, something CAR-T cannot do, and produced meaningful responses in a rare sarcoma with few options. It opens a path to TCR-T against other shared antigens and neoantigens. Restriction to one HLA type and one antigen, plus complex manufacturing, means it will help a small, defined group.","caveats":["Single-arm; approval based on response rate.","Eligibility limited to HLA-A*02 carriers with MAGE-A4 expression, excluding most patients.","Durability is modest and antigen loss or HLA loss can drive relapse.","Affinity-enhanced TCRs carry theoretical off-target cross-reactivity risk, as seen fatally with an earlier MAGE-A3 TCR."],"changedPractice":true,"participants":52},{"id":"paper-spearhead-1-lancet-2024","kind":"paper","name":"SPEARHEAD-1: afamitresgene autoleucel, the first engineered T-cell receptor therapy approved for a solid tumour, in synovial sarcoma","aka":[],"tldr":"T cells taken from patients and engineered to recognise the MAGE-A4 protein shrank tumours in about four in ten patients with advanced synovial sarcoma, leading to the first approval of a TCR T-cell therapy for any solid cancer.","summary":"Single-arm phase 2 trial of 52 patients (44 with synovial sarcoma, 8 with myxoid/round cell liposarcoma) who were HLA-A*02 positive with MAGE-A4-expressing tumours, previously treated with anthracycline or ifosfamide, treated with a single infusion of afamitresgene autoleucel (afami-cel), autologous T cells expressing an affinity-enhanced MAGE-A4-specific T-cell receptor, after lymphodepleting chemotherapy. Primary endpoint was objective response rate.\n\nThe response rate was 37% overall and 39% in synovial sarcoma, with a median duration of response of about 12 months. Cytokine release syndrome occurred in about 70% but was mostly low grade. It led to FDA accelerated approval in 2024 (Tecelra), the first TCR-T and the first engineered cell therapy approved for a solid tumour.","asOf":"2026-09-08","links":[{"label":"PubMed search: SPEARHEAD-1 afamitresgene autoleucel Lancet","url":"https://pubmed.ncbi.nlm.nih.gov/?term=SPEARHEAD-1+afamitresgene+autoleucel+synovial+sarcoma+Lancet"},{"label":"ClinicalTrials.gov NCT04044768","url":"https://clinicaltrials.gov/study/NCT04044768"}],"tags":[],"related":[],"cancers":["sarcoma"],"sections":[],"technologies":["tcr-t"],"targets":["mage-a4"],"drugs":["afamitresgene-autoleucel"],"companies":["adaptimmune"],"institutions":[],"pathways":[],"terms":["orr","crs","accelerated-approval"],"trials":[],"people":["jean-yves-blay"],"bottlenecks":["b-rare-cancers","b-manufacturing-cell-therapy","b-trial-diversity"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"authors":"D'Angelo SP, Araujo DM, Abdul Razak AR, et al.","paperType":"rct","findings":["Objective response 37% overall (19 of 52); 39% in synovial sarcoma and 25% in myxoid/round cell liposarcoma.","Median duration of response about 12 months; median PFS about 3.8 months and median OS about 15 months in a heavily pretreated population.","Cytokine release syndrome in about 70% of patients, grade 3 in around 2%; cytopenias were common after lymphodepletion.","Eligibility required both HLA-A*02 genotype and MAGE-A4 expression, satisfied by roughly a third of screened synovial sarcoma patients.","Manufacturing success was high but the process took several weeks per patient."],"whatItMeans":"Patients with advanced synovial sarcoma, a rare cancer of young adults with few effective drugs, now have an approved cell therapy that produces responses lasting about a year in a substantial minority, if their tissue type and tumour antigen match. It proves that engineered T cells can work against a solid tumour when a good target is present, which had been elusive. It is not a cure for most, requires specialised centres, and only a minority of patients are eligible.","caveats":["Single-arm trial with a response-rate endpoint; no randomised comparison and OS benefit is unproven.","Restricted to HLA-A*02-positive patients, which excludes many people of non-European ancestry.","Responses are usually not durable beyond a year; mechanisms of relapse (antigen loss, T-cell exhaustion) are being studied.","Very high cost and complex logistics for a rare indication."],"changedPractice":true,"participants":52},{"id":"paper-spotlight-lancet-2023","kind":"paper","name":"SPOTLIGHT: zolbetuximab, the first Claudin 18.2 antibody, added to chemotherapy in gastric cancer","aka":[],"tldr":"In stomach cancers that express the protein Claudin 18.2, adding the antibody zolbetuximab to chemotherapy extended survival by nearly three months, making Claudin 18.2 a new biomarker to test for.","summary":"Double-blind phase 3 trial of 565 patients with untreated, HER2-negative, Claudin 18.2-positive (moderate-to-strong staining in 75% or more of tumour cells) locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, randomised to zolbetuximab or placebo plus mFOLFOX6. Primary endpoint was PFS.\n\nMedian PFS was 10.6 vs 8.7 months (HR 0.75) and median OS 18.2 vs 15.5 months (HR 0.75). Together with the GLOW trial (zolbetuximab plus CAPOX) it led to approvals in 2024 and made Claudin 18.2 testing routine for HER2-negative gastric cancer, while opening a target now pursued by ADCs and CAR-T cells.","asOf":"2026-09-08","links":[{"label":"PubMed search: SPOTLIGHT zolbetuximab Lancet 2023","url":"https://pubmed.ncbi.nlm.nih.gov/?term=SPOTLIGHT+zolbetuximab+mFOLFOX6+Shitara+Lancet"},{"label":"ClinicalTrials.gov NCT03504397","url":"https://clinicaltrials.gov/study/NCT03504397"}],"tags":[],"related":[],"cancers":["gastric","esophageal"],"sections":[],"technologies":["monoclonal-antibody","histopathology-ihc","companion-diagnostic"],"targets":["cldn18-2"],"drugs":[],"companies":["astellas"],"institutions":["ncc-japan"],"pathways":[],"terms":["ihc","pfs","os","adcc","first-line"],"trials":[],"people":["shitara-kohei","bang-yung-jue","xu-rui-hua","kang-yoon-koo"],"bottlenecks":["b-biomarker-validation","b-combination-space"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"authors":"Shitara K, Lordick F, Bang YJ, et al.","paperType":"rct","findings":["Median PFS 10.61 vs 8.67 months; HR 0.751 (95% CI 0.598-0.942).","Median overall survival 18.23 vs 15.54 months; HR 0.750 (95% CI 0.601-0.936).","About 38% of screened patients were Claudin 18.2-positive by the trial definition.","Nausea (81% vs 61%) and vomiting (65% vs 35%) were much more common with zolbetuximab, particularly during the first infusions.","GLOW (Nature Medicine 2023) confirmed the result with CAPOX: PFS 8.2 vs 6.8 months (HR 0.69), OS 14.4 vs 12.2 months (HR 0.77)."],"whatItMeans":"Patients with newly diagnosed advanced stomach cancer should now have Claudin 18.2 tested alongside HER2, PD-L1 and mismatch repair, because roughly a third will be eligible for zolbetuximab, which adds about three months of median survival. The main practical problem is nausea and vomiting during infusions, which needs aggressive prophylaxis. How to sequence or combine it with immunotherapy in PD-L1-positive tumours is unresolved.","caveats":["The PD-L1-positive population, who would now receive nivolumab or pembrolizumab with chemotherapy, was not addressed; the trials predate that standard.","Claudin 18.2 immunohistochemistry cut-off (75% of cells at 2+/3+) is stringent and assay standardisation is incomplete.","Gastrointestinal toxicity leads to infusion interruptions in many patients.","Modest absolute gains for a costly antibody."],"changedPractice":true,"participants":565},{"id":"paper-ssg-xviii-adjuvant-imatinib-joensuu-jama-2012","kind":"paper","name":"SSG XVIII/AIO: one versus three years of adjuvant imatinib for operable gastrointestinal stromal tumour","aka":[],"tldr":"Three years of imatinib after surgery for high-risk gastrointestinal stromal tumour reduced recurrences and deaths compared with one year, setting the standard duration of adjuvant therapy.","summary":"Phase 3 trial of 400 patients with resected KIT-positive GIST at high risk of recurrence randomised to 12 or 36 months of adjuvant imatinib 400 mg daily.\n\nFive-year recurrence-free survival was 65.6 versus 47.9 percent (hazard ratio 0.46) and five-year overall survival 92.0 versus 81.7 percent (hazard ratio 0.45); ten-year follow-up confirmed the survival benefit, and discontinuation for adverse events was more common with longer treatment.","asOf":"2026-09-17","links":[{"label":"JAMA 2012","url":"https://doi.org/10.1001/jama.2012.347"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22453568/"}],"tags":[],"related":[],"cancers":["gist-kit-exon-11"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2012,"doi":"10.1001/jama.2012.347","pmid":"22453568","authors":"Joensuu H, Eriksson M, Sundby Hall K, et al.","paperType":"rct","findings":["Five-year recurrence-free survival 65.6 percent vs 47.9 percent; hazard ratio 0.46.","Five-year overall survival 92.0 percent vs 81.7 percent; hazard ratio 0.45."],"whatItMeans":"Three years of adjuvant imatinib is standard for high-risk resected GIST with imatinib-sensitive mutations; longer courses are being tested.","caveats":["Patients with PDGFRA D842V mutations, which are imatinib-resistant, do not benefit.","Recurrences resume after imatinib is stopped."],"changedPractice":true,"participants":400},{"id":"paper-stampede-abiraterone-high-risk-attard-lancet-2022","kind":"paper","name":"STAMPEDE: abiraterone with or without enzalutamide added to androgen deprivation for high-risk non-metastatic prostate cancer","aka":[],"tldr":"Adding two years of abiraterone to hormone therapy and radiotherapy for high-risk localised or node-positive prostate cancer halved the risk of metastases and cut deaths by 40 percent, while adding enzalutamide on top brought only extra toxicity.","summary":"Meta-analysis of two STAMPEDE comparisons including 1,974 men with high-risk non-metastatic prostate cancer (node-positive, or node-negative with at least two of T3/4, Gleason 8 to 10, PSA 40 or more) randomised to androgen deprivation with or without two years of abiraterone (with enzalutamide in the second comparison).\n\nSix-year metastasis-free survival was 82 versus 69 percent (hazard ratio 0.53) and overall survival 86 versus 77 percent (hazard ratio 0.60); enzalutamide added toxicity without efficacy.","asOf":"2026-09-17","links":[{"label":"Lancet 2022","url":"https://doi.org/10.1016/S0140-6736(21)02437-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34953525/"}],"tags":[],"related":[],"cancers":["prostate-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["abiraterone","enzalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["stampede"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2022,"doi":"10.1016/S0140-6736(21)02437-5","pmid":"34953525","authors":"Attard G, Murphy L, Clarke NW, et al.","paperType":"rct","findings":["Six-year metastasis-free survival 82 percent vs 69 percent; hazard ratio 0.53.","Six-year overall survival 86 percent vs 77 percent; hazard ratio 0.60."],"whatItMeans":"Two years of abiraterone with androgen deprivation and radiotherapy is the standard for very high-risk and node-positive localised prostate cancer.","caveats":["Most men received radiotherapy; benefit after prostatectomy is less certain.","Staging was by conventional imaging."],"changedPractice":true,"participants":1974},{"id":"paper-stampede-abiraterone-nejm-2017","kind":"paper","name":"STAMPEDE: adding abiraterone to hormone therapy at diagnosis of advanced prostate cancer","aka":[],"tldr":"Giving the hormone-pathway drug abiraterone from the start, alongside standard testosterone suppression, cut deaths by more than a third in men newly diagnosed with high-risk or metastatic prostate cancer.","summary":"STAMPEDE is a multi-arm, multi-stage platform trial. This comparison randomised 1,917 men with newly diagnosed locally advanced or metastatic prostate cancer starting androgen deprivation therapy (ADT) to ADT alone or ADT plus abiraterone and prednisolone. Primary endpoint was overall survival.\n\nOverall survival HR was 0.63 (3-year OS 83% vs 76%) and failure-free survival HR 0.29. Alongside LATITUDE, published the same day, it made early intensification of hormone therapy the standard for metastatic hormone-sensitive prostate cancer, and later STAMPEDE analyses extended this to high-risk non-metastatic disease. The platform design itself, testing many questions against one shared control arm, became a model for trial efficiency.","asOf":"2026-09-08","links":[{"label":"NEJM 2017","url":"https://doi.org/10.1056/NEJMoa1702900"},{"label":"ClinicalTrials.gov NCT00268476","url":"https://clinicaltrials.gov/study/NCT00268476"}],"tags":[],"related":[],"cancers":["prostate"],"sections":[],"technologies":["androgen-deprivation","endocrine-therapy"],"targets":["androgen-receptor"],"drugs":[],"companies":["johnson-johnson"],"institutions":["icr-london","royal-marsden","cruk"],"pathways":[],"terms":["basket-umbrella-platform","os","standard-of-care"],"trials":[],"people":["nicholas-james","johann-de-bono"],"bottlenecks":["b-trial-design","b-drug-pricing","b-generic-repurposing"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1702900","authors":"James ND, de Bono JS, Spears MR, et al.","paperType":"rct","findings":["Overall survival HR 0.63 (95% CI 0.52-0.76); 3-year OS 83% vs 76%.","Failure-free survival HR 0.29 (95% CI 0.25-0.34).","Benefit consistent in metastatic (M1) and high-risk non-metastatic (M0) subgroups at the primary analysis.","Grade 3-5 adverse events 47% vs 33%, driven by hypertension, liver enzyme elevation and cardiovascular events.","Later STAMPEDE analysis (Lancet 2022) showed abiraterone for two years in high-risk M0 disease improved 6-year metastasis-free survival from 69% to 82% (HR 0.53)."],"whatItMeans":"Men diagnosed with prostate cancer that has already spread, or that is locally advanced and high risk, should start abiraterone (or another androgen-receptor pathway inhibitor) at the same time as testosterone suppression rather than waiting for resistance. This roughly halves the risk of death over several years. The same platform later showed that docetaxel chemotherapy and, in high-volume metastatic disease, triple therapy also help, and that abiraterone benefits men with high-risk disease treated with radiotherapy.","caveats":["Abiraterone requires prednisolone and monitoring for hypertension, hypokalaemia and liver toxicity; cardiovascular risk is higher in older men.","Direct comparison with docetaxel (also in STAMPEDE) showed similar OS in metastatic disease, leaving the choice to toxicity and cost.","Cost of abiraterone was a barrier until generic versions became available.","Optimal duration in non-metastatic disease (two years in STAMPEDE) was chosen empirically."],"changedPractice":true,"participants":1917},{"id":"paper-storm-adjuvant-sorafenib-bruix-lancet-oncol-2015","kind":"paper","name":"STORM: adjuvant sorafenib after resection or ablation of hepatocellular carcinoma","aka":[],"tldr":"Four years of sorafenib after curative surgery or ablation for liver cancer did not delay recurrence or lengthen survival, and caused substantial toxicity, closing the door on kinase inhibitors as adjuvant therapy.","summary":"Phase 3 placebo-controlled trial of 1,114 patients with hepatocellular carcinoma after complete resection or ablation randomised to sorafenib or placebo for up to four years.\n\nMedian recurrence-free survival was 33.3 versus 33.7 months (hazard ratio 0.94) with no difference in time to recurrence or overall survival, and more than a quarter of sorafenib patients discontinued because of adverse events.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2015","url":"https://doi.org/10.1016/S1470-2045(15)00198-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26361969/"}],"tags":[],"related":[],"cancers":["hcc-early"],"sections":[],"technologies":[],"targets":[],"drugs":["sorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2015,"doi":"10.1016/S1470-2045(15)00198-9","pmid":"26361969","authors":"Bruix J, Takayama T, Mazzaferro V, et al.","paperType":"rct","findings":["Median recurrence-free survival 33.3 vs 33.7 months; hazard ratio 0.94.","Discontinuation for adverse events 24 percent vs 7 percent."],"whatItMeans":"No adjuvant systemic therapy is recommended after curative treatment of hepatocellular carcinoma, a conclusion reinforced by the later failure of IMbrave050.","caveats":["Population included patients with relatively low recurrence risk."],"changedPractice":true,"participants":1114},{"id":"paper-strass-lancet-oncol-2020","kind":"paper","name":"STRASS (EORTC 62092): preoperative radiotherapy plus surgery versus surgery alone for primary retroperitoneal sarcoma","aka":[],"tldr":"Adding radiotherapy before surgery for retroperitoneal sarcoma did not improve abdominal recurrence-free survival overall, so it is no longer routine, though a possible benefit in liposarcoma keeps it under discussion.","summary":"Phase 3 trial of 266 patients with primary resectable retroperitoneal sarcoma randomised to preoperative radiotherapy (50.4 Gy) followed by surgery or surgery alone.\n\nMedian abdominal recurrence-free survival was 4.5 versus 5.0 years (hazard ratio 1.01), with more serious adverse events in the radiotherapy group; exploratory analysis suggested benefit in well-differentiated and low-grade dedifferentiated liposarcoma but not leiomyosarcoma.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2020","url":"https://doi.org/10.1016/S1470-2045(20)30446-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32941794/"}],"tags":[],"related":[],"cancers":["retroperitoneal-sarcoma","liposarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["strass"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2020,"doi":"10.1016/S1470-2045(20)30446-0","pmid":"32941794","authors":"Bonvalot S, Gronchi A, Le Péchoux C, et al.","paperType":"rct","findings":["Median abdominal recurrence-free survival 4.5 vs 5.0 years; hazard ratio 1.01.","Serious adverse events 24 percent vs 10 percent."],"whatItMeans":"Surgery alone in a reference centre is the standard for primary retroperitoneal sarcoma; preoperative radiotherapy is considered case by case in liposarcoma.","caveats":["Trial did not meet its endpoint, but the liposarcoma subgroup signal remains debated.","Surgery-alone arm had excellent outcomes at expert centres."],"changedPractice":true,"participants":266},{"id":"paper-stupp-temozolomide-nejm-2005","kind":"paper","name":"Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma","aka":[],"tldr":"Adding the oral chemotherapy temozolomide during and after radiotherapy extended median survival in glioblastoma by about two and a half months and more than doubled the number of patients alive at two years; twenty years later it is still the standard.","summary":"Open-label phase 3 trial (EORTC 26981/NCIC CE.3) of 573 patients aged 18-70 with newly diagnosed glioblastoma randomised to radiotherapy alone (60 Gy) or radiotherapy with concomitant daily temozolomide followed by six cycles of adjuvant temozolomide. Primary endpoint was overall survival.\n\nMedian OS was 14.6 vs 12.1 months (HR 0.63) and 2-year OS 26.5% vs 10.4%. The companion paper by Hegi showed that MGMT promoter methylation predicted benefit. The 'Stupp protocol' became the global standard for glioblastoma and remains so, with only tumour-treating fields added since; the trial also illustrates how little progress has been made against this tumour.","asOf":"2026-09-08","links":[{"label":"NEJM 2005","url":"https://doi.org/10.1056/NEJMoa043330"},{"label":"Hegi et al. NEJM 2005 (MGMT)","url":"https://doi.org/10.1056/NEJMoa043331"}],"tags":[],"related":[],"cancers":["glioblastoma"],"sections":[],"technologies":["cytotoxic-chemotherapy","imrt-igrt","methylation-profiling","ttfields"],"targets":[],"drugs":[],"companies":[],"institutions":["curie-nki-eortc"],"pathways":[],"terms":["os","standard-of-care"],"trials":[],"people":["roger-stupp","michael-weller","denis-lacombe"],"bottlenecks":["b-brain-delivery","b-negative-results","b-undruggable-targets"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2005,"doi":"10.1056/NEJMoa043330","authors":"Stupp R, Mason WP, van den Bent MJ, et al.","paperType":"rct","findings":["Median overall survival 14.6 vs 12.1 months; HR 0.63 (95% CI 0.52-0.75).","2-year overall survival 26.5% vs 10.4%.","Five-year follow-up (Lancet Oncology 2009): 5-year OS 9.8% vs 1.9%.","MGMT promoter methylation (Hegi, NEJM 2005) identified patients with the greatest benefit: median OS 21.7 months with temozolomide in methylated tumours vs 12.7 months in unmethylated.","Grade 3-4 haematological toxicity in about 7% during concomitant treatment and 14% during adjuvant treatment."],"whatItMeans":"Patients with newly diagnosed glioblastoma who are fit and under about 70 receive six weeks of radiotherapy with daily temozolomide followed by six monthly cycles of temozolomide; this is still the backbone of treatment two decades later. Testing MGMT methylation identifies who benefits most and guides decisions in older patients. Median survival with the regimen remains only around 15-20 months, and no drug since has clearly improved on it, which is why glioblastoma is a priority for new approaches.","caveats":["Excluded patients over 70 and with poor performance status; later trials (e.g. Perry 2017) addressed short-course radiotherapy with temozolomide in the elderly.","The benefit in MGMT-unmethylated tumours is small, yet temozolomide is still usually given for lack of alternatives.","Open-label design; no quality-of-life data in the primary report.","Two decades of subsequent negative trials (bevacizumab, nivolumab, vaccines) make this the standard by default rather than by continued advance."],"changedPractice":true,"participants":573},{"id":"paper-zhukova-tp53-medulloblastoma-jco-2013","kind":"paper","name":"Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma","aka":[],"tldr":"TP53 mutations mark a very poor prognosis in SHH-subgroup medulloblastoma, with five-year survival around 40 percent, but have no effect in WNT tumours, so the mutation must be interpreted alongside the subgroup.","summary":"Analysis of 553 medulloblastomas for TP53 mutation by molecular subgroup in a discovery and validation cohort, finding TP53 mutations in 21 percent of SHH and 16 percent of WNT tumours but rarely in groups 3 and 4.