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Triple-negative breast cancer was named for what it lacks, the three receptors other breast cancers are treated through. This roadmap follows it from the receptor discoveries and the basal-like signature of 2000, through chemotherapy, platinum, PARP inhibitors, immunotherapy and antibody-drug conjugates, to the trials asking who can have less and who needs more, with registry dates to 2030.
For most of its history triple-negative breast cancer was a remainder. Oestrogen receptor testing, then HER2 (Slamon 1987), sorted breast cancers into those with a target; the tumours negative for all three were left with chemotherapy alone. Gene expression profiling gave the remainder a biology (Perou 2000; Sørlie 2001, 2003), linked it to germline BRCA1 (Sørlie 2003; Foulkes 2003; Atchley 2008) and to the founder mutations that concentrate hereditary disease in particular populations (Struewing 1997; Górski 2000), and registry studies of 2006 to 2007 gave it a name, a natural history (relapse peaking at three years, then subsiding) and a demography: younger women, Black and Hispanic women, poorer women, worse survival at every stage. In the United Kingdom the POSH cohort found the same excess in young Black women within a health service with equal access.
Chemotherapy was the whole of treatment until 2017, and it worked: anthracycline and taxane regimens cut breast cancer deaths by a third (EBCTCG 2012), tumours disappeared before surgery twice as often as in other subtypes (Liedtke 2008), and those that disappeared were largely cured (Cortazar 2014). Residual disease was the problem, graded from 2007 by the residual cancer burden score. Platinum raised the response rate (GeparSixto and CALGB 40603, 2014 to 2015) and later relapse-free survival (BrighTNess, GeparSixto follow-up), and capecitabine after residual disease became the first post-neoadjuvant treatment (CREATE-X 2017). Molecular subtyping (Lehmann 2011, 2016; Burstein 2015) showed the disease was several diseases, but pathway-targeted small molecules failed, most recently the AKT inhibitor capivasertib (CAPItello-290, 2026).
Three classes then arrived in six years. PARP inhibitors for germline BRCA carriers (OlympiAD, EMBRACA 2017 to 2018; OlympiA 2021, with a survival benefit sustained at six years). Immunotherapy: atezolizumab first (IMpassion130, 2018, later withdrawn after IMpassion131 and an assay dispute), then pembrolizumab first line for PD-L1 combined positive score of 10 or more (KEYNOTE-355) and before and after surgery for stage II to III disease (KEYNOTE-522, with a 7.9-point overall survival gain at five years reported in 2024). Antibody-drug conjugates: sacituzumab govitecan after two lines (ASCENT 2021), trastuzumab deruxtecan for the third of triple-negative tumours that are HER2-low (DESTINY-Breast04, 2022), then first line for all comers (ASCENT-03, ASCENT-04, TROPION-Breast02, 2025 to 2026), with median survival approaching two years against 13 months in 2008.
The open questions are now about selection and quantity. Who can have less: pembrolizumab omission after pathological complete response (OptimICE-pCR), anthracycline omission (SCARLET), chemotherapy omission in lymphocyte-rich stage I tumours. Who needs more: residual disease trials with antibody-drug conjugates (ASCENT-05, TROPION-Breast03) and the ctDNA-guided designs that c-TRAK TN showed must test earlier and more sensitively. And what the trials have not settled: PD-L1 assay concordance, the order of two topoisomerase-payload antibody-drug conjugates, brain metastases in half of metastatic patients, HER2-low scoring reproducibility, and a disparity in incidence and outcome that trial enrolment has not reflected. UK and NHS specifics are on the UK and NHS page for triple-negative breast cancer.
Oestrogen receptor assays sorted breast cancers into those that would respond to endocrine therapy and those that would not; in 1987 Slamon and colleagues found HER-2/neu amplified in 30 percent of 189 tumours and predictive of early relapse, adding a third test. The tumours negative for all three were a remainder with chemotherapy as their only treatment. The thresholds that define the remainder are conventions: the 2010 ASCO and CAP guideline fixed oestrogen and progesterone receptor positivity at 1 percent of nuclei after finding up to 20 percent of tests worldwide might be wrong, and the 1 to 10 percent low-positive band it created still behaves like triple-negative disease in many series.
Perou and colleagues read 8,102 genes in 65 tumours in 2000 and found breast cancer fell into groups, one of them basal epithelial-like; Sørlie showed in 2001 that the basal-like group had the worst outcome and in 2003 that the subtypes reproduced in other laboratories' data and that tumours from BRCA1 carriers fell into the basal group. Foulkes confirmed the BRCA1 link the same year with a cytokeratin 5/6 stain (odds ratio 9.0). The remainder now had a biology and a hereditary cause; basal-like and triple-negative overlap but are not the same set.
Struewing's 1997 study of 5,318 Ashkenazi Jewish volunteers put the breast cancer risk of the three founder mutations carried by over 2 percent of that population at 56 percent by age 70; Górski found in 2000 that three BRCA1 changes accounted for 82 percent of the mutations in 66 Polish families, one of them (5382insC) shared with the Ashkenazi set. Atchley's 2008 MD Anderson series showed 57 percent of BRCA1 carriers' tumours were triple-negative against 14 percent in non-carriers, which made a triple-negative diagnosis itself a reason to test. Founder panels make population testing cheap where they exist; where they do not, full sequencing is needed and uptake lags.