\n\nIn SHH tumours, TP53 mutation was associated with five-year overall survival of 41 percent against 81 percent for wild-type, often with germline mutations (Li-Fraumeni syndrome) and chromothripsis, whereas WNT tumours with TP53 mutations retained excellent survival.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2013","url":"https://doi.org/10.1200/JCO.2012.48.5052"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23835706/"}],"tags":[],"related":[],"cancers":["medulloblastoma-shh"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2013,"doi":"10.1200/JCO.2012.48.5052","pmid":"23835706","authors":"Zhukova N, Ramaswamy V, Remke M, et al.","paperType":"translational","findings":["SHH TP53-mutant: five-year overall survival 41 percent vs 81 percent for wild-type.","WNT TP53-mutant: survival unaffected (90 percent)."],"whatItMeans":"SHH-activated, TP53-mutant medulloblastoma is a separate WHO entity treated as very high risk, and its diagnosis prompts germline testing of the child and family.","caveats":["Retrospective; treatment varied across cohorts."],"changedPractice":true,"participants":553},{"id":"paper-sung-globocan-2020-cacancer-2021","kind":"paper","name":"Sung 2021: GLOBOCAN 2020, the year breast cancer overtook lung cancer as the most diagnosed cancer","aka":[],"tldr":"The IARC count for 2020: about 19.3 million new cancer cases worldwide, with female breast cancer overtaking lung cancer as the most commonly diagnosed cancer for the first time, and a projected rise to about 28 million cases a year by 2040.","summary":"GLOBOCAN 2020, from the International Agency for Research on Cancer, estimated incidence and mortality for 36 cancers in 185 countries. It counted an estimated 19.3 million new cases (18.1 million excluding non-melanoma skin cancer) in 2020. Female breast cancer became the most commonly diagnosed cancer, ahead of lung, colorectal, prostate and stomach cancers, while lung cancer remained the leading cause of cancer death. The authors projected 28.4 million cases in 2040, a 47% rise on 2020 driven by population growth and ageing, with the largest relative increases in countries undergoing economic transition.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21660"},{"label":"IARC Global Cancer Observatory","url":"https://gco.iarc.who.int/today"}],"tags":[],"related":["paper-bray-globocan-2022-cacancer-2024"],"cancers":["breast-hr-positive","nsclc","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":["bray-freddie"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2021,"doi":"10.3322/caac.21660","authors":"Sung H, Ferlay J, Siegel RL, et al.","paperType":"observational","findings":["About 19.3 million new cancer cases and almost 10 million cancer deaths worldwide in 2020.","Female breast cancer the most commonly diagnosed cancer (about 2.3 million cases, 11.7% of the total), overtaking lung cancer.","Lung cancer the leading cause of cancer death (about 1.8 million deaths, 18% of the total), followed by colorectal, liver, stomach and female breast cancers.","Projected 28.4 million cases in 2040, a 47% increase from 2020."],"whatItMeans":"This report marked the shift of the global cancer burden towards breast cancer and towards lower-income countries, and it is the baseline most 2020s policy documents cite. The GLOBOCAN 2022 release has since updated the totals.","caveats":["Estimates for 2020 were made before the COVID-19 pandemic's effect on diagnoses could be measured.","Many countries lack population-based registries, so their figures rest on modelling."],"changedPractice":false},{"id":"paper-demetri-sunitinib-gist-lancet-2006","kind":"paper","name":"Sunitinib in advanced gastrointestinal stromal tumour after failure of imatinib","aka":[],"tldr":"Sunitinib more than quadrupled the time to progression compared with placebo in gastrointestinal stromal tumours that had become resistant to or intolerant of imatinib, establishing the standard second-line treatment.","summary":"Phase 3 placebo-controlled trial of 312 patients with advanced gastrointestinal stromal tumour after imatinib failure randomised 2:1 to sunitinib 50 mg daily (four weeks on, two off) or placebo, unblinded early after an interim analysis.\n\nMedian time to progression was 27.3 versus 6.4 weeks (hazard ratio 0.33) with a survival benefit at interim analysis (hazard ratio 0.49); fatigue, diarrhoea, skin discolouration and hand-foot syndrome were common.","asOf":"2026-09-17","links":[{"label":"Lancet 2006","url":"https://doi.org/10.1016/S0140-6736(06)69446-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/17046465/"}],"tags":[],"related":[],"cancers":["gist-imatinib-resistant"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2006,"doi":"10.1016/S0140-6736(06)69446-4","pmid":"17046465","authors":"Demetri GD, van Oosterom AT, Garrett CR, et al.","paperType":"rct","findings":["Median time to progression 27.3 vs 6.4 weeks; hazard ratio 0.33.","Interim overall survival hazard ratio 0.49."],"whatItMeans":"Sunitinib is the standard second-line kinase inhibitor for GIST, with particular activity against KIT exon 9 and exon 13/14 secondary mutations.","caveats":["Trial unblinded early; final survival analysis confounded by crossover.","Less active against exon 17/18 secondary mutations."],"changedPractice":true,"participants":312},{"id":"paper-raymond-sunitinib-pnet-nejm-2011","kind":"paper","name":"Sunitinib malate for the treatment of pancreatic neuroendocrine tumours","aka":[],"tldr":"The multikinase inhibitor sunitinib doubled the time to progression in advanced pancreatic neuroendocrine tumours and was approved at the same time as everolimus, giving the disease its first targeted therapies.","summary":"Phase 3 placebo-controlled trial of 171 patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumours randomised to sunitinib 37.5 mg daily or placebo, stopped early after an independent monitoring committee observed more deaths and serious events with placebo.\n\nMedian progression-free survival was 11.4 versus 5.5 months (hazard ratio 0.42) with response of 9.3 versus 0 percent; hypertension, hand-foot syndrome and fatigue were the main toxicities.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2011","url":"https://doi.org/10.1056/NEJMoa1003825"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21306237/"}],"tags":[],"related":[],"cancers":["pancreatic-net"],"sections":[],"technologies":[],"targets":[],"drugs":["sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2011,"doi":"10.1056/NEJMoa1003825","pmid":"21306237","authors":"Raymond E, Dahan L, Raoul JL, et al.","paperType":"rct","findings":["Median progression-free survival 11.4 vs 5.5 months; hazard ratio 0.42.","Objective response 9.3 percent vs 0 percent."],"whatItMeans":"Sunitinib is a standard targeted option for progressive pancreatic neuroendocrine tumours; the choice between it and everolimus is guided by comorbidity and side-effect profile.","caveats":["Trial stopped early with 171 of a planned 340 patients, which can overestimate effect."],"changedPractice":true,"participants":171},{"id":"paper-sunlight-nejm-2023","kind":"paper","name":"SUNLIGHT: trifluridine-tipiracil plus bevacizumab in refractory metastatic colorectal cancer","aka":[],"tldr":"Adding bevacizumab to the oral chemotherapy trifluridine-tipiracil lengthened survival by about three months in patients with colorectal cancer that had already been treated with two regimens, making the combination the standard third-line treatment.","summary":"Phase 3 trial of 492 patients with metastatic colorectal cancer after two prior regimens randomised to trifluridine-tipiracil with or without bevacizumab.\n\nMedian overall survival was 10.8 versus 7.5 months (hazard ratio 0.61) and median progression-free survival 5.6 versus 2.4 months, with a longer time to worsening performance status and no unexpected toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/NEJMoa2214963"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37133585/"}],"tags":[],"related":[],"cancers":["kras-g12c-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["sunlight"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2214963","pmid":"37133585","authors":"Prager GW, Taieb J, Fakih M, et al.","paperType":"rct","findings":["Median overall survival 10.8 vs 7.5 months; hazard ratio 0.61.","Median progression-free survival 5.6 vs 2.4 months."],"whatItMeans":"Trifluridine-tipiracil plus bevacizumab is now the preferred third-line option for most patients regardless of KRAS status, including KRAS G12C tumours once targeted therapy is exhausted.","caveats":["Open-label; benefit was seen regardless of prior bevacizumab exposure but subgroup sizes were limited."],"changedPractice":true,"participants":492},{"id":"paper-sunrise-1-jco-2025","kind":"paper","name":"SunRISe-1: TAR-200, a gemcitabine-releasing device placed in the bladder, for BCG-unresponsive non-muscle-invasive bladder cancer","aka":[],"tldr":"A small pretzel-shaped device that slowly releases gemcitabine inside the bladder cleared carcinoma in situ in about four out of five patients whose cancer had stopped responding to BCG, offering an alternative to bladder removal.","summary":"Open-label phase 2b trial of patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer with carcinoma in situ, who declined or were unfit for radical cystectomy. Cohort 2 tested TAR-200 monotherapy, an intravesical drug-releasing system placed cystoscopically every three weeks then every twelve weeks for up to two years. Primary endpoint was complete response rate.\n\nThe complete response rate was about 84%, with most responses durable beyond a year and a low rate of serious adverse events, mostly urinary symptoms. It led to FDA approval in 2025, the first intravesical drug-releasing system and a rare new option for a group whose only curative alternative is cystectomy.","asOf":"2026-09-08","links":[{"label":"PubMed search: SunRISe-1 TAR-200","url":"https://pubmed.ncbi.nlm.nih.gov/?term=SunRISe-1+TAR-200+BCG-unresponsive"},{"label":"ClinicalTrials.gov NCT04640623","url":"https://clinicaltrials.gov/study/NCT04640623"}],"tags":[],"related":[],"cancers":["urothelial"],"sections":[],"technologies":["cytotoxic-chemotherapy"],"targets":[],"drugs":[],"companies":["johnson-johnson"],"institutions":[],"pathways":[],"terms":["orr","accelerated-approval"],"trials":[],"people":[],"bottlenecks":["b-surgery-radiation-innovation","b-toxicity-qol","b-trial-design"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2025,"authors":"Jacob JM, Daneshmand S, Necchi A, et al.","paperType":"rct","findings":["Complete response in about 84% of patients with carcinoma in situ (cohort 2, TAR-200 alone).","Median duration of response over two years, with a majority of responders remaining in complete response at 12 months.","Most adverse events were low-grade urinary symptoms (frequency, dysuria, urgency); grade 3 or higher treatment-related events in a small minority and rare discontinuations.","Placement and removal are outpatient cystoscopic procedures requiring no anaesthesia.","Response rates compared favourably with pembrolizumab (about 41%) and nadofaragene firadenovec (about 51%) in similar populations, though not in a randomised comparison."],"whatItMeans":"Patients with high-risk bladder cancer confined to the lining whose disease has not responded to BCG now have a bladder-sparing option that clears the cancer in most cases, delivered through a simple outpatient procedure. It may allow many to avoid or defer cystectomy, a life-changing operation. Whether responses translate into avoided progression and cystectomy over the long term, and how it compares with cystectomy on survival, remain to be shown.","caveats":["Single-arm phase 2b; no randomised comparison with cystectomy or other bladder-sparing options.","Follow-up is still relatively short for a disease where recurrence and progression occur over years.","Complete response is a surrogate; progression to muscle-invasive disease is the outcome that matters.","Requires regular cystoscopy for device exchange and surveillance, and cost is substantial."],"changedPractice":true,"participants":85},{"id":"paper-hpv-vaccine-sweden-nejm-2020","kind":"paper","name":"Swedish registry study: HPV vaccination almost eliminates cervical cancer when given before 17","aka":[],"tldr":"Among 1.7 million Swedish girls and women, quadrivalent HPV vaccination cut invasive cervical cancer by 88% when given before age 17 and by about half when given at 17-30.","summary":"A nationwide cohort of 1,672,983 girls and women aged 10-30 was followed from 2006 to 2017 through Swedish registries, linking HPV vaccination status to invasive cervical cancer diagnoses. Analyses adjusted for age, calendar year, county and parental characteristics.\n\nCumulative incidence of cervical cancer by age 30 was 47 per 100,000 in vaccinated women and 94 per 100,000 in unvaccinated women. The adjusted incidence rate ratio was 0.12 for women vaccinated before 17 and 0.47 for those vaccinated at 17-30.\n\nThis was the first population-level demonstration that HPV vaccination prevents invasive cancer, not just precancerous lesions.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1917338"}],"tags":[],"related":["paper-hpv-vaccine-england-lancet-2021","idea-prev-hpv-single-dose-switch-catchup","idea-moon-hpv-vaccine-confidence","idea-single-dose-hpv-self-sampling-elimination"],"cancers":["cervical","head-and-neck"],"sections":["prevention"],"technologies":["hpv-vaccine","hpv-testing"],"targets":[],"drugs":[],"companies":[],"institutions":["karolinska"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-prevention-adoption","b-misinformation","b-global-access"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa1917338","pmid":"32997908","authors":"Lei J, Ploner A, Elfström KM, et al.","paperType":"observational","findings":["Adjusted incidence rate ratio for cervical cancer 0.37 (95% CI 0.21-0.57) overall in vaccinated vs unvaccinated","Vaccinated before age 17: IRR 0.12 (95% CI 0.00-0.34), an 88% reduction","Vaccinated at 17-30: IRR 0.47 (95% CI 0.27-0.75)","Cumulative incidence by age 30: 47 vs 94 per 100,000"],"whatItMeans":"Vaccinating girls before they are exposed to HPV prevents most cervical cancers. Catch-up vaccination in young adults still helps, but less. Combined with HPV screening, elimination of cervical cancer as a public health problem is a realistic goal.","caveats":["Observational; residual confounding by health-seeking behaviour is possible despite adjustment","Follow-up ends at age 30, before most cervical cancers occur","Sweden used the quadrivalent vaccine; effects for bivalent and nonavalent vaccines are inferred","Does not address single-dose schedules or vaccination of boys"],"changedPractice":true,"participants":1672983},{"id":"paper-swog-8710-neoadjuvant-mvac-nejm-2003","kind":"paper","name":"SWOG 8710: neoadjuvant MVAC chemotherapy before cystectomy for muscle-invasive bladder cancer","aka":[],"tldr":"Giving three cycles of cisplatin-based chemotherapy before removing the bladder lengthened survival compared with surgery alone, and became the standard for fit patients with muscle-invasive bladder cancer.","summary":"Randomised trial of 317 patients with muscle-invasive urothelial bladder cancer (T2 to T4a) assigned to three cycles of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) followed by radical cystectomy, or cystectomy alone.\n\nMedian survival was 77 months with neoadjuvant chemotherapy against 46 months with surgery alone, and 38 percent of chemotherapy patients had no residual tumour at surgery compared with 15 percent, a finding tightly linked to long-term survival. The trial anchored neoadjuvant cisplatin-based chemotherapy as the standard of care.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2003","url":"https://doi.org/10.1056/NEJMoa022148"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12944571/"}],"tags":[],"related":[],"cancers":["muscle-invasive-bladder-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2003,"doi":"10.1056/NEJMoa022148","pmid":"12944571","authors":"Grossman HB, Natale RB, Tangen CM, et al.","paperType":"rct","findings":["Median overall survival 77 months with neoadjuvant MVAC vs 46 months with cystectomy alone.","Pathological complete response (pT0) in 38 percent vs 15 percent, with 85 percent five-year survival among pT0 patients."],"whatItMeans":"Fit patients with muscle-invasive bladder cancer should be offered cisplatin-based chemotherapy before cystectomy; a complete pathological response predicts cure. Newer regimens such as gemcitabine-cisplatin and dose-dense MVAC, and now durvalumab, build on this result.","caveats":["The survival difference reached only borderline statistical significance in the primary analysis.","Slow accrual over eleven years; MVAC has largely been replaced by better-tolerated cisplatin regimens."],"changedPractice":true,"participants":317},{"id":"paper-swog-s1826-nivolumab-avd-nejm-2024","kind":"paper","name":"SWOG S1826: nivolumab plus AVD chemotherapy versus brentuximab-AVD for advanced Hodgkin lymphoma in adolescents and adults","aka":[],"tldr":"Adding a PD-1 antibody to chemotherapy beat the brentuximab-based standard, with 92% of patients progression-free at two years and less nerve damage.","summary":"S1826 was a phase 3 trial run jointly by adult and paediatric cooperative groups, randomising 994 patients aged 12 and over with newly diagnosed stage III or IV classical Hodgkin lymphoma to nivolumab plus AVD (N-AVD) or brentuximab vedotin plus AVD (BV-AVD) for six cycles. Radiotherapy was discouraged and given to under 1%. The primary endpoint was PFS. At two years PFS was 92% versus 83% (hazard ratio 0.45), with benefit across ages including patients over 60. N-AVD caused less peripheral neuropathy and fewer treatment discontinuations, while immune-related events (mainly thyroid dysfunction and rash) were mostly low grade.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2405888"},{"label":"ClinicalTrials.gov NCT03907488","url":"https://clinicaltrials.gov/study/NCT03907488"}],"tags":[],"related":["pd1-plus-avd-hodgkin","paper-echelon-1-brentuximab-avd-nejm-2018"],"cancers":["hodgkin-lymphoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1","cd30"],"drugs":["nivolumab","brentuximab-vedotin","doxorubicin"],"companies":["bms"],"institutions":["swog","childrens-oncology-group"],"pathways":[],"terms":["pfs","irae"],"trials":["swog-s1826","echelon-1","hd21","ahod2131"],"people":["alex-herrera"],"bottlenecks":["b-trial-design","b-survivorship"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2405888","authors":"Herrera AF, LeBlanc M, Castellino SM, et al.","paperType":"rct","findings":["994 patients aged 12 and over (about a quarter under 18) with stage III-IV classical Hodgkin lymphoma; N-AVD vs BV-AVD.","2-year PFS 92% vs 83%; hazard ratio 0.45.","Benefit consistent in adolescents, adults and patients over 60.","Less peripheral neuropathy and fewer discontinuations with N-AVD; immune-related adverse events mostly grade 1-2.","Consolidative radiotherapy used in fewer than 1% of patients."],"whatItMeans":"S1826 moved checkpoint blockade into first-line Hodgkin lymphoma and made N-AVD a preferred regimen for advanced disease in patients from adolescence to older age, while removing radiotherapy for most. It also showed the value of a single trial spanning paediatric and adult groups. Longer follow-up is needed for overall survival and late immune effects in young patients.","caveats":["Overall survival data are immature; both arms have high survival.","Follow-up is short for a disease where late relapses and second cancers matter.","Comparison is with BV-AVD, not the European BrECADD regimen.","Nivolumab cost and access limit adoption in some health systems."],"changedPractice":true,"participants":994},{"id":"paper-laurie-licitra-salivary-systemic-jco-2006","kind":"paper","name":"Systemic therapy in the palliative management of advanced salivary gland cancers (review)","aka":[],"tldr":"This review of chemotherapy in salivary gland cancers concluded that responses are uncommon and short, that observation is reasonable for slowly progressing disease, and that trials of targeted agents based on tumour biology were needed.","summary":"Systematic review of systemic therapy studies in recurrent or metastatic salivary gland carcinoma, summarising response rates to single agents and combinations by histology, the natural history of indolent adenoid cystic carcinoma, and early experience with targeted agents.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2006","url":"https://doi.org/10.1200/JCO.2005.05.3025"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16763282/"}],"tags":[],"related":[],"cancers":["mucoepidermoid-carcinoma","adenoid-cystic-carcinoma","salivary-duct-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2006,"doi":"10.1200/JCO.2005.05.3025","pmid":"16763282","authors":"Laurie SA, Licitra L.","paperType":"review","findings":[],"whatItMeans":"The observation-first approach for indolent metastases and the move to biomarker-directed therapy (HER2, androgen receptor, NTRK) on the salivary cancer pages follow this review's conclusions.","caveats":["Predates the HER2, androgen receptor and immunotherapy studies that now guide treatment."],"changedPractice":false},{"id":"paper-tailorx-nejm-2018","kind":"paper","name":"TAILORx: adjuvant chemotherapy guided by the 21-gene recurrence score in hormone receptor-positive, node-negative breast cancer","aka":[],"tldr":"Women with hormone receptor-positive, HER2-negative, node-negative breast cancer and a mid-range 21-gene recurrence score did just as well with endocrine therapy alone as with chemotherapy added, sparing most of them chemotherapy.","summary":"Prospective trial of 10,273 women with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer; those with a recurrence score of 11 to 25 (6,711 women) were randomised to endocrine therapy alone or chemoendocrine therapy.\n\nNine-year invasive disease-free survival was 83.3 percent with endocrine therapy against 84.3 percent with chemoendocrine therapy, meeting non-inferiority. Some benefit from chemotherapy was seen in women aged 50 or younger with scores of 16 to 25.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2018","url":"https://doi.org/10.1056/NEJMoa1804710"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29860917/"}],"tags":[],"related":[],"cancers":["hr-positive-early-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tailorx"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2018,"doi":"10.1056/NEJMoa1804710","pmid":"29860917","authors":"Sparano JA, Gray RJ, Makower DF, et al.","paperType":"rct","findings":["Nine-year invasive disease-free survival 83.3 percent vs 84.3 percent for scores 11 to 25 (hazard ratio 1.08, non-inferior).","Women 50 or younger with scores 16 to 25 had some chemotherapy benefit."],"whatItMeans":"Most women with node-negative hormone receptor-positive breast cancer can safely skip chemotherapy on the basis of a genomic assay; the exception is premenopausal women with scores in the upper part of the intermediate range.","caveats":["The benefit in younger women may partly reflect chemotherapy-induced ovarian suppression.","Node-positive disease was addressed separately in RxPONDER."],"changedPractice":true,"participants":10273},{"id":"paper-jain-talicabtagene-lancet-haem-2025","kind":"paper","name":"Talicabtagene autoleucel for relapsed or refractory B-cell malignancies: an open-label, multicentre, phase 1/2 study","aka":[],"tldr":"The trial report behind India's first CAR-T therapy: about three in four heavily pretreated patients with lymphoma or leukaemia responded to cells engineered and made in Mumbai.","summary":"Open-label phase 1/2 study at six Indian tertiary centres enrolling 64 patients (14 phase 1, 50 phase 2) with relapsed or refractory B-cell lymphoma or B-ALL; phase 2 dose at least 5 x 10^6 CAR-T cells per kg (up to 2 x 10^9). Among 51 efficacy-evaluable patients (36 lymphoma, 15 B-ALL) the overall response rate was 73% (37 of 51; 95% CI 59-83). Grade 3 or worse neutropenia (96%), thrombocytopenia (65%) and anaemia (61%) were common; two deaths were treatment related. An accompanying commentary framed the approval as a model for CAR-T in lower-income countries.","asOf":"2026-09-10","links":[{"label":"Lancet Haematology 2025","url":"https://doi.org/10.1016/S2352-3026(24)00377-6"},{"label":"Commentary: CAR T-cell therapy in LMICs","url":"https://doi.org/10.1016/S2352-3026(25)00040-7"}],"tags":[],"related":[],"cancers":["dlbcl","all-leukemia"],"sections":[],"technologies":["car-t"],"targets":[],"drugs":["talicabtagene-autoleucel"],"companies":["immunoact"],"institutions":["tata-memorial","iit-bombay"],"pathways":[],"terms":[],"trials":["talicel-phase-1-2"],"people":["jain-hasmukh","narula-gaurav","purwar-rahul"],"bottlenecks":["b-manufacturing-cell-therapy","b-global-access"],"keyPapers":[],"journals":["lancet-haematology"],"dependsOn":[],"notes":[],"journal":"Lancet Haematology","year":2025,"doi":"10.1016/S2352-3026(24)00377-6","pmid":"40090352","authors":"Jain H, Karulkar A, Kalra D, et al.","paperType":"rct","findings":["Overall response rate 73% (37 of 51 evaluable patients).","Grade 3 or worse neutropenia in 96%, thrombocytopenia 65%, anaemia 61%.","Two treatment-related deaths (one with haemophagocytic lymphohistiocytosis and septic shock, one pulmonary bleed with cytokine release syndrome).","Product manufactured domestically with a humanised CD19 binder; approved by the DCGI in 2023."],"whatItMeans":"A lower-middle-income country can design, manufacture, trial and approve an autologous CAR-T therapy. Response rates are in the range of first-generation Western products in similar mixed populations, at a price an order of magnitude lower, which reopens the question of what CAR-T should cost everywhere.","caveats":["Single-arm, small, mixed histologies; durability data are short.","Response assessment and comparability to pivotal Western trials (which used disease-specific cohorts and complete response endpoints) are limited.","Haematological toxicity was very high and two deaths were treatment related; safety systems at 130-plus centres matter."],"changedPractice":true,"participants":64},{"id":"paper-roberts-ph-like-all-nejm-2014","kind":"paper","name":"Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukaemia","aka":[],"tldr":"Sequencing showed that Ph-like acute lymphoblastic leukaemia, which behaves like Philadelphia-positive disease without the BCR-ABL1 fusion, is driven by a range of kinase-activating alterations, many of them potentially treatable with existing kinase inhibitors.","summary":"Genomic study of 1,725 patients with B-ALL identifying the Ph-like subtype in 15 percent of children and over 25 percent of young adults, with transcriptome and genome sequencing of 154 Ph-like cases revealing ABL-class fusions, CRLF2 rearrangements with JAK mutations, and other JAK-STAT and Ras pathway lesions; cell lines and patient-derived xenografts responded to matching kinase inhibitors.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2014","url":"https://doi.org/10.1056/NEJMoa1403088"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25207766/"}],"tags":[],"related":[],"cancers":["all-ph-like"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/NEJMoa1403088","pmid":"25207766","authors":"Roberts KG, Li Y, Payne-Turner D, et al.","paperType":"translational","findings":["Ph-like ALL frequency rises with age: about 10 percent of standard-risk children to over 25 percent of young adults.","Kinase-activating alterations in 91 percent of Ph-like cases; ABL-class fusions in about 13 percent."],"whatItMeans":"Screening for Ph-like ALL and its underlying kinase lesion is now part of high-risk ALL protocols, directing ABL-class cases to imatinib or dasatinib and JAK-pathway cases to ruxolitinib trials.","caveats":["Efficacy of kinase inhibitors in Ph-like ALL is still being established in trials."],"changedPractice":true,"participants":1725},{"id":"paper-tcga-pancancer-atlas-cell-2018","kind":"paper","name":"TCGA Pan-Cancer Atlas: 10,000 tumours across 33 cancer types, classified by molecular features","aka":[],"tldr":"The capstone of The Cancer Genome Atlas integrated DNA, RNA, protein and methylation data on about 10,000 tumours, showing that cell of origin dominates molecular classification but that some cancers regroup across organs.","summary":"The Pan-Cancer Atlas was a set of 27 papers in Cell Press journals in April 2018 summarising a decade of TCGA. The flagship classification paper (Hoadley et al.) integrated five data types on 9,759 tumours from 33 cancer types and identified 28 molecular clusters. Most clusters were dominated by tissue of origin, but squamous cancers from different organs grouped together, as did gastrointestinal adenocarcinomas and kidney cancers of different histologies.\n\nCompanion papers catalogued 299 driver genes and over 3,400 driver mutations (Bailey et al.), showed that 89% of tumours had at least one driver alteration in ten canonical signalling pathways and 57% had at least one potentially targetable alteration (Sanchez-Vega et al.), and characterised immune subtypes, oncogenic processes and cell-of-origin patterns.\n\nTCGA data, freely available through the Genomic Data Commons, became the reference against which nearly every cancer genomics study is compared.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/j.cell.2018.03.022"},{"label":"Driver genes (Bailey 2018)","url":"https://doi.org/10.1016/j.cell.2018.02.060"},{"label":"NCI Genomic Data Commons","url":"https://portal.gdc.cancer.gov"}],"tags":[],"related":["tcga-gdc","paper-vogelstein-cancer-genome-landscapes-science-2013"],"cancers":[],"sections":["diagnostics","drug-discovery"],"technologies":["wes-wgs","rna-seq","methylation-profiling","cgp"],"targets":[],"drugs":[],"companies":[],"institutions":["nci","broad-institute"],"pathways":[],"terms":["mutational-signature","tmb","pam50"],"trials":[],"people":["gad-getz"],"bottlenecks":["b-data-silos","b-tumor-heterogeneity","b-trial-diversity"],"keyPapers":[],"journals":["cell"],"dependsOn":[],"notes":[],"journal":"Cell","year":2018,"doi":"10.1016/j.cell.2018.03.022","pmid":"29625048","authors":"Hoadley KA, Yau C, Hinoue T, et al. (The Cancer Genome Atlas Network)","paperType":"basic","findings":["9,759 tumours from 33 cancer types integrated across mRNA, miRNA, DNA methylation, copy number and protein data","28 iCluster molecular subtypes; about two-thirds dominated by tissue of origin, with cross-tissue clusters for squamous and pan-gastrointestinal cancers","Companion paper: 299 driver genes, of which about half were not previously in curated driver lists (Bailey et al.)","Companion paper: 89% of tumours had at least one alteration in ten signalling pathways; 57% had a potentially actionable alteration (Sanchez-Vega et al.)"],"whatItMeans":"Cancers are defined as much by the tissue they come from as by the mutations they carry, which is why the same drug can work in one organ and fail in another with the same mutation. TCGA is the shared public dataset behind most modern biomarkers and target discovery.","caveats":["Primary, untreated tumours only; metastatic and post-treatment biology are under-represented","Predominantly white US patients; ancestry diversity is limited","Bulk tissue profiling averages over heterogeneity later revealed by single-cell and spatial methods","Actionability estimates count alterations with any drug evidence, not proven clinical benefit"],"changedPractice":false,"participants":10000},{"id":"paper-temel-early-palliative-care-nejm-2010","kind":"paper","name":"Temel: early palliative care alongside chemotherapy improved quality of life, mood and survival in lung cancer","aka":[],"tldr":"Patients newly diagnosed with metastatic lung cancer who saw a palliative care team from diagnosis had better quality of life, less depression, less aggressive end-of-life care and lived a median 2.7 months longer than those receiving oncology care alone.","summary":"At Massachusetts General Hospital, 151 patients with newly diagnosed metastatic non-small-cell lung cancer were randomised to early palliative care integrated with standard oncology care (monthly visits with a palliative care clinician) or to standard oncology care with palliative care only on request.\n\nThe primary endpoint, change in quality of life at 12 weeks (FACT-L), favoured early palliative care (98.0 vs 91.5). Fewer patients had depressive symptoms (16% vs 38%), fewer received aggressive end-of-life care (33% vs 54%), and median survival was 11.6 versus 8.9 months.\n\nThe survival signal overturned the assumption that palliative care shortens life and led ASCO to recommend concurrent palliative care for all patients with metastatic cancer from diagnosis.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1000678"},{"label":"ClinicalTrials.gov NCT01038271","url":"https://clinicaltrials.gov/study/NCT01038271"}],"tags":[],"related":["hospice-end-of-life","idea-moon-palliative-care-from-diagnosis-everywhere","idea-acc-automatic-early-palliative-triggers","idea-acc-tele-palliative-care-default"],"cancers":["nsclc"],"sections":["supportive-care"],"technologies":["palliative-care","epro-symptom-monitoring"],"targets":[],"drugs":[],"companies":[],"institutions":["mgh"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-palliative","b-workforce","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2010,"doi":"10.1056/NEJMoa1000678","pmid":"20818875","authors":"Temel JS, Greer JA, Muzikansky A, et al.","paperType":"rct","findings":["Quality of life at 12 weeks: FACT-L 98.0 vs 91.5 (p = 0.03)","Depressive symptoms 16% vs 38% (p = 0.01)","Aggressive end-of-life care 33% vs 54%; more patients documented resuscitation preferences","Median overall survival 11.6 vs 8.9 months (p = 0.02) despite less chemotherapy near death"],"whatItMeans":"Palliative care is not what happens when treatment stops; it works best alongside cancer treatment from the start. Patients feel better, are less depressed and may live longer. Access remains the constraint: most of the world's patients never see a palliative care specialist.","caveats":["Single centre, unblinded, and survival was not the primary endpoint; later trials showed mixed survival effects","Small sample; the survival difference was not confirmed in the larger 2017 Temel trial across cancers","Requires trained palliative care workforce that most health systems lack","Mechanism (symptom control, less futile chemotherapy, better decision-making) remains debated"],"changedPractice":true,"participants":151},{"id":"paper-who-2021-cns-louis-neuro-oncology-2021","kind":"paper","name":"The 2021 WHO classification of tumours of the central nervous system: a summary","aka":[],"tldr":"The fifth-edition brain tumour classification makes molecular markers such as IDH mutation, 1p/19q codeletion and methylation class central to diagnosis, renaming and regrading many tumours, including separating IDH-mutant astrocytoma from glioblastoma.","summary":"Summary of the 2021 WHO classification of central nervous system tumours introducing integrated histological and molecular diagnoses, Arabic numeral grading within tumour types, new tumour types and families (paediatric-type diffuse gliomas, molecularly defined ependymomas and medulloblastoma groups), and grading of IDH-mutant astrocytoma up to grade 4 with CDKN2A/B deletion.","asOf":"2026-09-17","links":[{"label":"Neuro Oncol 2021","url":"https://doi.org/10.1093/neuonc/noab106"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34185076/"}],"tags":[],"related":[],"cancers":["idh-mutant-astrocytoma","oligodendroglioma","meningioma","paediatric-high-grade-glioma","spinal-cord-tumours","cns-germ-cell-tumours","medulloblastoma-group-3-4","medulloblastoma-shh","medulloblastoma-wnt"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["neuro-oncology"],"dependsOn":[],"notes":[],"journal":"Neuro-Oncology","year":2021,"doi":"10.1093/neuonc/noab106","pmid":"34185076","authors":"Louis DN, Perry A, Wesseling P, et al.","paperType":"guideline","findings":[],"whatItMeans":"Every brain tumour page on this site uses these names and grades; a tumour called glioblastoma before 2021 may now be an IDH-mutant astrocytoma with a different outlook and treatment.","caveats":["Requires molecular testing that is not available everywhere, leaving some diagnoses as not otherwise specified."],"changedPractice":true},{"id":"paper-cms-guinney-nat-med-2015","kind":"paper","name":"The consensus molecular subtypes of colorectal cancer","aka":[],"tldr":"An international consortium reconciled six competing gene-expression classifications of colorectal cancer into four consensus subtypes, from immune-active microsatellite-unstable tumours to mesenchymal tumours with the worst outlook.","summary":"Analysis of gene expression data from 4,151 colorectal cancers across 18 datasets by the Colorectal Cancer Subtyping Consortium, producing four consensus molecular subtypes: CMS1 (microsatellite instability, immune), CMS2 (canonical, WNT and MYC), CMS3 (metabolic, KRAS-enriched) and CMS4 (mesenchymal, stromal, worst survival), with about 13 percent of tumours unclassified.","asOf":"2026-09-17","links":[{"label":"Nat Med 2015","url":"https://doi.org/10.1038/nm.3967"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26457759/"}],"tags":[],"related":[],"cancers":["braf-v600e-colorectal","early-onset-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2015,"doi":"10.1038/nm.3967","pmid":"26457759","authors":"Guinney J, Dienstmann R, Wang X, et al.","paperType":"translational","findings":["Four subtypes with distinct biology; CMS4 had the worst overall and relapse-free survival, CMS1 the worst survival after relapse."],"whatItMeans":"The CMS framework organises colorectal cancer biology and trial stratification; BRAF V600E tumours cluster in CMS1, and CMS4's poor prognosis and stromal signalling are targets of ongoing research.","caveats":["Transcriptomic classification is not yet used to choose treatment in routine practice.","Intratumoural heterogeneity means single biopsies may misclassify."],"changedPractice":true,"participants":4151},{"id":"paper-ladanyi-aspl-tfe3-oncogene-2001","kind":"paper","name":"The der(17)t(X;17) of alveolar soft part sarcoma fuses TFE3 to ASPL","aka":[],"tldr":"This study identified the ASPL-TFE3 gene fusion created by the characteristic chromosome translocation in alveolar soft part sarcoma, giving the disease a defining molecular marker and a diagnostic test.","summary":"Molecular cloning of the unbalanced der(17)t(X;17)(p11;q25) translocation in alveolar soft part sarcoma showing fusion of the ASPL (ASPSCR1) gene on chromosome 17 to the TFE3 transcription factor gene on the X chromosome, producing a fusion transcription factor.","asOf":"2026-09-17","links":[{"label":"Oncogene 2001","url":"https://doi.org/10.1038/sj.onc.1204074"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/11244503/"}],"tags":[],"related":[],"cancers":["alveolar-soft-part-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["oncogene-journal"],"dependsOn":[],"notes":[],"journal":"Oncogene","year":2001,"doi":"10.1038/sj.onc.1204074","pmid":"11244503","authors":"Ladanyi M, Lui MY, Antonescu CR, et al.","paperType":"basic","findings":["ASPL-TFE3 fusion identified as the consistent alteration in alveolar soft part sarcoma."],"whatItMeans":"TFE3 immunostaining and ASPSCR1-TFE3 fusion testing confirm the diagnosis of alveolar soft part sarcoma and link it to a family of TFE3-rearranged tumours including a type of renal cell carcinoma.","caveats":["No direct therapeutic target has followed from the fusion itself."],"changedPractice":true},{"id":"paper-protac-concept-sakamoto-pnas-2001","kind":"paper","name":"The first PROTAC: a chimeric molecule that tags a protein for destruction","aka":[],"tldr":"Crews and Deshaies built a two-headed molecule linking a ligand for the target protein MetAP-2 to a peptide recognised by an E3 ubiquitin ligase, and showed it induced ubiquitination and degradation of the target, founding targeted protein degradation.","summary":"The proteolysis-targeting chimera (Protac-1) joined ovalicin, which binds methionine aminopeptidase-2, to the IkappaBalpha phosphopeptide recognised by the SCF-beta-TRCP E3 ligase. In Xenopus egg extracts, Protac-1 recruited MetAP-2 to the ligase and triggered its ubiquitination and proteasomal degradation.\n\nThe paper established the principle that a bifunctional molecule can hijack the cell's own disposal machinery to eliminate a chosen protein, including proteins with no enzymatic activity to inhibit. Peptide-based PROTACs were poorly cell-permeable; the field became practical when all-small-molecule degraders using VHL and cereblon ligands appeared (Bondeson 2015; Winter 2015, dBET1 degrading BRD4 in vivo).\n\nDegraders now include vepdegestrant (oestrogen receptor), ARV-110 and other androgen-receptor degraders, and the molecular glues (lenalidomide-class drugs) reinterpreted through the same mechanism.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1073/pnas.141230798"},{"label":"In vivo small-molecule degrader dBET1 (Winter 2015)","url":"https://doi.org/10.1126/science.aab1433"}],"tags":[],"related":["molecular-glue-platforms"],"cancers":[],"sections":["drug-discovery","targeted-therapy"],"technologies":["protac-degrader","degrader-antibody-conjugate"],"targets":["estrogen-receptor","androgen-receptor"],"drugs":["vepdegestrant"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["veritac-2"],"people":[],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"PNAS","year":2001,"doi":"10.1073/pnas.141230798","pmid":"11438690","authors":"Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ","paperType":"basic","findings":["Protac-1 induced ubiquitination and degradation of MetAP-2 in cell extracts by recruiting the SCF E3 ligase","Degradation required both halves of the chimera and an intact ubiquitin-proteasome pathway","Introduced the terminology and concept of proteolysis-targeting chimeras","Small-molecule successors (2015 onwards) achieved in vivo degradation of BRD4 and other targets at nanomolar potency"],"whatItMeans":"Instead of blocking a cancer protein, a drug can now remove it entirely, which works even for proteins without a druggable active site and can overcome resistance driven by target overexpression or mutation. Several degraders are in late-stage trials for breast and prostate cancer.","caveats":["The original molecule was a large peptide conjugate with no cell permeability; clinical degraders took 15 years","Degraders are large molecules with challenging oral bioavailability and pharmacokinetics","Ligase expression varies between tissues and tumours, and resistance via ligase loss has been documented","Clinical superiority over inhibitors has so far been modest in the first phase 3 readouts (for example vepdegestrant)"],"changedPractice":false},{"id":"paper-hallmarks-of-cancer-cell-2000","kind":"paper","name":"The Hallmarks of Cancer: six capabilities every tumour must acquire","aka":[],"tldr":"Hanahan and Weinberg distilled decades of cancer biology into six acquired capabilities shared by all cancers, giving the field a common organising framework that has been cited more than any other cancer paper.","summary":"Written for the millennium issue of Cell, this review proposed that the vast catalogue of cancer genotypes is a manifestation of six essential alterations in cell physiology: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Genome instability was presented as the enabling characteristic that lets cells acquire these traits.