Dent's Toronto cohort (2007) found triple-negative disease in 11.2 percent of 1,601 patients with a distant relapse hazard ratio of 2.6 that peaked at three years and faded after five; Bauer's California registry study (2007) of 6,370 cases fixed its demography as younger, Black, Hispanic and poorer women with worse survival at every stage. Carey's Carolina Breast Cancer Study (2006) had found the basal-like subtype in 39 percent of premenopausal African American women against 16 percent of others, and Lin (2008) showed 46 percent of metastatic patients developed brain metastases with a median survival of 13.3 months. National counts followed: 12.2 percent of US cases in 2010 (Howlader 2014), odds ratio 2.27 for Black women in 1.15 million cases (Scott 2019). In the UK the POSH cohort of women under 41 found 26.1 percent triple-negative disease in Black women against 18.6 percent in White women and five-year survival of 71.1 versus 82.4 percent despite equal chemotherapy use.
The Oxford overview of 123 trials (EBCTCG 2012) showed taxane-plus-anthracycline regimens cut breast cancer deaths by about a third regardless of receptor status, so chemotherapy's absolute benefit was largest in the high-risk remainder. Liedtke's MD Anderson series (2008) found triple-negative tumours disappeared completely before surgery twice as often as others (22 versus 11 percent) yet survival was worse, because women with residual disease relapsed early. Symmans graded residual disease with the residual cancer burden score in 2007; the CTNeoBC pooled analysis (2014) found pathological complete response predicted survival most strongly in triple-negative disease (event-free survival hazard ratio 0.24) but could not validate it as a trial-level surrogate. The US regulator nonetheless built an accelerated approval pathway on it.
Lehmann's 2011 analysis of 587 tumours defined six subtypes (basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor), each with candidate drugs from cell line work; the 2016 refinement showed two came from immune and stromal cells, cut the scheme to four, and found pathological complete response ranged from 41 percent in basal-like 1 to 18 percent in basal-like 2. Burstein's Baylor study (2015) reached a similar four-way split and showed immune activation within basal-like tumours separated good from poor prognosis. The subtypes shaped trial design (androgen receptor antagonists for the luminal androgen receptor group, platinum for basal-like 1) but no subtype-directed small molecule has succeeded in phase 3.
GeparSixto (2014) and CALGB 40603 (2015) showed carboplatin raised pathological complete response, in CALGB 40603 from 41 to 54 percent in breast and axilla. Survival followed: GeparSixto's final analysis (2018) gave a disease-free survival hazard ratio of 0.56 in triple-negative disease and found 70 percent of tumours homologous recombination deficient whether or not BRCA was mutated, with the deficiency predicting response but not carboplatin benefit; BrighTNess at 4.5 years (2022) gave an event-free survival hazard ratio of 0.57 for carboplatin over paclitaxel alone and nothing for added veliparib. The TNT trial showed carboplatin's advantage in metastatic disease was confined to germline BRCA carriers. St Gallen 2025 made platinum a consensus recommendation for early triple-negative disease.
CREATE-X randomised 910 Japanese and Korean women with HER2-negative residual disease after neoadjuvant chemotherapy to six months of capecitabine or nothing: five-year overall survival 89.2 versus 83.6 percent (hazard ratio 0.59), and in the triple-negative group 78.8 versus 70.3 percent (0.52), with hand-foot syndrome in 73 percent. It was the first proof that the post-neoadjuvant window could be used, the design OlympiA, ASCENT-05 and TROPION-Breast03 inherited, and capecitabine remains the option for residual disease without a BRCA variant in ESMO, NCCN and UK practice. Whether it adds to adjuvant pembrolizumab has never been tested.
OlympiAD (2017) and EMBRACA (2018) showed olaparib and talazoparib beat chemotherapy for progression-free survival in metastatic germline BRCA-mutated breast cancer, without a clear survival gain. OlympiA (2021) gave a year of adjuvant olaparib to 1,836 high-risk carriers, 82 percent with triple-negative disease, and improved invasive disease-free survival; the 2022 analysis showed an overall survival hazard ratio of 0.68 and the 2026 six-year update 0.72 (six-year survival 87.5 versus 83.2 percent) with no excess of leukaemia and fewer new BRCA-related cancers. Neoadjuvant PARP inhibition in unselected disease failed (BrighTNess veliparib arm). The 2020 ASCO, ASTRO and SSO hereditary guideline sets the surgical and systemic rules for carriers; whether olaparib adds to pembrolizumab or capecitabine in the same patient is untested.
IMpassion130 (2018) showed atezolizumab with nab-paclitaxel lengthened progression-free survival in PD-L1-positive metastatic disease by the SP142 assay; IMpassion131 with paclitaxel was negative, the US indication was withdrawn in 2021, and Rugo's assay comparison showed SP142, SP263 and 22C3 called 46, 75 and 73 percent of the same tumours positive with 69 percent concordance. KEYNOTE-355 (2020, survival 2022) established pembrolizumab with chemotherapy for 22C3 combined positive score of 10 or more. KEYNOTE-522 (2020) added pembrolizumab before and after surgery for stage II to III disease: pathological complete response 64.8 versus 51.2 percent, event-free survival gain in 2022, and in 2024 a 7.9-point five-year overall survival gain, the first survival benefit of immunotherapy in early breast cancer. ASCO reversed its 2021 guideline within 15 months; ESMO, NCCN and St Gallen followed. Leon-Ferre (2024) showed lymphocyte-rich stage I tumours do well without any chemotherapy, and OptimICE-pCR now asks whether adjuvant pembrolizumab can be dropped after complete response.
ASCENT (2021) doubled survival with sacituzumab govitecan after two or more lines (12.1 versus 6.7 months); DESTINY-Breast04 (2022) showed trastuzumab deruxtecan worked in HER2-low tumours, which are 36.6 percent of triple-negative disease though biologically indistinguishable from HER2-zero (Schettini 2021). ASCENT-03 and ASCENT-04 (2025 to 2026) and TROPION-Breast02 (2026: progression-free survival 10.8 versus 5.6 months, overall survival 23.7 versus 18.7) moved TROP2 antibody-drug conjugates to first line, alone or with pembrolizumab, and the bispecific EGFR and HER3 conjugate izalontamab brengitecan posted a positive phase 3 in pretreated disease. The same year the AKT inhibitor capivasertib failed to improve survival first line (CAPItello-290), the latest pathway-targeted small molecule to do so. Median survival in first-line trials now approaches two years against 13.3 months in the 2008 Dana-Farber series.