\n\nThe authors argued that tumours are not simply masses of proliferating cells but tissues composed of many cell types, anticipating the later emphasis on the microenvironment. They also predicted that cancer research would become a logical science with mechanism-based therapies targeting each hallmark.\n\nThe 2011 update added two hallmarks (reprogramming energy metabolism, evading immune destruction) and two enabling characteristics (genome instability, tumour-promoting inflammation).","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1016/S0092-8674(00)81683-9"},{"label":"Hallmarks of Cancer: The Next Generation (2011)","url":"https://doi.org/10.1016/j.cell.2011.02.013"}],"tags":[],"related":["paper-hallmarks-new-dimensions-cancer-discov-2022","sustaining-proliferative-signaling","evading-growth-suppressors","resisting-cell-death","enabling-replicative-immortality","inducing-angiogenesis","activating-invasion-metastasis","genome-instability-mutation"],"cancers":[],"sections":["drug-discovery"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["hallmarks-of-cancer","oncogene-addiction"],"trials":[],"people":[],"bottlenecks":["b-knowledge-diffusion","b-combination-space"],"keyPapers":[],"journals":["cell"],"dependsOn":[],"notes":[],"journal":"Cell","year":2000,"doi":"10.1016/S0092-8674(00)81683-9","pmid":"10647931","authors":"Hanahan D, Weinberg RA","paperType":"review","findings":["Six hallmarks: sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis","Genome instability proposed as the enabling characteristic underlying acquisition of the hallmarks","Tumours framed as complex tissues in which stromal and immune cells are active participants","The paper became the most-cited article in Cell and one of the most-cited in biomedicine"],"whatItMeans":"The hallmarks are the mental map most oncologists and researchers use to think about what cancer is and where drugs act. A newcomer can understand nearly every therapy as an attack on one hallmark: kinase inhibitors on proliferative signalling, checkpoint blockade on immune evasion, anti-VEGF drugs on angiogenesis.","caveats":["A conceptual review rather than new data; critics argue it over-generalises across very different diseases","Some hallmarks (angiogenesis) turned out to be less universally targetable than hoped","Did not anticipate the centrality of the immune system or of epigenetic and microbial factors, later added","Provides no quantitative framework for prioritising targets"],"changedPractice":false},{"id":"paper-inrg-cohn-jco-2009","kind":"paper","name":"The International Neuroblastoma Risk Group (INRG) classification system","aka":[],"tldr":"Analysing 8,800 patients worldwide, the INRG task force built a pretreatment classification for neuroblastoma using stage, age, histology, MYCN, chromosome 11q and ploidy that sorts children into very low, low, intermediate and high-risk groups.","summary":"Analysis of 8,800 children with neuroblastoma diagnosed between 1990 and 2002 from international cooperative groups, defining sixteen pretreatment groups by INRG stage, age, histological category, grade of differentiation, MYCN status, 11q aberration and ploidy, assigned to four risk groups by five-year event-free survival.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2009","url":"https://doi.org/10.1200/JCO.2008.16.6785"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19047291/"}],"tags":[],"related":[],"cancers":["neuroblastoma-high-risk","neuroblastoma-intermediate-risk","neuroblastoma-low-risk"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2009,"doi":"10.1200/JCO.2008.16.6785","pmid":"19047291","authors":"Cohn SL, Pearson AD, London WB, et al.","paperType":"methods","findings":["Sixteen pretreatment groups collapsed into very low (over 85 percent event-free survival), low, intermediate and high risk (under 50 percent)."],"whatItMeans":"Every neuroblastoma risk group on this site (very low, low, intermediate, high) is defined by the INRG system, which allows trials across continents to be compared.","caveats":["Based on patients treated in the 1990s; contemporary outcomes are better in most groups.","Segmental chromosome aberrations beyond 11q are being incorporated in revisions."],"changedPractice":true,"participants":8800},{"id":"paper-bolouri-paediatric-aml-genomics-nat-med-2018","kind":"paper","name":"The molecular landscape of paediatric acute myeloid leukaemia (TARGET)","aka":[],"tldr":"Sequencing nearly a thousand childhood acute myeloid leukaemias showed the disease differs sharply from adult disease, with fewer mutations, more structural rearrangements and age-specific drivers, so adult genetic risk groups cannot simply be transferred to children.","summary":"Comprehensive genomic study by the TARGET initiative of 993 children and young adults with AML, including whole-genome, exome, transcriptome and methylation profiling, identifying age-specific patterns of somatic mutations, structural variants such as KMT2A and NUP98 rearrangements, and novel focal deletions.","asOf":"2026-09-17","links":[{"label":"Nat Med 2018","url":"https://doi.org/10.1038/nm.4439"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29227476/"}],"tags":[],"related":[],"cancers":["aml-paediatric"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2018,"doi":"10.1038/nm.4439","pmid":"29227476","authors":"Bolouri H, Farrar JE, Triche T, et al.","paperType":"translational","findings":["Low mutation burden in childhood AML with structural variants and fusions predominating.","Distinct age-associated mutations, for example NPM1 and DNMT3A being rare in young children."],"whatItMeans":"Paediatric AML risk classification and targeted therapy development now rest on this landscape rather than on adult data.","caveats":["Discovery cohort; clinical translation into risk stratification is ongoing."],"changedPractice":true,"participants":993},{"id":"paper-cheasley-mucinous-ovarian-genomics-nat-commun-2019","kind":"paper","name":"The molecular origin and taxonomy of mucinous ovarian carcinoma","aka":[],"tldr":"Genomic analysis of over 200 mucinous ovarian tumours showed they arise in the ovary from benign and borderline precursors through KRAS, TP53 and CDKN2A changes, and are genuinely different from the gastrointestinal cancers they resemble.","summary":"Genomic study of 227 mucinous ovarian tumours (benign, borderline and carcinoma) identifying a progression model with KRAS mutation and CDKN2A loss early, TP53 mutation and copy-number gains including HER2 amplification in carcinomas, and a distinct profile from colorectal, gastric and pancreatic cancers.","asOf":"2026-09-17","links":[{"label":"Nat Commun 2019","url":"https://doi.org/10.1038/s41467-019-11862-x"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31477716/"}],"tags":[],"related":[],"cancers":["mucinous-ovarian-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-communications"],"dependsOn":[],"notes":[],"journal":"Nature Communications","year":2019,"doi":"10.1038/s41467-019-11862-x","pmid":"31477716","authors":"Cheasley D, Wakefield MJ, Ryland GL, et al.","paperType":"translational","findings":["KRAS mutation in about 65 percent, TP53 in 64 percent and CDKN2A loss in 76 percent of carcinomas.","HER2 amplification in about 26 percent of carcinomas."],"whatItMeans":"Mucinous ovarian carcinoma is confirmed as a primary ovarian disease with its own biology; HER2 amplification in about a fifth of cases is a possible treatment target.","caveats":["Treatment implications remain under investigation."],"changedPractice":true,"participants":227},{"id":"paper-tcga-chromophobe-davis-cancer-cell-2014","kind":"paper","name":"The somatic genomic landscape of chromophobe renal cell carcinoma (The Cancer Genome Atlas)","aka":[],"tldr":"Genomic analysis of 66 chromophobe kidney cancers showed they arise from a different cell of origin than clear cell tumours, carry characteristic whole-chromosome losses and TP53 and PTEN mutations, and have distinctive mitochondrial DNA changes and TERT promoter rearrangements.","summary":"Integrated genomic study by The Cancer Genome Atlas of 66 chromophobe renal cell carcinomas including whole-genome sequencing, showing loss of chromosomes 1, 2, 6, 10, 13 and 17, mutations in TP53 and PTEN, recurrent structural rearrangements within the TERT promoter, mitochondrial DNA mutations, and an expression profile pointing to the distal nephron as the cell of origin.","asOf":"2026-09-17","links":[{"label":"Cancer Cell 2014","url":"https://doi.org/10.1016/j.ccr.2014.07.014"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25155756/"}],"tags":[],"related":[],"cancers":["chromophobe-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-cell"],"dependsOn":[],"notes":[],"journal":"Cancer Cell","year":2014,"doi":"10.1016/j.ccr.2014.07.014","pmid":"25155756","authors":"Davis CF, Ricketts CJ, Wang M, et al.","paperType":"translational","findings":["Characteristic losses of chromosomes 1, 2, 6, 10, 13 and 17.","TP53 (32 percent) and PTEN (9 percent) mutations; TERT promoter rearrangements; distal nephron origin."],"whatItMeans":"Chromophobe renal cell carcinoma is a biologically distinct disease that should not be lumped with clear cell cancer in trials or treatment, which is why its page separates the two.","caveats":["Small cohort; therapeutic implications are still being worked out."],"changedPractice":true,"participants":66},{"id":"paper-tonon-crtc1-maml2-nat-genet-2003","kind":"paper","name":"The t(11;19) translocation in mucoepidermoid carcinoma creates a CRTC1-MAML2 fusion","aka":[],"tldr":"This study identified the gene fusion (CRTC1-MAML2, originally called MECT1-MAML2) created by the characteristic chromosome translocation in mucoepidermoid carcinoma, giving the tumour a defining molecular marker.","summary":"Molecular characterisation of the recurrent t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma showing fusion of the CREB coactivator MECT1 (CRTC1) to the Notch coactivator MAML2, producing a fusion protein that disrupts Notch signalling and activates CREB targets.","asOf":"2026-09-17","links":[{"label":"Nat Genet 2003","url":"https://doi.org/10.1038/ng1083"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/12539049/"}],"tags":[],"related":[],"cancers":["mucoepidermoid-carcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2003,"doi":"10.1038/ng1083","pmid":"12539049","authors":"Tonon G, Modi S, Wu L, et al.","paperType":"basic","findings":["Recurrent CRTC1-MAML2 fusion in mucoepidermoid carcinoma from the t(11;19) translocation."],"whatItMeans":"CRTC1-MAML2 fusion testing supports the diagnosis of mucoepidermoid carcinoma, particularly in difficult cases, and fusion-positive tumours tend to be lower grade with a better outlook.","caveats":["Not yet a therapeutic target."],"changedPractice":true},{"id":"paper-therasse-recist-jnci-2000","kind":"paper","name":"Therasse 2000: RECIST, the standard rules for measuring whether a tumour responds","aka":[],"tldr":"The guideline that defined how trials decide a tumour has shrunk, stayed stable or grown, using the longest diameter of a few measured lesions, so results from different trials can be compared.","summary":"RECIST (Response Evaluation Criteria in Solid Tumours) was drawn up by the EORTC, the US National Cancer Institute and the National Cancer Institute of Canada to replace the older WHO criteria, which used two perpendicular diameters. RECIST measures only the longest diameter of each target lesion and sums them: a partial response is a decrease of at least 30% in the sum, progressive disease an increase of at least 20%, and stable disease anything between. It set rules for which lesions are measurable, how many to follow and how to confirm responses, and its revision as RECIST 1.1 in 2009 reduced the number of target lesions and added rules for lymph nodes.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1093/jnci/92.3.205"},{"label":"RECIST 1.1 (Eisenhauer 2009)","url":"https://doi.org/10.1016/j.ejca.2008.10.026"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["recist","partial-response","progressive-disease","complete-response","orr"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":2000,"doi":"10.1093/jnci/92.3.205","authors":"Therasse P, Arbuck SG, Eisenhauer EA, et al.","paperType":"guideline","findings":["Response is judged on the sum of the longest diameters of selected target lesions rather than the products of two diameters.","Partial response: at least a 30% decrease in the sum; progressive disease: at least a 20% increase or new lesions; stable disease in between.","Revised in 2009 as RECIST 1.1: a maximum of five target lesions, two per organ, and lymph node criteria based on the short axis."],"whatItMeans":"Almost every response rate and progression-free survival figure quoted on this site rests on RECIST. Knowing that a partial response means a 30% shrinkage of a few measured lesions, not a cure, helps read trial results honestly, and the criteria's limits with immunotherapy led to iRECIST for delayed and mixed responses.","caveats":["Anatomical size does not capture necrosis or metabolic change, so RECIST can misjudge drugs that act without shrinking tumours.","Immunotherapy pseudoprogression prompted modified criteria (irRC, iRECIST).","Measurement variability between readers is real and affects small changes."],"changedPractice":true},{"id":"paper-thiery-emt-tumour-progression-nrc-2002","kind":"paper","name":"Thiery 2002: epithelial-mesenchymal transitions in tumour progression","aka":[],"tldr":"The review that brought the developmental idea of epithelial-mesenchymal transition into cancer biology, proposing it as the mechanism by which carcinoma cells detach, invade and travel to distant sites.","summary":"Thiery reviewed the evidence that carcinomas use an epithelial-mesenchymal transition to progress: loss of E-cadherin-based junctions, cytoskeletal remodelling and gain of migratory behaviour, driven by signals including TGF-beta, receptor tyrosine kinases, Wnt and the transcription factors Snail and Twist. He drew the parallel with gastrulation and neural crest migration in embryos and argued that EMT, and its reversal at secondary sites, could account for how metastases arise and why they often look epithelial again.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nrc822"}],"tags":[],"related":["paper-kalluri-weinberg-emt-basics-jci-2009"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["emt","metastatic-cascade"],"terms":["metastasis","activating-invasion-metastasis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Reviews Cancer","year":2002,"doi":"10.1038/nrc822","authors":"Thiery JP.","paperType":"review","findings":["Carcinoma progression involves loss of E-cadherin and epithelial polarity with gain of mesenchymal, migratory features.","The same signalling pathways and transcription factors drive EMT in embryos and in tumours.","Proposed EMT and its reversal as the basis of invasion and distant metastasis."],"whatItMeans":"This is the paper that made EMT a cancer concept, cited by almost every metastasis study since. It set the research agenda that later produced the EMT stem cell link and current work on partial EMT states.","caveats":["Largely based on cell culture and developmental analogies at the time.","Direct evidence for EMT in human metastasis has remained harder to obtain than the model predicts."],"changedPractice":false},{"id":"paper-thorsson-immune-landscape-of-cancer-immunity-2018","kind":"paper","name":"Thorsson 2018: the immune landscape of cancer across 10,000 tumours","aka":[],"tldr":"An analysis of more than 10,000 tumours from 33 cancer types in The Cancer Genome Atlas that sorted cancers into six immune subtypes, showing that the immune environment of a tumour cuts across its tissue of origin and affects prognosis.","summary":"As part of the TCGA PanCancer Atlas, Thorsson and colleagues integrated gene expression, immune cell estimates, neoantigen predictions, T and B cell receptor repertoires and other data for over 10,000 tumours across 33 cancer types. They defined six immune subtypes, named wound healing, interferon-gamma dominant, inflammatory, lymphocyte depleted, immunologically quiet and TGF-beta dominant, each found in many cancer types and associated with different outcomes. They also linked immune features to tumour genetics, such as copy number changes and specific driver mutations.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/j.immuni.2018.03.023"}],"tags":[],"related":["paper-galon-immune-contexture-colorectal-science-2006","paper-schreiber-cancer-immunoediting-science-2011"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["immune-system","tils","neoantigen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Immunity","year":2018,"doi":"10.1016/j.immuni.2018.03.023","authors":"Thorsson V, Gibbs DL, Brown SD, et al.","paperType":"translational","findings":["Immunogenomic analysis of more than 10,000 TCGA tumours across 33 cancer types.","Six immune subtypes spanning tumour types: wound healing, IFN-gamma dominant, inflammatory, lymphocyte depleted, immunologically quiet and TGF-beta dominant.","Immune subtype was associated with prognosis, and immune features correlated with tumour genomic features such as copy number burden."],"whatItMeans":"This atlas is the reference for how immune the different cancers are and is widely used to choose which tumours to test immunotherapies in and to interpret immune gene signatures. It shows why immunotherapy responses depend on the tumour's immune context as much as on its tissue.","caveats":["Bulk tumour data; cell types are inferred computationally rather than observed.","TCGA samples are mostly untreated primary tumours, not the metastatic disease treated with immunotherapy."],"changedPractice":false},{"id":"paper-toga-trastuzumab-gastric-lancet-2010","kind":"paper","name":"ToGA (Bang 2010): trastuzumab with chemotherapy for HER2-positive advanced gastric cancer","aka":[],"tldr":"The trial that brought HER2 testing and trastuzumab to stomach cancer: adding the antibody to chemotherapy prolonged survival in patients whose gastric or junction cancers overexpressed HER2, about a fifth of those screened.","summary":"ToGA screened 3,665 patients with advanced gastric or gastro-oesophageal junction cancer and found HER2 positivity in 22.1%. It randomised 594 HER2-positive patients to trastuzumab plus cisplatin and a fluoropyrimidine or to chemotherapy alone. Trastuzumab improved overall survival, progression-free survival and response rate, with the largest benefit in tumours with high HER2 expression (immunohistochemistry 3+ or 2+ with amplification), which became the definition of HER2 positivity used for gastric cancer.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1016/S0140-6736(10)61121-X"},{"label":"ClinicalTrials.gov NCT01041404","url":"https://clinicaltrials.gov/study/NCT01041404"}],"tags":[],"related":["paper-slamon-trastuzumab-nejm-2001"],"cancers":["gastric"],"sections":[],"technologies":[],"targets":["her2"],"drugs":["trastuzumab","cisplatin","capecitabine","fluorouracil"],"companies":["roche-genentech"],"institutions":[],"pathways":[],"terms":["her2-positive","ihc","os"],"trials":["toga"],"people":["bang-yung-jue"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2010,"doi":"10.1016/S0140-6736(10)61121-X","authors":"Bang YJ, Van Cutsem E, Feyereislova A, et al.","paperType":"rct","findings":["HER2 positivity in 22.1% of 3,665 screened patients; 594 randomised to trastuzumab plus chemotherapy or chemotherapy alone.","Median overall survival 13.8 vs 11.1 months, hazard ratio 0.74.","In tumours with IHC 3+ or IHC 2+ and FISH-positive HER2: median overall survival 16.0 vs 11.8 months.","Response rate 47% vs 35%; no increase in cardiac events of note."],"whatItMeans":"ToGA made gastric cancer the second disease treated by HER2 status and introduced gastric-specific HER2 scoring. It is the base on which trastuzumab deruxtecan and pembrolizumab combinations in HER2-positive gastric cancer have built.","caveats":["Open-label design.","Benefit was concentrated in high HER2 expressers; IHC 2+ FISH-negative and IHC 0 or 1+ FISH-positive tumours gained little.","Chemotherapy backbone was cisplatin with capecitabine or fluorouracil."],"changedPractice":true,"participants":594},{"id":"paper-topalian-anti-pd1-nejm-2012","kind":"paper","name":"Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer","aka":[],"tldr":"Nivolumab shrank tumours in roughly a fifth to a quarter of patients with three different advanced cancers, with responses that lasted more than a year and a hint that PD-L1 on the tumour predicted benefit.","summary":"This phase 1 dose-escalation and expansion study treated 296 patients with advanced melanoma, non-small-cell lung cancer, renal cell carcinoma, castration-resistant prostate cancer or colorectal cancer with the anti-PD-1 antibody BMS-936558 (nivolumab) at 0.1 to 10 mg/kg every two weeks. Objective responses occurred in 28% of melanoma, 18% of NSCLC and 27% of renal cancer patients, but none in prostate or colorectal cancer; of 31 responders followed for a year or more, 20 had responses lasting at least a year. Grade 3-4 drug-related adverse events occurred in 14%, and there were three deaths from pneumonitis. In 42 patients with tumour PD-L1 staining, 9 of 25 PD-L1-positive tumours responded versus none of 17 PD-L1-negative tumours. A companion paper (Brahmer et al.) reported similar activity for an anti-PD-L1 antibody.