Radovich (2020) showed ctDNA after neoadjuvant chemotherapy in 142 residual-disease patients carried a distant relapse hazard ratio of 2.99 and a death hazard ratio of 4.16. The UK c-TRAK TN trial (2023) then tested acting on it: 27 percent of 161 women turned ctDNA-positive within a year, but 72 percent of those already had metastases on staging and none of five given pembrolizumab cleared their DNA, so later designs test earlier, with tumour-informed assays, and use drugs with more single-agent activity. Meanwhile the residual cancer burden score, validated across 5,161 patients (Yau 2022), became the entry criterion for antibody-drug conjugate trials after neoadjuvant therapy: ASCENT-05 (sacituzumab govitecan with pembrolizumab, 1,514 patients) and TROPION-Breast03 (datopotamab deruxtecan with or without durvalumab, 1,174 patients).
The de-escalation trials are large and slow: OptimICE-pCR (pembrolizumab versus observation after pathological complete response, 1,295 estimated, primary completion May 2033) and SCARLET (anthracycline-free chemo-immunotherapy, 2,400 estimated, March 2033). The escalation trials report sooner: ASCENT-05 (June 2027) and TROPION-Breast03 (September 2027) for residual disease. First-line combinations follow: TROPION-Breast05 (datopotamab deruxtecan with durvalumab against chemotherapy with pembrolizumab in PD-L1-positive disease, 625 estimated, July 2027), IZABRIGHT-Breast01 (izalontamab brengitecan first line in immunotherapy-ineligible disease, 600, March 2028) and the PD-L1 and VEGF bispecific PM8002 with nab-paclitaxel (392, July 2027). KEYNOTE-522 completed on the registry in October 2025; OlympiA's study completion is listed for May 2029.
Four things the trials have not settled. PD-L1 assays disagree on a quarter of patients and only one, 22C3 combined positive score of 10, has an approved drug attached. Two TROP2 antibody-drug conjugates and trastuzumab deruxtecan share a topoisomerase I payload and no randomised trial has asked which to give first or whether the second works after the first. Brain metastases occur in about half of metastatic patients (Lin 2008) and most trials exclude active brain disease. And the disease is twice as common in Black women in the United States, with worse survival in the UK POSH cohort despite equal access, yet trial enrolment does not reflect it. Each has an idea on this page; the UK-specific gaps are set out on the UK and NHS page for triple-negative breast cancer.
Readouts, decisions and registry completion dates ahead. Each date is quoted from its source, not inferred; a missing date means no source states one.
Oestrogen receptor assays sorted breast cancers into those that would respond to endocrine therapy and those that would not; in 1987 Slamon and colleagues found HER-2/neu amplified in 30 percent of 189 tumours and predictive of early relapse, adding a third test. The tumours negative for all three were a remainder with chemotherapy as their only treatment. The thresholds that define the remainder are conventions: the 2010 ASCO and CAP guideline fixed oestrogen and progesterone receptor positivity at 1 percent of nuclei after finding up to 20 percent of tests worldwide might be wrong, and the 1 to 10 percent low-positive band it created still behaves like triple-negative disease in many series.
The 1987 discovery that about a third of breast cancers carry extra copies of the HER2 gene and that these patients relapse sooner and die earlier; it gave breast cancer its third receptor and, by exclusion, the definition of triple-negative disease.
The 2010 rule that fixed the line between hormone receptor-positive and negative breast cancer at 1 percent of stained tumour nuclei, after finding that up to a fifth of receptor tests worldwide might be wrong; it is the threshold that defines triple-negative disease.
A growth-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers.
Staining a tissue slice with antibodies so a protein shows up in colour under the microscope.
A breast cancer that lacks the three receptors (oestrogen, progesterone, HER2) that other breast cancers can be treated through. It was the hardest subtype for decades; since 2020 immunotherapy and ADCs have changed that.
Perou and colleagues read 8,102 genes in 65 tumours in 2000 and found breast cancer fell into groups, one of them basal epithelial-like; Sørlie showed in 2001 that the basal-like group had the worst outcome and in 2003 that the subtypes reproduced in other laboratories' data and that tumours from BRCA1 carriers fell into the basal group. Foulkes confirmed the BRCA1 link the same year with a cytokeratin 5/6 stain (odds ratio 9.0). The remainder now had a biology and a hereditary cause; basal-like and triple-negative overlap but are not the same set.
The 2000 study that read the activity of 8,102 genes in 65 breast tumours and found the tumours fell into distinct groups, one of them the basal-like group that most triple-negative cancers belong to.
The 2001 follow-up showing that the gene-expression groups of breast cancer predict how patients fare, with the basal-like group doing worst; it made the subtypes clinical rather than descriptive.
The 2003 paper that found the same breast cancer subtypes in other laboratories' data and showed that tumours from women with an inherited BRCA1 fault fall into the basal-like group, linking hereditary and triple-negative disease.
A 2003 study using an ordinary pathology stain, cytokeratin 5/6, to show that breast cancers in women with an inherited BRCA1 fault are nine times more likely to have the basal pattern; it brought the basal-like idea from the microarray to the pathology bench.
Defined the molecular subtypes of breast cancer (luminal, HER2-enriched, basal-like) that clinicians now use every day.
A 50-gene test that sorts breast cancers into luminal A, luminal B, HER2-enriched, and basal-like.
Measuring which genes a tumour is actively using, which reveals its subtype and finds gene fusions.
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
Struewing's 1997 study of 5,318 Ashkenazi Jewish volunteers put the breast cancer risk of the three founder mutations carried by over 2 percent of that population at 56 percent by age 70; Górski found in 2000 that three BRCA1 changes accounted for 82 percent of the mutations in 66 Polish families, one of them (5382insC) shared with the Ashkenazi set. Atchley's 2008 MD Anderson series showed 57 percent of BRCA1 carriers' tumours were triple-negative against 14 percent in non-carriers, which made a triple-negative diagnosis itself a reason to test. Founder panels make population testing cheap where they exist; where they do not, full sequencing is needed and uptake lags.
The 1997 study of 5,318 Ashkenazi Jewish volunteers that measured the real-world breast cancer risk of the three founder mutations carried by more than 2 percent of that population: 56 percent by age 70, lower than the 85 percent estimated from high-risk families.
A 2000 study of 66 Polish families with breast and ovarian cancer in which three BRCA1 mutations accounted for more than four in five of the faults found, showing that a short national test panel could replace full gene sequencing in Poland.
A 2008 MD Anderson series showing that 57 percent of breast cancers in BRCA1 carriers were triple-negative against 14 percent in women without a BRCA fault, the clinical number behind the rule that triple-negative diagnosis should prompt a genetic test.
The 2020 joint US guideline for breast cancer in people who carry an inherited fault in BRCA1, BRCA2 or another risk gene: breast-conserving surgery is allowed, bilateral mastectomy should be discussed, platinum beats taxanes in advanced disease and PARP inhibitors beat single-agent chemotherapy.
A test of the DNA you were born with, to find inherited risk genes such as BRCA or Lynch syndrome.
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
In 1990 she showed that a single gene on chromosome 17, BRCA1, causes inherited breast and ovarian cancer, when most of the field doubted such a gene existed. Genetic testing and risk-reducing care followed.
Most people who carry a high-risk cancer gene do not know it until they or a relative gets cancer.
Every triple-negative patient under 60 in the UK should be offered a BRCA test at diagnosis because the result now changes treatment, and many should be offered a trial, but no one publishes how many are. A national audit through existing cancer registration and genomic laboratory data would show the gap by region before anyone tries to close it.
Dent's Toronto cohort (2007) found triple-negative disease in 11.2 percent of 1,601 patients with a distant relapse hazard ratio of 2.6 that peaked at three years and faded after five; Bauer's California registry study (2007) of 6,370 cases fixed its demography as younger, Black, Hispanic and poorer women with worse survival at every stage. Carey's Carolina Breast Cancer Study (2006) had found the basal-like subtype in 39 percent of premenopausal African American women against 16 percent of others, and Lin (2008) showed 46 percent of metastatic patients developed brain metastases with a median survival of 13.3 months. National counts followed: 12.2 percent of US cases in 2010 (Howlader 2014), odds ratio 2.27 for Black women in 1.15 million cases (Scott 2019). In the UK the POSH cohort of women under 41 found 26.1 percent triple-negative disease in Black women against 18.6 percent in White women and five-year survival of 71.1 versus 82.4 percent despite equal chemotherapy use.
The 2007 Toronto study that gave triple-negative breast cancer its clinical portrait: 11 percent of cases, a risk of distant relapse 2.6 times higher than other breast cancers, a peak at three years and then a fall, so that women who reach five years without relapse are largely safe.
The 2007 population study of 6,370 Californian women that fixed the demographics of triple-negative breast cancer: younger, more often Black or Hispanic, poorer, diagnosed later and with worse survival at every stage; Black women with late-stage disease had 14 percent five-year survival.
The 2006 North Carolina study that found the basal-like subtype in 39 percent of breast cancers in premenopausal African American women against 16 percent in other women, offering a biological reason for the worse survival of young Black women with breast cancer.
A 2008 Dana-Farber series of 116 women with metastatic triple-negative breast cancer in which 46 percent developed brain metastases before death, median survival after spread was 13.3 months and after a brain diagnosis 4.9 months.
The first US national count of breast cancer by receptor subtype, from 2010 when cancer registries began recording HER2: 12.2 percent of cases were triple-negative, and Black women had the highest rate of that subtype.
A count of 1.15 million US breast cancers from 2010 to 2014 in which Black women had 2.27 times the odds of a triple-negative diagnosis and women under 40 nearly twice the odds, confirming the disparity at national scale.
The UK cohort of 2,915 women diagnosed with breast cancer at 40 or younger in which Black women had more triple-negative tumours (26 versus 19 percent) and worse survival despite the same access to care and the same use of chemotherapy.
Breast medical oncologist and Deputy CEO for clinical operations at the National Cancer Centre Singapore, an international leader in triple-negative breast cancer trials.
Nancy Lin is the leading authority on brain metastases from breast cancer, including the HER2CLIMB tucatinib data in patients with active brain disease.
Tumour deposits that have travelled to the brain from a cancer elsewhere, ten times more common than cancers that start in the brain, mostly from lung, breast, melanoma and kidney cancer. Because the blood-brain barrier excludes most drugs, whether a medicine reaches and shrinks them now decides which drug is chosen, and trials report intracranial progression separately.
Older, Black, Hispanic, Asian, rural, poor and multimorbid patients are under-represented, so results may not apply to them.
Black women in the United States have about twice the odds of a triple-negative diagnosis and, in the UK POSH cohort, worse survival than White women despite equal chemotherapy use. The pivotal trials enrolled few of them. Enrolment targets tied to incidence, reported by ethnicity in every primary paper, would make the evidence match the disease.