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1200690"},{"label":"Companion anti-PD-L1 paper (Brahmer 2012)","url":"https://doi.org/10.1056/NEJMoa1200694"}],"tags":[],"related":["paper-hodi-ipilimumab-melanoma-nejm-2010","pd1-checkpoint"],"cancers":["melanoma","nsclc"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["nivolumab","pembrolizumab","atezolizumab"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["irae","orr"],"trials":[],"people":["suzanne-topalian","julie-brahmer","drew-pardoll","f-stephen-hodi"],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1200690","authors":"Topalian SL, Hodi FS, Brahmer JR, et al.","paperType":"translational","findings":["296 patients across five tumour types; nivolumab 0.1-10 mg/kg every 2 weeks.","Objective response: melanoma 28%, NSCLC 18% (including squamous and non-squamous), renal cell carcinoma 27%; none in prostate or colorectal cancer.","Responses durable: 20 of 31 responders with a year or more of follow-up had responses lasting at least 1 year.","Grade 3-4 drug-related adverse events 14%; 3 deaths from pneumonitis.","PD-L1 expression: 9 of 25 PD-L1-positive tumours responded vs 0 of 17 PD-L1-negative."],"whatItMeans":"This study is why PD-1 inhibitors were developed across cancers rather than in melanoma alone: unexpected activity in lung cancer, historically thought immune-resistant, changed drug development priorities industry-wide. It also introduced PD-L1 immunohistochemistry as a candidate biomarker and pneumonitis as a signature toxicity. Within five years PD-1 blockade was approved in more than ten cancers.","caveats":["Phase 1 with heterogeneous doses and small tumour cohorts; response rates are imprecise.","PD-L1 analysis was on 42 patients with archival tissue; the biomarker later proved imperfect.","No colorectal responses masked the later dMMR story (the one responder in an earlier study was dMMR).","Survival was not assessed."],"changedPractice":true,"participants":296},{"id":"paper-topaz-1-nejm-evidence-2022","kind":"paper","name":"TOPAZ-1: durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer","aka":[],"tldr":"Adding durvalumab to gemcitabine-cisplatin lengthened survival in advanced bile duct and gallbladder cancer, the first improvement on chemotherapy alone in more than a decade, with about a quarter of patients alive at two years.","summary":"Phase 3 placebo-controlled trial of 685 patients with previously untreated unresectable or metastatic biliary tract cancer randomised to durvalumab or placebo with gemcitabine and cisplatin for up to eight cycles followed by durvalumab or placebo maintenance.\n\nMedian overall survival was 12.8 versus 11.5 months (hazard ratio 0.80) with 24-month survival 24.9 versus 10.4 percent, progression-free survival 7.2 versus 5.7 months, and no meaningful increase in toxicity.","asOf":"2026-09-17","links":[{"label":"NEJM Evid 2022","url":"https://doi.org/10.1056/EVIDoa2200015"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38319896/"}],"tags":[],"related":[],"cancers":["extrahepatic-cholangiocarcinoma","intrahepatic-cholangiocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","durvalumab","gemcitabine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["topaz-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm-evidence"],"dependsOn":[],"notes":[],"journal":"NEJM Evidence","year":2022,"doi":"10.1056/EVIDoa2200015","pmid":"38319896","authors":"Oh DY, Ruth He A, Qin S, et al.","paperType":"rct","findings":["Median overall survival 12.8 vs 11.5 months; hazard ratio 0.80.","24-month overall survival 24.9 percent vs 10.4 percent."],"whatItMeans":"Durvalumab with gemcitabine-cisplatin is a first-line standard for advanced biliary tract cancer, with pembrolizumab (KEYNOTE-966) as the alternative.","caveats":["Modest median gain; benefit concentrated in a minority of long-term survivors.","No validated biomarker to select patients."],"changedPractice":true,"participants":685},{"id":"paper-torre-global-cancer-statistics-2012-cacancer-2015","kind":"paper","name":"Torre 2015: Global cancer statistics, 2012","aka":[],"tldr":"The GLOBOCAN-based world count for 2012: about 14.1 million new cancer cases, with more than half of cases and almost two thirds of deaths occurring in less developed regions, and lung cancer leading in men while breast cancer led in women.","summary":"Torre, Bray, Siegel and colleagues summarised the GLOBOCAN 2012 estimates for the American Cancer Society. They reported about 14.1 million new cases and 8.2 million deaths in 2012, with 57% of cases and 65% of deaths in less developed regions. Lung cancer was the leading cancer in men for both incidence and mortality; breast cancer led in women. The paper highlighted the rising share of the burden in transitioning countries and the potential of prevention, early detection and treatment to reduce it.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.3322/caac.21262"}],"tags":[],"related":["paper-bray-globocan-2018-cacancer-2018"],"cancers":["nsclc","breast-hr-positive"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["iarc"],"pathways":[],"terms":["incidence-vs-prevalence","mortality"],"trials":[],"people":["bray-freddie"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"CA: A Cancer Journal for Clinicians","year":2015,"doi":"10.3322/caac.21262","authors":"Torre LA, Bray F, Siegel RL, et al.","paperType":"observational","findings":["About 14.1 million new cancer cases and 8.2 million cancer deaths worldwide in 2012.","57% of cases and 65% of deaths occurred in less developed regions.","Lung cancer the leading cause of cancer incidence and death in men; breast cancer the leading cancer in women."],"whatItMeans":"One of the most cited descriptions of the global cancer burden of the 2010s, it framed the shift of cancer towards lower-income countries that later GLOBOCAN releases have confirmed.","caveats":["Superseded by the 2018, 2020 and 2022 GLOBOCAN releases.","Estimates for many countries were modelled from limited registry data."],"changedPractice":false},{"id":"paper-tpextreme-lancet-oncol-2021","kind":"paper","name":"TPExtreme (GORTEC 2014-01): docetaxel, cisplatin and cetuximab versus the EXTREME regimen in recurrent or metastatic head and neck cancer","aka":[],"tldr":"Replacing fluorouracil with docetaxel in the cetuximab-platinum regimen for advanced head and neck cancer did not lengthen survival but was less toxic and much easier to give, so TPEx is an accepted alternative.","summary":"Randomised phase 2 trial of 541 patients with recurrent or metastatic head and neck squamous cell carcinoma randomised to TPEx (docetaxel, cisplatin and cetuximab for four cycles then cetuximab maintenance) or the EXTREME regimen.\n\nMedian overall survival was 14.5 versus 13.4 months (not significant), with fewer grade 4 or higher adverse events (34 versus 50 percent) and shorter treatment duration in the TPEx arm.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2021","url":"https://doi.org/10.1016/S1470-2045(20)30755-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33684370/"}],"tags":[],"related":[],"cancers":["recurrent-metastatic-hnscc"],"sections":[],"technologies":[],"targets":[],"drugs":["cetuximab","cisplatin","docetaxel"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tpextreme"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(20)30755-5","pmid":"33684370","authors":"Guigay J, Aupérin A, Fayette J, et al.","paperType":"rct","findings":["Median overall survival 14.5 vs 13.4 months (not significantly different).","Grade 4 or higher adverse events 34 percent vs 50 percent."],"whatItMeans":"TPEx is a less toxic, more convenient chemotherapy backbone for patients who need cetuximab-based first-line therapy, for instance when immunotherapy is unsuitable.","caveats":["Did not meet its superiority endpoint.","Both arms performed better than historical EXTREME data, reflecting later-line immunotherapy."],"changedPractice":true,"participants":541},{"id":"paper-trabectedin-vs-dacarbazine-demetri-jco-2016","kind":"paper","name":"Trabectedin versus dacarbazine for metastatic liposarcoma or leiomyosarcoma after anthracycline failure","aka":[],"tldr":"Trabectedin reduced the risk of progression by 45 percent compared with dacarbazine in previously treated liposarcoma and leiomyosarcoma, leading to its approval in the United States, though survival was not improved.","summary":"Phase 3 trial of 518 patients with advanced liposarcoma or leiomyosarcoma after an anthracycline and at least one other regimen randomised 2:1 to trabectedin or dacarbazine.\n\nMedian progression-free survival was 4.2 versus 1.5 months (hazard ratio 0.55) with benefit in both histologies and particularly in myxoid liposarcoma; median overall survival was 12.4 versus 12.9 months (not significant). Transaminase elevation and myelosuppression were the main toxicities.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2016","url":"https://doi.org/10.1200/JCO.2015.62.4734"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26371143/"}],"tags":[],"related":[],"cancers":["liposarcoma","leiomyosarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":["dacarbazine","trabectedin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2016,"doi":"10.1200/JCO.2015.62.4734","pmid":"26371143","authors":"Demetri GD, von Mehren M, Jones RL, et al.","paperType":"rct","findings":["Median progression-free survival 4.2 vs 1.5 months; hazard ratio 0.55.","No overall survival difference (12.4 vs 12.9 months)."],"whatItMeans":"Trabectedin is a standard later-line option for liposarcoma and leiomyosarcoma and is especially active in myxoid liposarcoma.","caveats":["Open-label; dacarbazine control performed poorly on progression-free survival."],"changedPractice":true,"participants":518},{"id":"paper-tracerx-evolution-nature-2023","kind":"paper","name":"TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse","aka":[],"tldr":"Analysis of 1,644 tumour regions from 421 patients confirmed that subclonal expansions and whole-genome doubling predict relapse, mapped which drivers are selected late, and showed that the metastasising subclone is often a minor population in the primary.","summary":"The full TRACERx 421 cohort report was published as a set of Nature papers in April 2023. Frankell and colleagues analysed 1,644 regions from 421 early-stage NSCLC tumours with whole-exome sequencing and phylogenetic reconstruction.\n\nSubclonal selection was pervasive, with evidence of positive selection acting on late-arising drivers such as those in the PI3K pathway and chromatin modifiers; subclonal expansions (a large subclone dominating a region) and whole-genome doubling were associated with worse disease-free survival. Companion papers showed that the metastasis-seeding clone was frequently a minor subclone in the primary (Al Bakir), that ctDNA at surgery and subclonal copy-number alterations predicted outcome (Abbosh), and that a mutation-independent mechanism by which air pollution promotes EGFR-mutant lung cancer (Hill) operates through inflammation acting on pre-existing mutant cells.\n\nTRACERx is the largest longitudinal tumour-evolution dataset and the model for evolutionary studies in other cancers.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1038/s41586-023-05783-3"},{"label":"TRACERx Nature collection 2023","url":"https://www.nature.com/collections/tracerx"}],"tags":[],"related":["paper-tracerx-100-nejm-2017","whole-genome-doubling","idea-prev-clean-air-never-smoker-endpoints","idea-bio1-clonal-clearance-endpoint"],"cancers":["nsclc"],"sections":["diagnostics"],"technologies":["wes-wgs","liquid-biopsy","mrd-testing"],"targets":[],"drugs":[],"companies":[],"institutions":["francis-crick","cruk"],"pathways":["clonal-evolution","chromosomal-instability","inflammation-nfkb"],"terms":["ctdna","mrd"],"trials":[],"people":["charles-swanton"],"bottlenecks":["b-tumor-heterogeneity","b-metastasis-biology","b-dormancy-mrd"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2023,"doi":"10.1038/s41586-023-05783-3","pmid":"37046096","authors":"Frankell AM, Dietzen M, Al Bakir M, et al. (TRACERx Consortium)","paperType":"translational","findings":["1,644 regions from 421 tumours; subclonal expansions and recent whole-genome doubling associated with shorter disease-free survival","Positive selection detected on subclonal drivers, including in the PI3K pathway and chromatin regulators, meaning late drivers are not merely passengers","Companion paper: metastases frequently seeded by minor subclones of the primary, and by polyclonal seeding in a substantial fraction","Companion paper: air pollutant PM2.5 promotes lung cancer in EGFR-mutant cells via IL-1beta-driven inflammation without new mutations","Companion paper: preoperative ctDNA detection and its dynamics predicted relapse"],"whatItMeans":"Relapse after surgery is driven by particular subclones that can be identified in the primary tumour and tracked in blood, which argues for evolution-aware adjuvant strategies. The pollution finding reframes carcinogenesis: some agents promote already-mutant cells rather than causing mutations.","caveats":["Observational and correlative; interventions based on evolutionary metrics have not been tested","Whole-exome data limits detection of structural and non-coding events","Predominantly UK patients with resectable disease; evolutionary dynamics in advanced and treated disease differ","Cost and complexity of multi-region sequencing preclude routine clinical use"],"changedPractice":false,"participants":421},{"id":"paper-tracerx-100-nejm-2017","kind":"paper","name":"TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse","aka":[],"tldr":"Multi-region sequencing of 327 regions from the first 100 TRACERx lung cancers showed that most driver mutations are early and shared while copy-number chaos continues to evolve, and that tumours with high copy-number heterogeneity were nearly five times more likely to relapse or kill the patient.","summary":"TRACERx (TRAcking Cancer Evolution through therapy) is a Cancer Research UK prospective study following patients with resected stage I-IIIA non-small-cell lung cancer from surgery to relapse or death. This first report analysed 327 tumour regions from 100 patients with whole-exome sequencing.\n\nIntratumour heterogeneity was pervasive: a median of 30% of mutations were subclonal, and 48% of tumours had subclonal driver alterations. Driver mutations in EGFR, MET, BRAF and TP53 were almost always clonal (early), whereas alterations in PIK3CA, NF1 and chromatin modifiers were often late. Ongoing chromosomal instability (subclonal copy-number alterations) rather than mutational heterogeneity predicted recurrence-free survival: patients whose tumours had elevated copy-number heterogeneity had a hazard ratio of 4.9 for recurrence or death.\n\nA companion paper (Abbosh, Nature 2017) showed phylogenetic ctDNA tracking could detect relapse a median 70 days before imaging.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1616288"},{"label":"Phylogenetic ctDNA analysis (Abbosh 2017)","url":"https://doi.org/10.1038/nature22364"},{"label":"ClinicalTrials.gov NCT01888601","url":"https://clinicaltrials.gov/study/NCT01888601"}],"tags":[],"related":["paper-gerlinger-intratumour-heterogeneity-nejm-2012","paper-tracerx-evolution-nature-2023","whole-genome-doubling","idea-bio1-clonal-neoantigen-vaccines"],"cancers":["nsclc"],"sections":["diagnostics"],"technologies":["wes-wgs","liquid-biopsy","mrd-testing"],"targets":[],"drugs":[],"companies":[],"institutions":["francis-crick","cruk"],"pathways":["clonal-evolution","chromosomal-instability"],"terms":["ctdna","mrd","neoantigen"],"trials":[],"people":["charles-swanton"],"bottlenecks":["b-tumor-heterogeneity","b-dormancy-mrd","b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1616288","pmid":"28445112","authors":"Jamal-Hanjani M, Wilson GA, McGranahan N, et al. (TRACERx Consortium)","paperType":"translational","findings":["327 regions from 100 tumours; median 30% of mutations subclonal, 48% of tumours with subclonal drivers","Elevated copy-number intratumour heterogeneity associated with recurrence or death: HR 4.9 (95% CI 1.8-13.1)","EGFR, MET, BRAF and TP53 mutations almost always clonal; PIK3CA, NF1 and chromatin-modifier mutations often subclonal","Whole-genome doubling occurred in most tumours and preceded much of the copy-number diversification","Companion ctDNA paper: relapse detected a median 70 days before CT in tracked patients"],"whatItMeans":"Lung cancers keep evolving after they form, and it is ongoing chromosomal instability rather than the number of mutations that best predicts who will relapse. This gives a rationale for targeting the earliest (clonal) drivers and neoantigens and for tracking evolution in blood after surgery.","caveats":["Early-stage, surgically resected tumours only; the interim cohort of 100 was later expanded to 421","Exome sequencing does not capture non-coding or structural events fully","The prognostic value of copy-number heterogeneity needed validation in the full cohort and other cancers","Clinical utility of clonal-neoantigen targeting remained hypothetical at the time"],"changedPractice":false,"participants":100},{"id":"paper-train-2-lancet-oncol-2018","kind":"paper","name":"TRAIN-2: neoadjuvant chemotherapy with or without anthracyclines alongside dual HER2 blockade","aka":[],"tldr":"Leaving out anthracyclines from neoadjuvant chemotherapy made no difference to how many HER2-positive breast cancers disappeared completely when trastuzumab and pertuzumab were given, so the heart-toxic drugs can be dropped.","summary":"Phase 3 trial of 438 patients with stage II to III HER2-positive breast cancer randomised to nine cycles of carboplatin-paclitaxel with trastuzumab and pertuzumab, with or without three initial cycles of an anthracycline-containing regimen.\n\nPathological complete response was 67 percent with anthracyclines and 68 percent without; three-year event-free survival was similar, while febrile neutropenia and cardiac events were more common with anthracyclines.","asOf":"2026-09-17","links":[{"label":"Lancet Oncol 2018","url":"https://doi.org/10.1016/S1470-2045(18)30570-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30413379/"}],"tags":[],"related":[],"cancers":["her2-positive-early-breast-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["train-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2018,"doi":"10.1016/S1470-2045(18)30570-9","pmid":"30413379","authors":"van Ramshorst MS, van der Voort A, van Werkhoven ED, et al.","paperType":"rct","findings":["Pathological complete response 67 percent with vs 68 percent without anthracyclines.","Three-year event-free survival 92.7 percent vs 93.6 percent."],"whatItMeans":"Anthracycline-free carboplatin-taxane chemotherapy with dual HER2 blockade is a standard neoadjuvant regimen, sparing patients cardiac risk without losing efficacy.","caveats":["Not powered for long-term survival differences.","Both arms used nine cycles of chemotherapy, longer than some current regimens."],"changedPractice":true,"participants":438},{"id":"paper-transform-liso-cel-lancet-2022","kind":"paper","name":"TRANSFORM: liso-cel CAR-T versus salvage chemotherapy and transplant in early-relapsing large B-cell lymphoma","aka":[],"tldr":"In TRANSFORM, a second CD19 CAR-T, lisocabtagene maraleucel, also beat chemotherapy-plus-transplant as second-line treatment, with a low rate of severe side effects.","summary":"TRANSFORM randomised 184 patients with large B-cell lymphoma refractory to or relapsed within 12 months of first-line therapy to lisocabtagene maraleucel (liso-cel) or standard salvage chemotherapy with autologous transplant for responders. Bridging chemotherapy was allowed and crossover to liso-cel was permitted for standard-arm failures. The primary endpoint was event-free survival. At the interim analysis median EFS was 10.1 versus 2.3 months (hazard ratio 0.35) with complete response 66% versus 39%; in the primary analysis median EFS was not reached versus 2.4 months (hazard ratio 0.36). Grade 3 CRS occurred in 1% and grade 3 neurological events in 4%. Overall survival was not significantly different, in part because of crossover.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=TRANSFORM%20lisocabtagene%20maraleucel%20second-line%20Kamdar%20Lancet%202022"},{"label":"ClinicalTrials.gov NCT03575351","url":"https://clinicaltrials.gov/study/NCT03575351"}],"tags":[],"related":["car-t-before-transplant-lbcl","paper-zuma-7-axi-cel-second-line-nejm-2022"],"cancers":["dlbcl"],"sections":[],"technologies":["car-t","autologous-stem-cell-transplant"],"targets":["cd19"],"drugs":["lisocabtagene-maraleucel"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["efs","crs","icans"],"trials":["transform","zuma-7","belinda"],"people":[],"bottlenecks":["b-manufacturing-cell-therapy","b-toxicity-qol"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2022,"authors":"Kamdar M, Solomon SR, Arnason J, et al.","paperType":"rct","findings":["184 patients with primary refractory or early-relapsing LBCL; liso-cel vs salvage chemotherapy and transplant.","Interim: median EFS 10.1 vs 2.3 months; hazard ratio 0.35; complete response 66% vs 39%.","Primary analysis: median EFS not reached vs 2.4 months; hazard ratio 0.36.","Grade 3 CRS 1%; grade 3 neurological events 4%; no grade 4-5 CRS or neurotoxicity.","Crossover to liso-cel allowed; OS not significantly different."],"whatItMeans":"TRANSFORM confirmed ZUMA-7's conclusion with a different CD19 CAR-T and a more permissive design that allowed bridging chemotherapy, making the results closer to real-world practice. Liso-cel's low toxicity makes it attractive for older or frailer patients and for outpatient delivery. Together the two trials made CAR-T the standard second-line therapy for early-relapsing aggressive lymphoma.","caveats":["Smaller than ZUMA-7 and reported at interim analysis; EFS rather than OS was the endpoint.","Crossover blunted any survival comparison.","Excludes late relapse.","Liso-cel manufacturing involves separate CD4 and CD8 components, adding complexity."],"changedPractice":true,"participants":184},{"id":"paper-williams-bep-vs-pvb-nejm-1987","kind":"paper","name":"Treatment of disseminated germ cell tumours with cisplatin, bleomycin and either vinblastine or etoposide","aka":[],"tldr":"Replacing vinblastine with etoposide in cisplatin-based chemotherapy for testicular cancer cured as many men with far less nerve and muscle toxicity and improved survival in advanced disease, establishing the BEP regimen used ever since.","summary":"Phase 3 trial of 261 men with disseminated germ cell tumours randomised to cisplatin, bleomycin and vinblastine (PVB) or cisplatin, bleomycin and etoposide (BEP).\n\nComplete response rates were similar (74 versus 83 percent), but BEP caused less neuromuscular toxicity, and in patients with advanced disease it gave higher disease-free and overall survival.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 1987","url":"https://doi.org/10.1056/NEJM198706043162302"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/2437455/"}],"tags":[],"related":[],"cancers":["non-seminoma"],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","cisplatin","etoposide","vinblastine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1987,"doi":"10.1056/NEJM198706043162302","pmid":"2437455","authors":"Williams SD, Birch R, Einhorn LH, et al.","paperType":"rct","findings":["Disease-free status in 61 percent (PVB) vs 60 percent (BEP) overall; superior survival with BEP in advanced disease.","Substantially less neuromuscular toxicity with BEP."],"whatItMeans":"BEP has been the backbone of curative chemotherapy for testicular cancer for nearly forty years.","caveats":["Small trial by modern standards; later trials defined cycle number by risk group."],"changedPractice":true,"participants":261},{"id":"paper-trident-1-repotrectinib-nejm-2024","kind":"paper","name":"TRIDENT-1: repotrectinib in ROS1 fusion-positive non-small-cell lung cancer","aka":[],"tldr":"The next-generation ROS1 and TRK inhibitor repotrectinib shrank tumours in almost four in five untreated patients with ROS1-positive lung cancer, kept the disease under control for nearly three years, and worked in about four in ten patients after crizotinib including those with the resistant G2032R mutation.","summary":"Phase 1/2 study of 171 patients with ROS1 fusion-positive non-small-cell lung cancer treated with repotrectinib, including 71 who had not received a ROS1 inhibitor and 56 previously treated with one.\n\nIn ROS1 inhibitor-naive patients, objective response was 79 percent with median progression-free survival 35.7 months; in patients after one prior ROS1 inhibitor without chemotherapy, response was 38 percent with median progression-free survival 9.0 months, and 59 percent of G2032R-mutant tumours responded. Dizziness was the most frequent side effect.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2024","url":"https://doi.org/10.1056/NEJMoa2302299"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38197815/"}],"tags":[],"related":[],"cancers":["ntrk-fusion-nsclc","ros1-positive-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["repotrectinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2024,"doi":"10.1056/NEJMoa2302299","pmid":"38197815","authors":"Drilon A, Camidge DR, Lin JJ, et al.","paperType":"observational","findings":["ROS1 inhibitor-naive: objective response 79 percent; median progression-free survival 35.7 months.","After one prior ROS1 inhibitor: objective response 38 percent; 59 percent in G2032R-mutant tumours."],"whatItMeans":"Repotrectinib is a preferred first-line ROS1 inhibitor because of its durability and coverage of resistance mutations, and it is also approved for NTRK fusion-positive tumours after prior TRK inhibitors.","caveats":["Single-arm; dizziness in about 60 percent and dysgeusia in half.","No randomised comparison with crizotinib or entrectinib."],"changedPractice":true,"participants":171},{"id":"paper-tropion-breast01-jco-2024","kind":"paper","name":"TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival","aka":[],"tldr":"The TROP2-directed antibody-drug conjugate Dato-DXd delayed progression by about two months compared with chemotherapy, but patients did not live longer, which stalled its approval in breast cancer.","summary":"Open-label phase 3 trial of 732 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer after one or two lines of chemotherapy, randomised to datopotamab deruxtecan (Dato-DXd, 6 mg/kg) or investigator's choice chemotherapy (eribulin, vinorelbine, capecitabine or gemcitabine). Dual primary endpoints were PFS by blinded review and overall survival.\n\nPFS was improved (6.9 vs 4.9 months, HR 0.63) with fewer high-grade adverse events, but the final overall survival analysis showed no difference. The trial is a cautionary example that a TROP2 ADC can beat chemotherapy on PFS in an unselected population without changing survival.","asOf":"2026-09-08","links":[{"label":"PubMed search: TROPION-Breast01","url":"https://pubmed.ncbi.nlm.nih.gov/?term=TROPION-Breast01+datopotamab+deruxtecan+Bardia"},{"label":"ClinicalTrials.gov NCT05104866","url":"https://clinicaltrials.gov/study/NCT05104866"}],"tags":[],"related":["idea-trop2-pet-selection","idea-payload-switching"],"cancers":["breast-hr-positive"],"sections":[],"technologies":["adc","topoisomerase-inhibitors"],"targets":["trop2"],"drugs":["datopotamab-deruxtecan"],"companies":["daiichi-sankyo","astrazeneca"],"institutions":[],"pathways":[],"terms":["pfs","os","adc-sequencing","ihc"],"trials":["tropion-breast01","tropion-breast02"],"people":["im-seock-ah","xu-binghe","barrios-carlos"],"bottlenecks":["b-biomarker-validation","b-trial-design","b-negative-results"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2024,"authors":"Bardia A, Jhaveri K, Im SA, et al.","paperType":"rct","findings":["Median PFS by blinded central review 6.9 vs 4.9 months; HR 0.63 (95% CI 0.52-0.76).","Objective response rate 36.4% vs 22.9%.","Grade 3 or higher treatment-related adverse events about 21% vs 45%; stomatitis and ocular surface events were the characteristic Dato-DXd toxicities.","Final overall survival analysis (2024): no significant difference (HR close to 1.0).","TROP2 expression by immunohistochemistry did not select responders."],"whatItMeans":"For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.","caveats":["Open-label; PFS assessed by blinded review but subsequent therapy was at physician discretion.","Post-progression therapy, including other ADCs, likely diluted any survival effect.","The population was chemotherapy-pretreated and heterogeneous; a first-line or biomarker-selected trial might behave differently.","Immunohistochemistry for TROP2 was not predictive, leaving no validated way to choose patients."],"changedPractice":false,"participants":732},{"id":"paper-tumeh-pd1-adaptive-immune-resistance-nature-2014","kind":"paper","name":"Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge","aka":[],"tldr":"Melanomas that responded to pembrolizumab already contained killer T cells pressed up against tumour cells expressing PD-L1, showing that the drug works by releasing an immune attack that is already there rather than creating a new one.","summary":"Tumeh, Ribas and colleagues at UCLA studied tumour biopsies from 46 patients with metastatic melanoma before and during pembrolizumab. Responding tumours had higher densities of CD8 T cells, PD-1 and PD-L1 at the invasive margin and in the tumour before treatment, with T cells and PD-L1 in close proximity, and their T cell receptor repertoires were more clonal and expanded further on treatment. The authors proposed that PD-L1 is induced as an adaptive resistance mechanism in response to interferon from attacking T cells and that pembrolizumab reverses it.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature13954"}],"tags":[],"related":["paper-rizvi-mutational-landscape-pd1-science-2015"],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["pembrolizumab"],"companies":[],"institutions":["ucla-jonsson"],"pathways":[],"terms":["tils","immune-checkpoint"],"trials":[],"people":["antoni-ribas"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2014,"doi":"10.1038/nature13954","authors":"Tumeh PC, Harview CL, Yearley JH, et al.","paperType":"translational","findings":["Serial biopsies from 46 melanoma patients treated with pembrolizumab.","Pre-treatment CD8 T cell density and PD-1 and PD-L1 expression at the invasive margin and in the tumour were higher in responders.","Responders showed more clonal T cell receptor repertoires that expanded during treatment.","A predictive model based on these features identified most responders in a validation set."],"whatItMeans":"This paper explained why PD-1 antibodies work in some patients and not others and introduced the idea of inflamed versus non-inflamed tumours that now guides combination strategies designed to bring T cells into cold tumours.","caveats":["Small cohort from a single centre.","Biopsies sample one site and may not represent all metastases."],"changedPractice":false,"participants":46},{"id":"paper-tuxedo-1-trastuzumab-deruxtecan-brain-metastases-nat-med-2022","kind":"paper","name":"TUXEDO-1: trastuzumab deruxtecan in HER2-positive breast cancer with active brain metastases","aka":[],"tldr":"In a small trial, the antibody-drug conjugate trastuzumab deruxtecan shrank brain metastases in almost three quarters of women with HER2-positive breast cancer, showing that a large antibody-based drug can work inside the brain.","summary":"Single-arm phase 2 trial of 15 patients with HER2-positive breast cancer and newly diagnosed or progressing brain metastases not needing immediate local therapy, treated with trastuzumab deruxtecan 5.4 mg/kg.\n\nIntracranial response by RANO-BM criteria was 73.3 percent in the intention-to-treat population, with a median progression-free survival of 14 months and preserved quality of life. The larger DESTINY-Breast12 study later confirmed intracranial activity in a broader population.","asOf":"2026-09-17","links":[{"label":"Nat Med 2022","url":"https://doi.org/10.1038/s41591-022-01935-8"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35941372/"}],"tags":[],"related":[],"cancers":["her2-positive-breast-brain-metastases"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tuxedo-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2022,"doi":"10.1038/s41591-022-01935-8","pmid":"35941372","authors":"Bartsch R, Berghoff AS, Furtner J, et al.","paperType":"observational","findings":["Intracranial objective response 73.3 percent.","Median progression-free survival 14 months."],"whatItMeans":"Trastuzumab deruxtecan is an option for active HER2-positive brain metastases, complementing tucatinib-based therapy, and challenges the assumption that antibody-drug conjugates cannot reach the brain.","caveats":["Very small single-centre study.","Patients with lesions needing urgent local treatment were excluded."],"changedPractice":true,"participants":15},{"id":"paper-ucart19-allogeneic-car-t-lancet-2020","kind":"paper","name":"UCART19: the first gene-edited, donor-derived CAR-T cells in children and adults with relapsed B-cell ALL","aka":[],"tldr":"Off-the-shelf CAR-T cells made from a healthy donor, gene-edited to avoid rejection and graft-versus-host disease, produced remission in 14 of 21 patients with relapsed ALL.","summary":"This report pooled two phase 1 studies (PALL in 7 children and CALM in 14 adults) of UCART19, allogeneic CD19 CAR-T cells from healthy donors in which TALEN gene editing disrupted the T-cell receptor alpha constant gene (to prevent graft-versus-host disease) and CD52 (to allow alemtuzumab in lymphodepletion). Patients with relapsed or refractory CD19-positive B-cell ALL received fludarabine and cyclophosphamide with or without alemtuzumab followed by UCART19. Complete remission or remission with incomplete count recovery occurred in 14 of 21 patients (67%) at day 28; UCART19 expansion was only seen in patients who received alemtuzumab. Cytokine release syndrome occurred in 91% (grade 3-4 in 3 patients), neurotoxicity in 38% (all grade 1-2), and grade 1 skin graft-versus-host disease in two patients. Most responders proceeded to allogeneic transplant, and durability without transplant was limited.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=UCART19%20genome-edited%20donor-derived%20allogeneic%20anti-CD19%20CAR%20T%20Benjamin%20Lancet%202020"},{"label":"ClinicalTrials.gov NCT02746952","url":"https://clinicaltrials.gov/study/NCT02746952"},{"label":"ClinicalTrials.gov NCT02808442","url":"https://clinicaltrials.gov/study/NCT02808442"}],"tags":[],"related":["allogeneic-cell-banking","point-of-care-cell-manufacturing","paper-eliana-tisagenlecleucel-nejm-2018"],"cancers":["all-leukemia"],"sections":[],"technologies":["allogeneic-cell-therapy","car-t","in-vivo-car-t"],"targets":["cd19"],"drugs":[],"companies":["servier","allogene"],"institutions":[],"pathways":[],"terms":["crs"],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy","b-resistance"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2020,"authors":"Benjamin R, Graham C, Yallop D, et al.","paperType":"translational","findings":["21 patients (7 children, 14 adults) with relapsed/refractory B-ALL treated with donor-derived, TALEN-edited CD19 CAR-T cells.","Complete remission or CRi in 14 of 21 (67%) at day 28.","CAR-T expansion required alemtuzumab-containing lymphodepletion; no expansion without it.","CRS 91% (3 grade 3-4); neurotoxicity 38%, all grade 1-2; grade 1 skin GvHD in 2 patients.","10 responders proceeded to allogeneic transplant; persistence of UCART19 was short (weeks), limiting durability."],"whatItMeans":"The UCART19 report was the first clinical evidence that a universal, pre-manufactured CAR-T made from a donor can work, avoiding the weeks of autologous manufacturing and the problem of patients whose own T cells are too damaged. It set the template for later allogeneic programmes (including cemacabtagene autoleucel in the ALPHA studies) and for in vivo CAR generation. Short persistence and the need for deep lymphodepletion remain the central weaknesses.","caveats":["Very small phase 1 with heterogeneous dosing.","Remissions were mostly a bridge to transplant; few durable responses without further therapy.","Alemtuzumab-based lymphodepletion causes profound, prolonged immunosuppression and infection risk.","Gene editing raises questions about off-target effects and chromosomal rearrangements."],"changedPractice":false,"participants":21},{"id":"paper-rueth-inflammatory-breast-trimodality-jco-2014","kind":"paper","name":"Underuse of trimodality treatment and survival in inflammatory breast cancer (National Cancer Data Base)","aka":[],"tldr":"In a national registry, only about a third of women with inflammatory breast cancer received all three recommended treatments, chemotherapy, mastectomy and radiotherapy, and those who did lived substantially longer.","summary":"Analysis of 10,197 women with non-metastatic inflammatory breast cancer in the National Cancer Data Base between 1998 and 2010 examining receipt of chemotherapy, surgery and radiotherapy and its association with survival.\n\nOnly 58.4 percent received all three modalities in recent years, with wide variation by facility and region; median survival was longest with trimodality therapy, and its use was an independent predictor of survival.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2014","url":"https://doi.org/10.1200/JCO.2014.55.1978"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24888808/"}],"tags":[],"related":[],"cancers":["inflammatory-breast-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2014,"doi":"10.1200/JCO.2014.55.1978","pmid":"24888808","authors":"Rueth NM, Lin HY, Bedrosian I, et al.","paperType":"observational","findings":["Trimodality therapy associated with improved overall survival compared with any lesser combination.","Use of trimodality therapy varied substantially by treatment facility type."],"whatItMeans":"The gap between guideline and practice in inflammatory breast cancer is large; this paper is the reason guidelines insist on referral to centres that deliver the full sequence.","caveats":["Registry data with selection bias; healthier patients are more likely to complete all treatments."],"changedPractice":true,"participants":10197},{"id":"paper-unger-trial-participation-barriers-jnci-2019","kind":"paper","name":"Unger: most patients never get the chance to join a cancer trial, and when offered, half say yes","aka":[],"tldr":"Pooling 13 studies of 8,883 patients, 56% had no trial available at their site and a further 22% were ineligible for the trials that existed; among patients actually offered a trial, roughly half enrolled, so overall participation was about 8%.","summary":"Unger and colleagues systematically reviewed studies that tracked consecutive cancer patients through the decision pathway to trial enrolment, quantifying structural, clinical and physician-or-patient barriers at each step. Thirteen studies (nine academic, four community) with 8,883 patients were pooled.\n\nStructural barriers dominated: 55.6% of patients had no trial available for their cancer type and stage at their institution. Of the remainder, 21.5% were ineligible for the available trial. Physician and patient factors (not offered, or declined) accounted for 14.8%. Overall trial participation was 8.1%; but among patients who had an available trial and were eligible, about half enrolled. Participation was lower in community settings.\n\nThe analysis reframed low enrolment from a problem of patient reluctance to one of trial availability and eligibility criteria, shaping ASCO and FDA initiatives to broaden eligibility and decentralise trials.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1093/jnci/djy221"}],"tags":[],"related":["idea-tr1-remote-consent-tele-screening","idea-tr1-protected-physician-time-for-enrolment","idea-tr1-incidence-weighted-enrolment-targets"],"cancers":[],"sections":["drug-discovery"],"technologies":["decentralised-clinical-trials","community-oncology-networks","ai-trial-matching"],"targets":[],"drugs":[],"companies":[],"institutions":["fred-hutch"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-trial-enrolment","b-trial-diversity","b-care-fragmentation"],"keyPapers":[],"journals":["jnci"],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":2019,"doi":"10.1093/jnci/djy221","pmid":"30783627","authors":"Unger JM, Vaidya R, Hershman DL, Minasian LM, Fleury ME","paperType":"meta-analysis","findings":["55.6% of patients had no trial available at their site (95% CI 43.7-67.3)","21.5% were ineligible for available trials (95% CI 10.9-33.9)","14.8% did not enrol for physician or patient reasons (not offered, declined)","Overall participation 8.1%; about 55% of eligible patients offered a trial enrolled","Academic centres had higher participation (15.9%) than community sites (7.0%)"],"whatItMeans":"Patients are not the bottleneck; trial access is. Bringing trials to community practices, loosening restrictive eligibility criteria and reducing site burden would do more for enrolment than patient education. Trials today reflect the minority of patients who happen to be treated where trials exist.","caveats":["Included studies were heterogeneous and mostly US-based; barriers differ in single-payer and low-resource systems","Studies varied in how they recorded reasons for non-enrolment, so barrier categories overlap","Academic centres are over-represented in the source studies","Does not capture racial, ethnic or socioeconomic disparities within each barrier category"],"changedPractice":false,"participants":8883},{"id":"paper-uspstf-crc-screening-45-jama-2021","kind":"paper","name":"US Preventive Services Task Force recommendation: colorectal cancer screening from age 45","aka":[],"tldr":"In 2021 the US Preventive Services Task Force lowered the recommended age to start colorectal cancer screening from 50 to 45 for average-risk adults, in response to rising rates in younger people.","summary":"Recommendation statement based on systematic review and modelling concluding with moderate certainty that screening adults aged 45 to 49 has moderate net benefit (B recommendation), continuing the A recommendation for ages 50 to 75, with a range of acceptable tests including colonoscopy, faecal immunochemical testing, stool DNA testing and CT colonography.","asOf":"2026-09-17","links":[{"label":"JAMA 2021","url":"https://doi.org/10.1001/jama.2021.6238"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34003218/"}],"tags":[],"related":[],"cancers":["early-onset-colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jama"],"dependsOn":[],"notes":[],"journal":"JAMA","year":2021,"doi":"10.1001/jama.2021.6238","pmid":"34003218","authors":"US Preventive Services Task Force, Davidson KW, Barry MJ, et al.","paperType":"guideline","findings":[],"whatItMeans":"Screening from 45 is now standard in the United States and has been adopted or debated elsewhere; it is the main policy response to early-onset colorectal cancer.","caveats":["Modelling-based; uptake in the 45 to 49 group has been slow.","Benefit for those under 45 remains unaddressed."],"changedPractice":true},{"id":"paper-johnson-alternative-medicine-jnci-2018","kind":"paper","name":"Use of alternative medicine for cancer and its impact on survival","aka":[],"tldr":"People with curable breast, lung or bowel cancer who chose alternative medicine instead of conventional treatment were two and a half times as likely to die during follow-up as matched patients who had standard treatment.","summary":"Using the US National Cancer Database (2004 to 2013), the authors identified 281 patients with non-metastatic breast, prostate, lung or colorectal cancer whose only recorded treatment was 'other-unproven: cancer treatments administered by non-medical personnel', and matched each to two patients (560) who received conventional treatment on cancer type, age, stage, comorbidity, insurance, race, year and clinical group.