Nearly half of women with metastatic triple-negative breast cancer develop brain metastases and survive under five months after the diagnosis, yet the trials that set the standard mostly exclude active brain disease. Requiring a brain metastasis cohort in every phase 3, with intracranial response as an endpoint, would answer whether the new drugs reach the brain.
The Oxford overview of 123 trials (EBCTCG 2012) showed taxane-plus-anthracycline regimens cut breast cancer deaths by about a third regardless of receptor status, so chemotherapy's absolute benefit was largest in the high-risk remainder. Liedtke's MD Anderson series (2008) found triple-negative tumours disappeared completely before surgery twice as often as others (22 versus 11 percent) yet survival was worse, because women with residual disease relapsed early. Symmans graded residual disease with the residual cancer burden score in 2007; the CTNeoBC pooled analysis (2014) found pathological complete response predicted survival most strongly in triple-negative disease (event-free survival hazard ratio 0.24) but could not validate it as a trial-level surrogate. The US regulator nonetheless built an accelerated approval pathway on it.
The Oxford overview of 123 trials and 100,000 women showing that anthracycline and taxane chemotherapy cuts breast cancer deaths by about a third, largely regardless of age, nodes, size, grade or hormone receptor status; it is the foundation triple-negative chemotherapy rests on.
The 2008 MD Anderson series of 1,118 women that defined the triple-negative paradox: these tumours disappear completely with pre-surgery chemotherapy twice as often as other breast cancers, yet survival is worse, because the women left with residual disease relapse early and often.
Paper cited by one term page, indexed on Europe PMC as PubMed record 17785706 and published in Journal of Clinical Oncology; the citing page links this DOI, which is how the record was matched.
The 2017 validation of the residual cancer burden score, which graded how much triple-negative tumour is left after pre-surgery chemotherapy and found ten-year relapse-free survival of 86 percent with no residual tumour, 81 percent with minimal, 55 percent with moderate and 23 percent with extensive residual disease.
A pooled analysis of 5,161 patients from 12 European and US institutions and trials confirming that the residual cancer burden score predicts relapse in every breast cancer subtype, and proposing it become part of standard pathology reporting after pre-surgery chemotherapy.
The US regulator's pooled analysis of 11,955 patients in 12 trials that found complete disappearance of the tumour before surgery predicts survival most strongly in triple-negative disease, but that a trial raising the complete response rate does not reliably improve survival.
The US oncology society's 2021 rules for treatment before surgery: triple-negative tumours of 1 cm or more, or with involved nodes, should get anthracycline and taxane chemotherapy, carboplatin may be added, and at that date the evidence for adding immunotherapy was judged insufficient.
A family of red chemotherapy drugs derived from a soil bacterium that damage cancer DNA. Cornerstones of breast cancer, lymphoma, leukaemia and sarcoma treatment, but they weaken the heart in a dose-dependent way, so there is a lifetime limit.
Chemotherapy drugs originally from the yew tree that freeze the cell's internal scaffolding (microtubules) so it cannot divide. Used in breast, lung, ovarian, prostate, gastric and head and neck cancers; their main lasting side effect is nerve damage in the hands and feet.
No invasive cancer left in the breast and lymph nodes when the surgeon removes the tissue after pre-surgery treatment.
A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials.
Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind.
Drugs that kill fast-dividing cells. Still the backbone of many cures, and now the warhead inside smarter drugs.
Lehmann's 2011 analysis of 587 tumours defined six subtypes (basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor), each with candidate drugs from cell line work; the 2016 refinement showed two came from immune and stromal cells, cut the scheme to four, and found pathological complete response ranged from 41 percent in basal-like 1 to 18 percent in basal-like 2. Burstein's Baylor study (2015) reached a similar four-way split and showed immune activation within basal-like tumours separated good from poor prognosis. The subtypes shaped trial design (androgen receptor antagonists for the luminal androgen receptor group, platinum for basal-like 1) but no subtype-directed small molecule has succeeded in phase 3.
The 2011 Vanderbilt analysis of 587 triple-negative tumours that split the disease into six molecular groups, two basal-like, an immune group, two mesenchymal groups and a luminal androgen receptor group, and matched each to cell lines and candidate drugs.
The 2016 revision that cut the six triple-negative subtypes to four after showing the immune and stem-like signals came from surrounding cells, and found that response to standard chemotherapy before surgery ranged from 41 percent in basal-like 1 to 18 percent in basal-like 2.
A 2015 Baylor study of 198 triple-negative tumours that found four stable subtypes, luminal androgen receptor, mesenchymal, basal-like immune-suppressed and basal-like immune-activated, with the immune-activated group faring best and the immune-suppressed worst.
The hormone switch that drives prostate cancer, attacked by castration and by pills that block the receptor.
How a cancer cell changes shape to migrate and to shrug off drugs. Transcription factors like ZEB1 and SNAIL loosen the cell, switch on pumps that eject chemotherapy, and hide it from the immune system.
The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
Every tumour is a population of genetically distinct clones: in multi-region sequencing of kidney tumours, roughly two thirds of mutations were missing from at least one region. Treatment kills the dominant clones and leaves resistant minor clones to grow back, yet a single diagnostic biopsy is still treated as the whole disease.
GeparSixto (2014) and CALGB 40603 (2015) showed carboplatin raised pathological complete response, in CALGB 40603 from 41 to 54 percent in breast and axilla. Survival followed: GeparSixto's final analysis (2018) gave a disease-free survival hazard ratio of 0.56 in triple-negative disease and found 70 percent of tumours homologous recombination deficient whether or not BRCA was mutated, with the deficiency predicting response but not carboplatin benefit; BrighTNess at 4.5 years (2022) gave an event-free survival hazard ratio of 0.57 for carboplatin over paclitaxel alone and nothing for added veliparib. The TNT trial showed carboplatin's advantage in metastatic disease was confined to germline BRCA carriers. St Gallen 2025 made platinum a consensus recommendation for early triple-negative disease.