\n\nAlternative medicine users were more likely to be younger, female, wealthier and better educated, and more likely to have breast or lung cancer and stage II or III disease. Five-year survival was lower with alternative medicine overall, and the adjusted hazard ratio for death was 2.50 across cancers, 5.68 in breast cancer, 4.57 in colorectal cancer and 2.17 in lung cancer; in prostate cancer, where observation is often reasonable, there was no significant difference. The companion JAMA Oncology paper showed that complementary medicine users were more likely to refuse surgery, chemotherapy, radiotherapy or hormone therapy and that this refusal explained their worse survival.","asOf":"2026-09-10","links":[{"label":"Johnson et al., Use of alternative medicine for cancer and its impact on survival (JNCI 2018)","url":"https://doi.org/10.1093/jnci/djx145"},{"label":"Companion analysis: complementary medicine, refusal of conventional therapy and survival (JAMA Oncol 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.2487"}],"tags":["complementary"],"related":[],"cancers":["breast-hr-positive","tnbc","colorectal","nsclc","prostate"],"sections":[],"technologies":["alternative-medicine-instead-of-treatment","integrative-oncology"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-misinformation"],"keyPapers":[],"journals":["jnci"],"dependsOn":[],"notes":[],"journal":"JNCI: Journal of the National Cancer Institute","year":2018,"doi":"10.1093/jnci/djx145","authors":"Johnson SB, Park HS, Gross CP, Yu JB","paperType":"observational","findings":["281 alternative-medicine-only patients matched to 560 conventionally treated patients from the National Cancer Database, 2004 to 2013.","Hazard ratio for death with alternative medicine: 2.50 overall (95% CI 1.88 to 3.27).","By cancer: breast 5.68, colorectal 4.57, lung 2.17; prostate not significantly different.","Users were younger, more often female, with higher income and education, and more often had stage II or III disease."],"whatItMeans":"Complementary approaches used alongside treatment are one thing; substituting an alternative therapy for surgery, chemotherapy, radiotherapy or hormone therapy in a curable cancer is associated with a large increase in the risk of dying. The finding is the evidence base for offering complementary therapies inside cancer centres and for asking every patient, without judgement, what else they are using.","caveats":["Observational and reliant on a single coded field; the specific alternative therapies are unknown.","Patients who choose alternative medicine may differ in unmeasured ways, although matching and adjustment reduced the imbalance.","Follow-up ended at a median of around five years; the absolute survival difference varies by cancer and stage."],"changedPractice":false,"participants":841},{"id":"paper-basu-single-dose-hpv-lancet-oncol-2021","kind":"paper","name":"Vaccine efficacy against persistent HPV 16/18 infection at 10 years after one, two and three doses of quadrivalent HPV vaccine in girls in India","aka":[],"tldr":"Ten years after vaccination, Indian girls who had received a single dose of HPV vaccine were as well protected against the cancer-causing HPV types as those who had two or three doses, which let the world switch to one-dose programmes.","summary":"Multicentre prospective cohort study arising from an IARC trial at nine Indian centres whose recruitment was suspended in 2010, leaving cohorts of girls aged 10 to 18 who had received one (4,949), two (4,980) or three (4,348) doses of quadrivalent HPV vaccine. At a median follow-up of 9.0 years (IQR 8.2-9.6), vaccine efficacy against persistent HPV 16/18 infection was 95.4% (95% CI 85.0-99.9) after one dose, 93.1% (77.3-99.8) after two and 93.3% (77.5-99.7) after three, compared with unvaccinated married women of similar age.","asOf":"2026-09-10","links":[{"label":"Lancet Oncology 2021","url":"https://doi.org/10.1016/S1470-2045(21)00453-8"}],"tags":[],"related":[],"cancers":["cervical"],"sections":[],"technologies":["hpv-vaccine"],"targets":[],"drugs":["gardasil-9","cervavac"],"companies":[],"institutions":["iarc"],"pathways":[],"terms":[],"trials":["iarc-india-hpv-dose-study","ken-she"],"people":["basu-partha","sankaranarayanan-rengaswamy"],"bottlenecks":["b-prevention-adoption","b-dose-optimisation"],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"Lancet Oncology","year":2021,"doi":"10.1016/S1470-2045(21)00453-8","authors":"Basu P, Malvi SG, Joshi S, et al.","paperType":"observational","findings":["Single-dose efficacy against persistent HPV 16/18 infection 95.4% at a median of 9 years.","Two-dose 93.1% and three-dose 93.3%: no meaningful difference between schedules.","Antibody levels after one dose were lower but stable over time.","Cohorts were defined by default after the 2010 suspension, not by randomisation to one dose."],"whatItMeans":"One dose protects. WHO endorsed one- or two-dose schedules in 2022, halving the cost and the logistics of vaccinating girls, which is decisive for India (about 127,500 cervical cancers a year) and for the global elimination target. It also removed the main barrier to India's national programme with its home-made vaccine.","caveats":["Non-randomised comparison of dose groups; confounding by who happened to receive fewer doses cannot be fully excluded.","Endpoint is persistent infection, not cervical cancer, although the link is well established.","Quadrivalent vaccine; nonavalent and bivalent products rely on separate evidence (KEN SHE, Costa Rica)."],"changedPractice":true,"participants":17729},{"id":"paper-tarpswg-retroperitoneal-sarcoma-gronchi-ann-surg-2016","kind":"paper","name":"Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (TARPSWG)","aka":[],"tldr":"Pooling over a thousand patients from eight expert centres showed that recurrence after retroperitoneal sarcoma surgery depends on histology: liposarcoma recurs locally, leiomyosarcoma spreads distantly, which shapes follow-up and the case for radiotherapy or chemotherapy by subtype.","summary":"Retrospective analysis of 1,007 patients with primary retroperitoneal sarcoma treated with curative-intent surgery at eight Trans-Atlantic Retroperitoneal Sarcoma Working Group centres, describing patterns of local and distant recurrence and survival by histology.\n\nFive-year overall survival was 67 percent; well-differentiated liposarcoma recurred locally with almost no metastases, dedifferentiated liposarcoma recurred both ways, and leiomyosarcoma had a high distant recurrence rate with low local recurrence.","asOf":"2026-09-17","links":[{"label":"Ann Surg 2016","url":"https://doi.org/10.1097/SLA.0000000000001447"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26727100/"}],"tags":[],"related":[],"cancers":["retroperitoneal-sarcoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Annals of Surgery","year":2016,"doi":"10.1097/SLA.0000000000001447","pmid":"26727100","authors":"Gronchi A, Strauss DC, Miceli R, et al.","paperType":"observational","findings":["Five-year overall survival 67 percent after complete resection.","Local recurrence dominant in liposarcoma; distant recurrence dominant in leiomyosarcoma."],"whatItMeans":"Histology-specific strategies, such as considering neoadjuvant chemotherapy for leiomyosarcoma and high-grade dedifferentiated liposarcoma in STRASS2, follow from these patterns.","caveats":["Retrospective data from expert centres; results may not generalise to non-specialist surgery."],"changedPractice":true,"participants":1007},{"id":"paper-veber-oral-bioavailability-jmedchem-2002","kind":"paper","name":"Veber 2002: molecular properties that influence the oral bioavailability of drug candidates","aka":[],"tldr":"An analysis of over a thousand experimental drug candidates that found molecules with few rotatable bonds and a modest polar surface area were far more likely to be absorbed when swallowed, giving medicinal chemists two simple rules that shaped the design of oral cancer drugs.","summary":"Veber and colleagues at GlaxoSmithKline analysed rat oral bioavailability data for about 1,100 drug candidates and related it to calculated molecular properties. Compounds with ten or fewer rotatable bonds and a polar surface area of 140 square angstroms or less (or twelve or fewer hydrogen bond donors and acceptors) had a high probability of good oral bioavailability, largely independent of molecular weight, which had been the emphasis of earlier rules. The paper argued that reduced molecular flexibility and polar surface area, not size alone, are what predict oral absorption.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1021/jm020017n"}],"tags":[],"related":[],"cancers":[],"sections":["drug-discovery"],"technologies":["protac-degrader"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["pharmacokinetics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Medicinal Chemistry","year":2002,"doi":"10.1021/jm020017n","authors":"Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD.","paperType":"methods","findings":["Analysis of oral bioavailability in rats for about 1,100 drug candidates.","Ten or fewer rotatable bonds and polar surface area of 140 square angstroms or less predicted good oral bioavailability.","Molecular weight was a weaker predictor than flexibility and polarity."],"whatItMeans":"Veber's rules, alongside Lipinski's rule of five, are used across the industry to decide whether a molecule can become a pill. They set the boundaries within which most oral kinase inhibitors and other targeted cancer drugs were designed, and the current push into larger molecules such as PROTACs and macrocycles is partly an effort to work beyond them.","caveats":["Based on rat data from one company's compounds.","Later oral drugs, including many beyond these limits, show the rules are guides rather than laws."],"changedPractice":true},{"id":"paper-carlson-link-vestibular-schwannomas-nejm-2021","kind":"paper","name":"Vestibular schwannomas (review)","aka":[],"tldr":"A clinical review of acoustic neuromas covering how they present, why observation is now the first choice for most small tumours, and how microsurgery and radiosurgery compare for tumours that grow.","summary":"Review article summarising the epidemiology, natural history, imaging, hearing outcomes and management of sporadic vestibular schwannoma, including the shift towards observation with serial MRI, indications and outcomes for stereotactic radiosurgery and microsurgery, quality-of-life considerations and NF2-related disease.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2021","url":"https://doi.org/10.1056/NEJMra2020394"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33826821/"}],"tags":[],"related":[],"cancers":["vestibular-schwannoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMra2020394","pmid":"33826821","authors":"Carlson ML, Link MJ.","paperType":"review","findings":[],"whatItMeans":"The observation-first approach and the framing of treatment as a trade between facial nerve function, hearing and tumour control on the vestibular schwannoma page reflect this review.","caveats":["No randomised trials compare the three main strategies; recommendations rest on observational data."],"changedPractice":false},{"id":"paper-viale-a-venetoclax-azacitidine-nejm-2020","kind":"paper","name":"VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy","aka":[],"tldr":"Adding the BCL-2 inhibitor venetoclax to azacitidine more than doubled remission rates and extended median survival from 9.6 to 14.7 months in unfit AML patients.","summary":"VIALE-A randomised 431 patients with newly diagnosed AML who were ineligible for intensive induction (median age 76) in a 2:1 ratio to azacitidine plus venetoclax or azacitidine plus placebo. Primary endpoints were overall survival and composite complete remission. Median OS was 14.7 versus 9.6 months (hazard ratio 0.66); complete remission was 36.7% versus 17.9% and complete remission with incomplete count recovery 66.4% versus 28.3%, with responses achieved faster and more often MRD-negative. Febrile neutropenia (42% versus 19%) and infections were more frequent with venetoclax. The regimen became the global standard for unfit AML.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2012971"},{"label":"ClinicalTrials.gov NCT02993523","url":"https://clinicaltrials.gov/study/NCT02993523"}],"tags":[],"related":["venetoclax-plus-hma","menin-plus-venetoclax-hma"],"cancers":["aml"],"sections":[],"technologies":[],"targets":["bcl2"],"drugs":["venetoclax","azacitidine"],"companies":["abbvie"],"institutions":["md-anderson"],"pathways":[],"terms":["os","mrd-negative-cr"],"trials":["viale-a"],"people":[],"bottlenecks":["b-aging-comorbidity","b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2012971","authors":"DiNardo CD, Jonas BA, Pullarkat V, et al.","paperType":"rct","findings":["431 patients unfit for intensive chemotherapy, median age 76; azacitidine + venetoclax vs azacitidine + placebo (2:1).","Median OS 14.7 vs 9.6 months; hazard ratio 0.66.","Complete remission 36.7% vs 17.9%; CR + CRi 66.4% vs 28.3%.","Responses were faster (median 1.3 months to first response) and more often MRD-negative.","Febrile neutropenia 42% vs 19%; grade 3 or higher infections more frequent."],"whatItMeans":"VIALE-A turned a palliative regimen into one that produces remission in two-thirds of older AML patients and is now the reference treatment for anyone not fit for intensive chemotherapy. It shifted the field towards lower-intensity targeted combinations and opened the door to adding FLT3, IDH and menin inhibitors to the backbone. Cure remains uncommon and most patients relapse within two years.","caveats":["Median survival gain was about five months; long-term survival is still poor.","Benefit was smaller in TP53-mutated and adverse-karyotype disease.","Prolonged cytopenias require dose interruptions and expertise; real-world outcomes are worse than trial results.","No comparison against intensive chemotherapy in fit patients."],"changedPractice":true,"participants":431},{"id":"paper-vision-nejm-2021","kind":"paper","name":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer","aka":[],"tldr":"A radioactive drug that homes to the PSMA protein on prostate cancer cells helped men with heavily pretreated metastatic prostate cancer live about four months longer, launching radioligand therapy as a mainstream treatment.","summary":"Open-label phase 3 trial of 831 men with PSMA-PET-positive metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor pathway inhibitor and one or two taxanes, randomised 2:1 to 177Lu-PSMA-617 (7.4 GBq every six weeks for up to six cycles) plus protocol-permitted standard care, or standard care alone. Primary endpoints were radiographic PFS and OS.\n\nMedian OS was 15.3 vs 11.3 months (HR 0.62) and median rPFS 8.7 vs 3.4 months (HR 0.40). It led to FDA and EMA approval of Pluvicto in 2022, the first radioligand therapy to show a survival benefit in a common cancer, and made PSMA PET a theranostic gatekeeper.","asOf":"2026-09-08","links":[{"label":"NEJM 2021","url":"https://doi.org/10.1056/NEJMoa2107322"},{"label":"ClinicalTrials.gov NCT03511664","url":"https://clinicaltrials.gov/study/NCT03511664"}],"tags":[],"related":["psma-pet-to-rlt"],"cancers":["prostate"],"sections":[],"technologies":["radioligand-therapy","psma-pet","pet-ct"],"targets":["psma"],"drugs":["pluvicto"],"companies":["novartis"],"institutions":[],"pathways":[],"terms":["theranostics","alpha-vs-beta","dosimetry","os","pfs"],"trials":["vision","psmafore"],"people":["johann-de-bono","karim-fizazi","michael-morris"],"bottlenecks":["b-global-access","b-workforce","b-trial-design"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMoa2107322","authors":"Sartor O, de Bono J, Chi KN, et al.","paperType":"rct","findings":["Median overall survival 15.3 vs 11.3 months; HR 0.62 (95% CI 0.52-0.74).","Median radiographic PFS 8.7 vs 3.4 months; HR 0.40 (99.2% CI 0.29-0.57).","PSA decline of 50% or more in 46% vs 7%; objective response in measurable disease 30% vs 2%.","Grade 3 or higher adverse events 53% vs 38%, mainly anaemia, thrombocytopenia and fatigue; dry mouth was common but rarely severe.","About 13% of screened patients were excluded by PSMA PET (PSMA-negative lesions), and early dropout in the control arm required protocol changes."],"whatItMeans":"Men with metastatic castration-resistant prostate cancer that has progressed after hormonal therapy and chemotherapy, and whose tumours show PSMA on a PET scan, can now receive lutetium-PSMA, which extends life, controls pain and is usually better tolerated than further chemotherapy. It has established a new treatment class in which a scan decides who gets the matching radioactive drug, and it is now being tested earlier in the disease (PSMAfore, PSMAddition).","caveats":["Standard care in the control arm excluded chemotherapy, radium-223 and other active drugs, and about 56% of control patients withdrew early, weakening the comparison.","Open-label; the OS benefit is nonetheless robust to sensitivity analyses.","Requires nuclear medicine infrastructure, isotope supply and PSMA PET access, which are unequally distributed.","PSMAfore in the pre-chemotherapy setting improved rPFS but not OS, because most control patients crossed over."],"changedPractice":true,"participants":831},{"id":"paper-vision-tepotinib-paik-nejm-2020","kind":"paper","name":"VISION: tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations","aka":[],"tldr":"The once-daily MET inhibitor tepotinib shrank tumours in about half of patients with MET exon 14-skipping lung cancer, detected either in tissue or in a blood test, supporting approval and the use of liquid biopsy to find the alteration.","summary":"Phase 2 study of 152 patients with advanced non-small-cell lung cancer with MET exon 14 skipping detected by liquid or tissue biopsy treated with tepotinib 500 mg daily.\n\nObjective response by independent review was 46 percent overall (48 percent in liquid-biopsy and 50 percent in tissue-biopsy groups) with a median duration of response of 11.1 months; peripheral oedema was the main toxicity.","asOf":"2026-09-17","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa2004407"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32469185/"}],"tags":[],"related":[],"cancers":["met-altered-nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["tepotinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2004407","pmid":"32469185","authors":"Paik PK, Felip E, Veillon R, et al.","paperType":"observational","findings":["Objective response 46 percent; median duration of response 11.1 months.","Similar responses whether detected by liquid or tissue biopsy."],"whatItMeans":"Tepotinib is an approved alternative to capmatinib for MET exon 14 lung cancer, and the trial validated circulating tumour DNA as a way to find the alteration.","caveats":["Single-arm; grade 3 or higher peripheral oedema in 7 percent."],"changedPractice":true,"participants":152},{"id":"paper-robinson-vismodegib-shh-medulloblastoma-jco-2015","kind":"paper","name":"Vismodegib in recurrent sonic hedgehog-subgroup medulloblastoma (PBTC-025B and PBTC-032)","aka":[],"tldr":"The hedgehog pathway inhibitor vismodegib produced responses in recurrent SHH-subgroup medulloblastoma but not in other subgroups, and only in tumours whose mutation lay upstream of the drug's target, showing that molecular subgrouping must guide its use.","summary":"Two phase 2 studies of vismodegib in 43 patients (adults and children) with recurrent medulloblastoma, analysed by molecular subgroup and mutation.\n\nResponses occurred in 3 of 12 adults and 1 of 8 children with SHH-subgroup tumours and in none of the 20 non-SHH patients; responders had PTCH1 or SMO alterations, while tumours with downstream SUFU or GLI2 alterations did not respond, and growth plate fusion occurred in children.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2015","url":"https://doi.org/10.1200/JCO.2014.60.1591"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26169613/"}],"tags":[],"related":[],"cancers":["medulloblastoma-shh"],"sections":[],"technologies":[],"targets":[],"drugs":["vismodegib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2015,"doi":"10.1200/JCO.2014.60.1591","pmid":"26169613","authors":"Robinson GW, Orr BA, Wu G, et al.","paperType":"observational","findings":["Responses only in SHH-subgroup tumours with upstream (PTCH1, SMO) alterations.","No responses in non-SHH medulloblastoma."],"whatItMeans":"Vismodegib or sonidegib is reserved for skeletally mature patients with relapsed SHH medulloblastoma and upstream pathway mutations, a niche defined by this trial.","caveats":["Small numbers; responses were transient.","Irreversible growth plate closure in growing children."],"changedPractice":true,"participants":43},{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","aka":[],"tldr":"A concise map of the p53 system as a network: the stresses that activate it, the many genes it controls, and the feedback loops that keep it in check, explaining why a single gene sits at the centre of so much of cancer biology.","summary":"Written by three of the field's founders, this review presented p53 as a signalling network rather than a single switch. Upstream, DNA damage, oncogene activation, hypoxia and nucleotide depletion converge on p53 through kinases and the MDM2 and ARF regulators; downstream, p53 activates genes for cell cycle arrest, apoptosis, DNA repair and inhibition of angiogenesis. The authors emphasised the MDM2 negative feedback loop, the effects of viral oncoproteins and the fact that most cancers disable the network at one point or another, whether by mutating p53 itself or by altering its regulators.