GeparSixto showed that adding carboplatin to chemotherapy given before surgery made triple-negative breast tumours disappear completely far more often, and in longer follow-up cut relapses, which put platinum into the standard neoadjuvant regimen for this type.
Published report from the GeparSixto trial registered as NCT01426880, in The Lancet Oncology (2014), chosen as the most cited paper whose own text cites the registry id.
The final GeparSixto report: adding carboplatin before surgery cut relapse in triple-negative disease by 44 percent, and a DNA-repair deficiency score predicted which tumours would disappear, though it did not predict who gained from the platinum.
The US trial of 443 women that showed adding carboplatin to pre-surgery paclitaxel, doxorubicin and cyclophosphamide raised complete tumour disappearance in breast and nodes from 41 to 54 percent, at the cost of more low blood counts and skipped doses; it and GeparSixto made platinum standard.
BrighTNess showed that adding the platinum drug carboplatin to standard chemotherapy before surgery makes triple-negative breast tumours vanish completely more often, and later that fewer people relapsed, while the PARP inhibitor veliparib added on top made no difference.
Published report from the BrighTNess trial registered as NCT02032277, in The Lancet Oncology (2018), chosen as the most cited paper whose own text cites the registry id.
The 4.5-year follow-up of BrighTNess showing that adding carboplatin to pre-surgery chemotherapy in 634 women cut relapse or death by about 40 percent without more second cancers, while adding the PARP inhibitor veliparib added nothing.
Paper cited by one pairing page, indexed on Europe PMC as PubMed record 29713086 and published in Nature Medicine; the citing page links this DOI, which is how the record was matched.
The 2025 international consensus on early breast cancer, which recommends platinum chemotherapy and immunotherapy for triple-negative disease, updated genetic testing guidance and shorter radiotherapy schedules.
Carboplatin is a platinum chemotherapy that crosslinks DNA; it is part of the standard pre-surgery regimen for triple-negative breast cancer.
Platinum agents such as cisplatin and carboplatin work by crosslinking DNA. They are curative in testicular cancer and central to lung, ovarian, bladder, head and neck, and TNBC treatment.
A tumour that cannot properly repair double-strand DNA breaks, usually because of BRCA or related gene loss.
DNA-crosslinking chemotherapy is especially effective in tumours that cannot repair double-strand breaks.
Leads the German Breast Group, whose GeparX trials defined neoadjuvant chemotherapy and immunotherapy in breast cancer.
The German academic group whose GeparX trials established carboplatin and neoadjuvant strategies in triple-negative breast cancer.
CREATE-X randomised 910 Japanese and Korean women with HER2-negative residual disease after neoadjuvant chemotherapy to six months of capecitabine or nothing: five-year overall survival 89.2 versus 83.6 percent (hazard ratio 0.59), and in the triple-negative group 78.8 versus 70.3 percent (0.52), with hand-foot syndrome in 73 percent. It was the first proof that the post-neoadjuvant window could be used, the design OlympiA, ASCENT-05 and TROPION-Breast03 inherited, and capecitabine remains the option for residual disease without a BRCA variant in ESMO, NCCN and UK practice. Whether it adds to adjuvant pembrolizumab has never been tested.
The Japanese and Korean trial of 910 women whose tumours had survived pre-surgery chemotherapy, in which six months of capecitabine tablets cut deaths by 41 percent, and by 48 percent in the triple-negative group; the first treatment ever shown to help after residual disease.
Capecitabine (Xeloda) is a tablet form of the chemotherapy fluorouracil. It is a backbone of treatment for bowel cancer and a standard option in advanced breast cancer.
A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials.
Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind.
The European oncology society's 2024 guideline for breast cancer that has not spread, covering diagnosis, surgery, radiotherapy, drug treatment before and after surgery, and follow-up; the reference standard for European and UK care of early triple-negative disease.
After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run.
OlympiAD (2017) and EMBRACA (2018) showed olaparib and talazoparib beat chemotherapy for progression-free survival in metastatic germline BRCA-mutated breast cancer, without a clear survival gain. OlympiA (2021) gave a year of adjuvant olaparib to 1,836 high-risk carriers, 82 percent with triple-negative disease, and improved invasive disease-free survival; the 2022 analysis showed an overall survival hazard ratio of 0.68 and the 2026 six-year update 0.72 (six-year survival 87.5 versus 83.2 percent) with no excess of leukaemia and fewer new BRCA-related cancers. Neoadjuvant PARP inhibition in unselected disease failed (BrighTNess veliparib arm). The 2020 ASCO, ASTRO and SSO hereditary guideline sets the surgical and systemic rules for carriers; whether olaparib adds to pembrolizumab or capecitabine in the same patient is untested.
OlympiAD was the first trial to show a PARP inhibitor tablet beats chemotherapy in breast cancer, delaying progression by about three months in women with an inherited BRCA mutation and with fewer side effects, though it did not lengthen life overall.
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.
EMBRACA showed that the PARP inhibitor talazoparib delays progression by about three months compared with chemotherapy in women with an inherited BRCA mutation and advanced breast cancer, with better quality of life but no gain in overall survival.
Published report from the EMBRACA trial registered as NCT01945775, in New England Journal of Medicine (2018), chosen as the most cited paper whose own text cites the registry id.
Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations.
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.
The second planned analysis of OlympiA, at 3.5 years, in which a year of olaparib tablets after standard treatment cut deaths by 32 percent in women with an inherited BRCA fault, the first time a PARP inhibitor had lengthened life in early breast cancer.
The six-year OlympiA update: the year of olaparib still cut relapse by 35 percent and death by 28 percent, six-year survival was 87.5 versus 83.2 percent, there were fewer new BRCA-related breast and ovarian cancers, and no excess of leukaemia.
The 2020 joint US guideline for breast cancer in people who carry an inherited fault in BRCA1, BRCA2 or another risk gene: breast-conserving surgery is allowed, bilateral mastectomy should be discussed, platinum beats taxanes in advanced disease and PARP inhibitors beat single-agent chemotherapy.
Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer.
Talazoparib is a PARP inhibitor that traps PARP on DNA about 100 times more strongly than olaparib, which is why it works at a 1 mg daily dose. It is approved for germline BRCA-mutant HER2-negative breast cancer and, with enzalutamide, for HRR-mutant castration-resistant prostate cancer; anaemia is its dominant side effect.
Pills that block a DNA repair backup, killing cancer cells that already lost their main repair system (BRCA).
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
A test of the DNA you were born with, to find inherited risk genes such as BRCA or Lynch syndrome.
A blood test for inherited BRCA mutations unlocks a year of olaparib after surgery, which improves survival.
A leading authority on inherited cancer risk and how BRCA carriers should be treated and screened.
Led OlympiA, the trial that showed a year of olaparib after surgery improves survival in BRCA-mutated breast cancer.
New York breast oncologist and cancer geneticist who led OlympiAD, the trial that made olaparib the first PARP inhibitor approved for BRCA-mutated breast cancer.
Jennifer Litton led the EMBRACA trial that brought talazoparib to BRCA-mutated breast cancer.
AstraZeneca is the most ADC-committed large pharma, co-owner of Enhertu and Datroway, with deep targeted-therapy and radiopharma bets.
Bought Seagen for $43B to become an ADC leader; also makes Ibrance, Lorbrena, Braftovi, and the first PROTAC.
IMpassion130 (2018) showed atezolizumab with nab-paclitaxel lengthened progression-free survival in PD-L1-positive metastatic disease by the SP142 assay; IMpassion131 with paclitaxel was negative, the US indication was withdrawn in 2021, and Rugo's assay comparison showed SP142, SP263 and 22C3 called 46, 75 and 73 percent of the same tumours positive with 69 percent concordance. KEYNOTE-355 (2020, survival 2022) established pembrolizumab with chemotherapy for 22C3 combined positive score of 10 or more. KEYNOTE-522 (2020) added pembrolizumab before and after surgery for stage II to III disease: pathological complete response 64.8 versus 51.2 percent, event-free survival gain in 2022, and in 2024 a 7.9-point five-year overall survival gain, the first survival benefit of immunotherapy in early breast cancer. ASCO reversed its 2021 guideline within 15 months; ESMO, NCCN and St Gallen followed. Leon-Ferre (2024) showed lymphocyte-rich stage I tumours do well without any chemotherapy, and OptimICE-pCR now asks whether adjuvant pembrolizumab can be dropped after complete response.
IMpassion130 was the first immunotherapy success in breast cancer, later undermined when a sister trial failed and the approval was withdrawn.
Published report from the IMpassion130 trial registered as NCT02425891, in New England Journal of Medicine (2018), chosen as the most cited paper whose own text cites the registry id.
IMpassion131 was the sister trial to the first immunotherapy success in breast cancer. It failed, and the approval it was meant to confirm was withdrawn.
Published report from the IMpassion131 trial registered as NCT03125902, in Annals of Oncology (2021), chosen as the most cited paper whose own text cites the registry id.
Three different PD-L1 tests run on the same 614 IMpassion130 tumours called 46, 75 and 73 percent of them positive and agreed with each other only about 69 percent of the time; the benefit of atezolizumab was concentrated in the tumours all three called positive.
Established immunotherapy plus chemotherapy as first-line treatment for metastatic triple-negative breast cancer with PD-L1 expression.
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.
The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival.
Published report from the KEYNOTE-522 trial registered as NCT03036488, in New England Journal of Medicine (2020), chosen as the most cited paper whose own text cites the registry id.
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.
Later report from the KEYNOTE-522 trial registered as NCT03036488, in New England Journal of Medicine (2024); its title describes an updated or longer-term analysis.
The 2022 fast-track amendment in which the US oncology society added pembrolizumab before and after surgery for high-risk early triple-negative breast cancer, a year after its main guideline had said the evidence was insufficient.
A pooled study of 1,966 women with early triple-negative breast cancer treated with surgery and radiotherapy but no chemotherapy, in which those whose tumours were half or more immune cells had 94 percent five-year freedom from distant relapse in stage I disease against 78 percent for immune-poor tumours.
Asks whether patients whose cancer completely disappeared before surgery still need a year of immunotherapy afterwards.
Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines.
A PD-L1 blocker used in lung, liver, and bladder cancer. In 2026 it became the first drug approved based on a blood test showing leftover cancer after bladder surgery.
Immune checkpoint inhibitors are antibodies against CTLA-4, PD-1 or PD-L1 that release the brakes on T cells so they attack the cancer. They are approved in more than 20 tumour types and produce lasting, sometimes curative responses that chemotherapy rarely does, but most patients do not respond and autoimmune side effects are the cost.
A PD-L1 score that counts stained tumour cells and immune cells together.
Immune cells that have got inside the tumour. More of them means better outcomes in triple-negative breast cancer.
PD-L1 is the tumour's side of the PD-1 brake, and also the biomarker that decides who gets immunotherapy.
Led KEYNOTE-522 and IMpassion130, the trials that brought immunotherapy into triple-negative breast cancer.
Breast oncologist who led DESTINY-Breast03 and DESTINY-Breast09, the trials that made Enhertu the HER2-positive standard.