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/35042675"}],"tags":[],"related":["paper-levine-p53-gatekeeper-cell-1997","paper-hollstein-p53-mutations-science-1991"],"cancers":[],"sections":[],"technologies":[],"targets":["tp53","mdm2"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":["p53-cell-cycle","p53-mdm2-axis"],"terms":["tp53-mutated","tumour-suppressor-gene"],"trials":[],"people":["bert-vogelstein"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2000,"doi":"10.1038/35042675","authors":"Vogelstein B, Lane D, Levine AJ.","paperType":"review","findings":["p53 integrates signals from DNA damage, oncogene activation and hypoxia through MDM2, ARF and stress kinases.","Its outputs include cell cycle arrest, apoptosis, DNA repair and anti-angiogenic genes.","Most cancers disable the network, either by TP53 mutation or by altering upstream regulators such as MDM2 amplification or ARF loss."],"whatItMeans":"This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.","caveats":["A review from 2000; many network components and p53 isoforms were identified later.","Concise by design, so it omits much mechanistic detail."],"changedPractice":false},{"id":"paper-who-2022-lymphoid-alaggio-leukemia-2022","kind":"paper","name":"WHO classification of haematolymphoid tumours, fifth edition: lymphoid neoplasms","aka":[],"tldr":"The 2022 World Health Organization classification of lymphomas and lymphoid leukaemias, the reference for how these diseases are named, defined and separated.","summary":"Summary of the fifth-edition WHO classification of lymphoid neoplasms, reorganising B-cell and T-cell lymphomas, plasma cell neoplasms and lymphoid leukaemias with updated entities, new genetically defined subtypes and revised terminology.","asOf":"2026-09-17","links":[{"label":"Leukemia 2022","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35732829/"}],"tags":[],"related":[],"cancers":["richter-transformation-cll","primary-mediastinal-b-cell-lymphoma","marginal-zone-lymphoma","cutaneous-t-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["leukemia"],"dependsOn":[],"notes":[],"journal":"Leukemia","year":2022,"doi":"10.1038/s41375-022-01620-2","pmid":"35732829","authors":"Alaggio R, Amador C, Anagnostopoulos I, et al.","paperType":"guideline","findings":[],"whatItMeans":"Every lymphoma diagnosis on this site refers to an entity in this classification or the parallel International Consensus Classification.","caveats":["Coexists with the 2022 International Consensus Classification, which differs in some entity names."],"changedPractice":true},{"id":"paper-who-2022-myeloid-khoury-leukemia-2022","kind":"paper","name":"WHO classification of haematolymphoid tumours, fifth edition: myeloid and histiocytic neoplasms","aka":[],"tldr":"The 2022 World Health Organization classification redefines myeloid cancers, including myelodysplastic neoplasms, acute myeloid leukaemia by genetic type, and the boundaries between them.","summary":"Summary of the fifth-edition WHO classification of myeloid and histiocytic neoplasms, renaming myelodysplastic syndromes as myelodysplastic neoplasms, removing the 20 percent blast threshold for AML with defining genetic abnormalities, and reorganising AML, myeloproliferative neoplasms and secondary myeloid neoplasms around genetics.","asOf":"2026-09-17","links":[{"label":"Leukemia 2022","url":"https://doi.org/10.1038/s41375-022-01613-1"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35732831/"}],"tags":[],"related":[],"cancers":["mds-higher-risk","aml-secondary","cml-advanced-phase"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["leukemia"],"dependsOn":[],"notes":[],"journal":"Leukemia","year":2022,"doi":"10.1038/s41375-022-01613-1","pmid":"35732831","authors":"Khoury JD, Solary E, Abla O, et al.","paperType":"guideline","findings":[],"whatItMeans":"The names and definitions on a marrow report (for example MDS with biallelic TP53 inactivation, or AML myelodysplasia-related) come from this document or from the parallel International Consensus Classification.","caveats":["Differs in places from the International Consensus Classification published the same year, which can complicate trial eligibility."],"changedPractice":true},{"id":"paper-who-2022-gu-moch-eur-urol-2022","kind":"paper","name":"WHO classification of tumours of the urinary system and male genital organs, 2022: renal, penile and testicular tumours","aka":[],"tldr":"The 2022 World Health Organization classification of kidney tumours reorganises renal cell carcinoma into morphologically and molecularly defined types, including new molecularly defined entities, and clarifies chromophobe, papillary and clear cell subtypes.","summary":"Summary of the fifth-edition WHO classification for renal, penile and testicular tumours, introducing molecularly defined renal cell carcinomas (TFE3-rearranged, TFEB-altered, ELOC-mutated, fumarate hydratase-deficient, SDH-deficient, ALK-rearranged, SMARCB1-deficient medullary), abolishing type 1 and type 2 papillary subdivision, and refining eosinophilic and oncocytic tumours.","asOf":"2026-09-17","links":[{"label":"Eur Urol 2022","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35853783/"}],"tags":[],"related":[],"cancers":["chromophobe-rcc","papillary-rcc","clear-cell-rcc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["european-urology"],"dependsOn":[],"notes":[],"journal":"European Urology","year":2022,"doi":"10.1016/j.eururo.2022.06.016","pmid":"35853783","authors":"Moch H, Amin MB, Berney DM, et al.","paperType":"guideline","findings":[],"whatItMeans":"Kidney cancer subtype pages use these definitions; several rare entities are now diagnosed by molecular testing rather than appearance alone.","caveats":["Many new entities lack subtype-specific treatment evidence."],"changedPractice":true},{"id":"paper-hayward-melanoma-whole-genome-nature-2017","kind":"paper","name":"Whole-genome landscapes of major melanoma subtypes","aka":[],"tldr":"Whole-genome sequencing of 183 melanomas showed that acral and mucosal melanomas have far fewer mutations than sun-exposed skin melanomas but many more structural rearrangements, confirming they are biologically different diseases.","summary":"Whole-genome sequencing of 183 melanomas including cutaneous, acral and mucosal subtypes, characterising mutation burden, ultraviolet signatures, structural variants, telomerase promoter alterations and driver genes.\n\nCutaneous melanomas carried a high ultraviolet-signature mutation load, whereas acral and mucosal melanomas had low point-mutation burden, frequent structural variants and amplifications (including KIT, CDK4 and CCND1), and different driver patterns.","asOf":"2026-09-17","links":[{"label":"Nature 2017","url":"https://doi.org/10.1038/nature22071"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28467829/"}],"tags":[],"related":[],"cancers":["acral-melanoma","mucosal-melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2017,"doi":"10.1038/nature22071","pmid":"28467829","authors":"Hayward NK, Wilmott JS, Waddell N, et al.","paperType":"translational","findings":["Acral and mucosal melanomas: low mutation burden, high structural variant load.","Frequent amplifications of KIT, CDK4 and CCND1 in non-sun-exposed subtypes."],"whatItMeans":"The lower response of acral and mucosal melanoma to immunotherapy and the interest in KIT and CDK4/6 inhibitors for these subtypes follow from this genomic picture.","caveats":["Relatively small numbers of acral and mucosal tumours."],"changedPractice":true,"participants":183},{"id":"paper-yarden-sliwkowski-erbb-network-nrmcb-2001","kind":"paper","name":"Yarden and Sliwkowski 2001: untangling the ErbB signalling network","aka":[],"tldr":"The classic account of the HER family of receptors, explaining why HER2 is such a powerful cancer driver: it is the preferred partner for the other three receptors and turns their signals up, which is what trastuzumab and later HER2 drugs exploit.","summary":"Yarden and Sliwkowski described the four ErbB receptors (EGFR, HER2, HER3 and HER4) as a layered signalling network in which ligands select receptor pairs, the pairs determine which intracellular pathways are engaged, and the network's outputs control proliferation, survival and differentiation. They emphasised that HER2 has no ligand of its own but is the preferred dimerisation partner, that HER3 lacks kinase activity but couples strongly to PI3K, and that HER2 overexpression or EGFR mutation deregulates the whole network, which explains the activity of antibodies and kinase inhibitors against these receptors.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/35052073"}],"tags":[],"related":["paper-lemmon-schlessinger-rtk-signalling-cell-2010","paper-slamon-her2-amplification-science-1987"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr","her2","her3","erbb4"],"drugs":[],"companies":["roche-genentech"],"institutions":[],"pathways":["rtk-activation"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Reviews Molecular Cell Biology","year":2001,"doi":"10.1038/35052073","authors":"Yarden Y, Sliwkowski MX.","paperType":"review","findings":["The four ErbB receptors form a network of homo- and heterodimers whose composition determines signalling output.","HER2 is ligand-less but the preferred and most potent dimerisation partner; HER3 is kinase-impaired but a strong activator of PI3K.","Deregulation by HER2 amplification or EGFR mutation underlies many cancers and is targetable with antibodies and small molecules."],"whatItMeans":"This review is the conceptual basis for trastuzumab, pertuzumab, HER2 antibody-drug conjugates and EGFR inhibitors, and for the HER3-mediated resistance that later drugs try to overcome.","caveats":["A review; structural details of the receptor dimers were resolved later.","Written before most HER2 and EGFR drugs reached the clinic."],"changedPractice":false},{"id":"paper-zeta-vandetanib-mtc-wells-jco-2012","kind":"paper","name":"ZETA: vandetanib in locally advanced or metastatic medullary thyroid cancer","aka":[],"tldr":"Vandetanib was the first drug shown to delay progression in medullary thyroid cancer, roughly doubling progression-free survival compared with placebo, and became the first approved therapy for the disease.","summary":"Phase 3 placebo-controlled trial of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer randomised 2:1 to vandetanib 300 mg daily or placebo.\n\nMedian progression-free survival was predicted at 30.5 versus 19.3 months (hazard ratio 0.46) with response 45 versus 13 percent (placebo responses reflecting slow disease and crossover); QT prolongation, diarrhoea and rash were the main toxicities.","asOf":"2026-09-17","links":[{"label":"J Clin Oncol 2012","url":"https://doi.org/10.1200/JCO.2011.35.5040"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22025146/"}],"tags":[],"related":[],"cancers":["medullary-thyroid-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["vandetanib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["zeta"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2012,"doi":"10.1200/JCO.2011.35.5040","pmid":"22025146","authors":"Wells SA, Robinson BG, Gagel RF, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.46; predicted median 30.5 vs 19.3 months.","Objective response 45 percent vs 13 percent."],"whatItMeans":"Vandetanib is an approved option for progressive medullary thyroid cancer, used less since selpercatinib for RET-mutant disease.","caveats":["Enrolled patients with indolent disease, some not progressing; QT monitoring required."],"changedPractice":true,"participants":331},{"id":"paper-zuma-1-axi-cel-nejm-2017","kind":"paper","name":"ZUMA-1: axicabtagene ciloleucel for refractory large B-cell lymphoma, the first CAR-T approved for lymphoma","aka":[],"tldr":"In lymphoma refractory to chemotherapy, where expected survival was around six months, a single CAR-T infusion produced responses in 82% of patients and long-term remission in about 40%.","summary":"ZUMA-1 was a multicentre single-arm phase 2 trial of axicabtagene ciloleucel (axi-cel), a CD19 CAR-T with a CD28 costimulatory domain, in 111 enrolled and 101 treated patients with refractory diffuse large B-cell, primary mediastinal or transformed follicular lymphoma. Manufacturing succeeded in 99% and the median time from apheresis to delivery was 17 days. The objective response rate was 82% with complete response in 54%; at a median follow-up of 15.4 months 42% remained in response (40% in complete response), and 18-month overall survival was 52%. Grade 3 or higher cytokine release syndrome occurred in 13% and neurological events in 28%. Five-year follow-up showed overall survival of about 43% with a plateau, consistent with cure in a substantial minority. It supported FDA approval in October 2017.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1707447"},{"label":"ClinicalTrials.gov NCT02348216","url":"https://clinicaltrials.gov/study/NCT02348216"}],"tags":[],"related":["paper-zuma-7-axi-cel-second-line-nejm-2022","paper-juliet-tisagenlecleucel-dlbcl-nejm-2019"],"cancers":["dlbcl","follicular-lymphoma"],"sections":[],"technologies":["car-t"],"targets":["cd19"],"drugs":["axicabtagene-ciloleucel"],"companies":["gilead"],"institutions":["md-anderson","moffitt"],"pathways":[],"terms":["crs","icans","orr"],"trials":["zuma-7"],"people":["frederick-locke"],"bottlenecks":["b-manufacturing-cell-therapy","b-toxicity-qol"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1707447","authors":"Neelapu SS, Locke FL, Bartlett NL, et al.","paperType":"translational","findings":["111 enrolled, 101 treated patients with chemotherapy-refractory large B-cell lymphoma; 22 centres.","Manufacturing success 99%; median 17 days from apheresis to delivery; no bridging chemotherapy allowed.","Objective response 82%; complete response 54%; 42% still responding at 15.4 months median follow-up.","18-month overall survival 52%; 5-year overall survival about 43% with a plateau.","Grade 3 or higher CRS 13%; grade 3 or higher neurological events 28%; 3 deaths during treatment."],"whatItMeans":"ZUMA-1 showed that CAR-T can cure a meaningful fraction of adults whose aggressive lymphoma no longer responds to chemotherapy, a group with a historical median survival of about six months (SCHOLAR-1). Axi-cel became the first CAR-T approved for lymphoma and later the first to beat standard second-line therapy in ZUMA-7. The comparatively high neurotoxicity of CD28-costimulated products was also first characterised here.","caveats":["Single-arm with a historical comparator (SCHOLAR-1).","No bridging therapy was allowed, selecting patients with slower-growing disease.","Roughly 60% of patients eventually relapsed or died; long-term survivors are a minority.","Toxicity required intensive-care-capable centres; real-world use has since expanded with prophylactic steroids."],"changedPractice":true,"participants":101},{"id":"paper-zuma-2-brexu-cel-mantle-cell-nejm-2020","kind":"paper","name":"ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors","aka":[],"tldr":"In mantle cell lymphoma that had stopped responding to BTK inhibitors, a single CAR-T infusion produced responses in 93% of patients and complete remissions in two-thirds.","summary":"ZUMA-2 was a single-arm phase 2 study of KTE-X19 (brexucabtagene autoleucel), a CD19 CAR-T manufactured with removal of circulating tumour cells, in relapsed or refractory mantle cell lymphoma after up to five prior lines including a BTK inhibitor. Of 74 patients enrolled, 68 received the product. In the primary efficacy analysis of the first 60 treated patients the overall response rate was 93% and complete response 67%; estimated 12-month PFS was 61% and OS 83%. Grade 3 or higher CRS occurred in 15% and neurological events in 31%. It led to FDA approval in 2020, the first CAR-T for mantle cell lymphoma.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1914347"},{"label":"ClinicalTrials.gov NCT02601313","url":"https://clinicaltrials.gov/study/NCT02601313"}],"tags":[],"related":["paper-zuma-1-axi-cel-nejm-2017"],"cancers":["mantle-cell-lymphoma"],"sections":[],"technologies":["car-t"],"targets":["cd19","btk"],"drugs":["brexucabtagene-autoleucel","ibrutinib","pirtobrutinib"],"companies":["gilead"],"institutions":["md-anderson"],"pathways":[],"terms":["crs","icans","orr"],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa1914347","authors":"Wang M, Munoz J, Goy A, et al.","paperType":"translational","findings":["74 enrolled, 68 treated; all had prior BTK inhibitor; 60 in primary efficacy analysis.","Overall response 93%; complete response 67%.","Estimated 12-month PFS 61%; 12-month OS 83%.","Grade 3 or higher CRS 15%; grade 3 or higher neurological events 31%.","Responses seen in high-risk features including TP53 mutation and blastoid morphology."],"whatItMeans":"ZUMA-2 gave patients with BTK-inhibitor-refractory mantle cell lymphoma, who previously had a median survival under a year, a therapy with durable remissions in a substantial fraction. Brexu-cel is now standard after BTK inhibitor failure and CAR-T is being tested earlier in the disease. Neurotoxicity rates are higher than in other lymphoma CAR-T trials.","caveats":["Single-arm; no randomised comparison.","High rates of neurological toxicity, and a treatment-related death rate that requires experienced centres.","Later real-world data showed lower complete response rates than the trial.","Long-term durability is limited by late relapses in roughly half of responders."],"changedPractice":true,"participants":68},{"id":"paper-zuma-7-axi-cel-second-line-nejm-2022","kind":"paper","name":"ZUMA-7: axi-cel CAR-T instead of salvage chemotherapy and transplant for large B-cell lymphoma that relapses early","aka":[],"tldr":"For lymphoma that came back within a year, going straight to CAR-T beat the decades-old chemotherapy-then-transplant approach, and later improved survival.","summary":"ZUMA-7 randomised 359 patients with large B-cell lymphoma that was refractory to, or relapsed within 12 months of, first-line chemo-immunotherapy to axicabtagene ciloleucel (axi-cel) or standard second-line salvage chemotherapy followed by high-dose therapy and autologous transplant in responders. The primary endpoint was event-free survival. Median EFS was 8.3 versus 2.0 months (hazard ratio 0.40) and 24-month EFS 41% versus 16%; complete response was 65% versus 32%. Only about a third of standard-arm patients reached transplant, and 56% went on to receive CAR-T off protocol. Despite that crossover, the later analysis (Westin et al., NEJM 2023) showed improved overall survival with axi-cel (4-year OS 54.6% versus 46.0%; hazard ratio 0.73).","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa2116133"},{"label":"Overall survival analysis (Westin 2023)","url":"https://doi.org/10.1056/NEJMoa2301665"},{"label":"ClinicalTrials.gov NCT03391466","url":"https://clinicaltrials.gov/study/NCT03391466"}],"tags":[],"related":["car-t-before-transplant-lbcl","paper-transform-liso-cel-lancet-2022"],"cancers":["dlbcl"],"sections":[],"technologies":["car-t","autologous-stem-cell-transplant"],"targets":["cd19"],"drugs":["axicabtagene-ciloleucel"],"companies":["gilead"],"institutions":["moffitt"],"pathways":[],"terms":["efs","os","crs","icans"],"trials":["zuma-7","transform","belinda"],"people":["frederick-locke"],"bottlenecks":["b-manufacturing-cell-therapy","b-global-access"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2116133","authors":"Locke FL, Miklos DB, Jacobson CA, et al.","paperType":"rct","findings":["359 patients with primary refractory or early-relapsing (within 12 months) LBCL; axi-cel vs salvage chemotherapy plus autologous transplant.","Median EFS 8.3 vs 2.0 months; hazard ratio 0.40; 24-month EFS 41% vs 16%.","Overall response 83% vs 50%; complete response 65% vs 32%.","Only 36% of standard-arm patients proceeded to transplant; 56% later received cellular therapy off protocol.","Overall survival improved (4-year OS 54.6% vs 46.0%; HR 0.73), the first survival gain in this setting in decades.","Grade 3 or higher CRS 6%; grade 3 or higher neurological events 21%; no bridging chemotherapy allowed (steroids only)."],"whatItMeans":"ZUMA-7 rewrote second-line treatment for aggressive lymphoma: patients whose disease returns within a year of R-CHOP should be offered CAR-T rather than salvage chemotherapy and transplant. It is also one of the few cell-therapy trials to show an overall survival benefit despite crossover. Patients relapsing later than 12 months were not studied and transplant remains standard for them if chemosensitive.","caveats":["Applies only to early relapse or primary refractory disease; late relapse was excluded.","No bridging chemotherapy was permitted, so patients with rapidly progressive disease may not have been enrolled.","The parallel BELINDA trial of tisagenlecleucel in the same setting was negative, showing the result depends on product and logistics.","Costs and centre capacity limit uptake outside high-income countries."],"changedPractice":true,"participants":359}]