Breast oncologist who led key ADC and CDK4/6 trials and moved from UCSF to City of Hope in 2024.
Merck & Co. (MSD) makes Keytruda, the world's best-selling cancer drug, and is now building the next act around TROP2 ADCs and personalised vaccines.
Creator of Herceptin, Avastin, and Rituxan, and owner of Foundation Medicine; the company that defined antibody oncology.
Immunotherapy helps the patient's own immune system recognise and destroy the cancer.
Three PD-L1 tests run on the same tumours called 46, 75 and 73 percent of them positive and agreed only 69 percent of the time. With atezolizumab withdrawn, pembrolizumab's test (22C3, combined positive score of 10) is the only one that matters, yet laboratories still run whichever kit they have. One assay, one score and a proficiency scheme would end answers that vary by postcode.
Two thirds of women treated on the KEYNOTE-522 regimen have no tumour left at surgery and about 92 percent of them are alive without relapse at five years, yet all receive nine more cycles of pembrolizumab. Trials are now testing whether the best responders can stop early, skip the anthracycline, or in lymphocyte-rich stage I tumours skip chemotherapy altogether.
ASCENT (2021) doubled survival with sacituzumab govitecan after two or more lines (12.1 versus 6.7 months); DESTINY-Breast04 (2022) showed trastuzumab deruxtecan worked in HER2-low tumours, which are 36.6 percent of triple-negative disease though biologically indistinguishable from HER2-zero (Schettini 2021). ASCENT-03 and ASCENT-04 (2025 to 2026) and TROPION-Breast02 (2026: progression-free survival 10.8 versus 5.6 months, overall survival 23.7 versus 18.7) moved TROP2 antibody-drug conjugates to first line, alone or with pembrolizumab, and the bispecific EGFR and HER3 conjugate izalontamab brengitecan posted a positive phase 3 in pretreated disease. The same year the AKT inhibitor capivasertib failed to improve survival first line (CAPItello-290), the latest pathway-targeted small molecule to do so. Median survival in first-line trials now approaches two years against 13.3 months in the 2008 Dana-Farber series.
The trial that proved a TROP2 ADC could nearly double survival in heavily pretreated triple-negative breast cancer.
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.
Created a new category of breast cancer, HER2-low, by showing Enhertu works in tumours previously called HER2-negative.
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.
A 3,689-patient study showing that 36.6 percent of triple-negative tumours are HER2-low, that in triple-negative disease HER2-low tumours are biologically no different from HER2-zero ones, and that pathologists agree poorly on the score; the label matters only because a drug now depends on it.
Moved Trodelvy into first-line use for triple-negative patients who cannot receive immunotherapy.
Published report from the ASCENT-03 trial registered as NCT05382299, in New England Journal of Medicine (2025), chosen as the most cited paper whose own text cites the registry id.
Showed that pairing an ADC with immunotherapy beats chemotherapy plus immunotherapy in first-line PD-L1-positive TNBC.
Published report from the ASCENT-04 trial registered as NCT05382286, in New England Journal of Medicine (2026), chosen as the most cited paper whose own text cites the registry id.
The first trial to show an overall survival benefit for a first-line ADC in triple-negative breast cancer.
The trial of 644 women with newly metastatic triple-negative breast cancer who could not have immunotherapy, in which the antibody-drug conjugate datopotamab deruxtecan held the cancer still for 10.8 months against 5.6 with chemotherapy and lengthened life from 18.7 to 23.7 months.
The first phase 3 win for a bispecific ADC, in triple-negative breast cancer, announced February 2026.
A phase 3 trial of Capivasertib in triple-negative breast cancer, run by AstraZeneca, active and no longer recruiting.
The 812-patient trial in which adding the AKT inhibitor capivasertib to first-line paclitaxel did not lengthen life in metastatic triple-negative breast cancer (17.7 versus 18.0 months), even in the 31 percent of patients whose tumours carried the pathway alterations it targets.
The first TROP2-targeted ADC. It delivers a strong chemotherapy directly to breast and bladder cancer cells and is now a first-line option in triple-negative breast cancer.
Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy.
Trastuzumab deruxtecan (Enhertu) is the most successful ADC ever. It redefined HER2 by working in tumours with only tiny amounts of the protein, and in 2026 moved into early-stage breast cancer.
Izalontamab brengitecan is the first bispecific ADC to succeed in a phase 3 trial, hitting two growth receptors at once in triple-negative breast cancer.
Capivasertib (Truqap) is the first AKT inhibitor, for breast cancer with PI3K-pathway mutations and, since 2026, for prostate cancer with PTEN loss.
TROP2 is a surface glycoprotein present at high levels on most epithelial cancers (breast, lung, urothelial, gastric, pancreatic) and at low levels on normal tissue. It does not drive the cancer; it is a delivery address, used by the approved ADCs sacituzumab govitecan and datopotamab deruxtecan and by sacituzumab tirumotecan, with a TROP2 PET tracer in development to pick patients.
Tumours with a little HER2 (IHC 1+ or 2+ without amplification), or a trace (ultralow), which older HER2 drugs ignored but Enhertu can attack.
An antibody-drug conjugate is an antibody that homes to a protein on the tumour cell, is swallowed, and releases a chemotherapy payload inside it. That widens chemotherapy's safe dose window about a hundredfold, which is why payloads too toxic to give alone can be used, though lung inflammation, neutropenia and eye toxicity from the payload still occur.
A bispecific ADC is an ADC whose antibody grabs two different proteins on the cancer cell, so it sticks better to tumour and less to healthy tissue.
One target, three approved-or-nearly-approved drugs, and a fourth wave. How TROP2 went from an obscure trophoblast antigen to the centre of breast and lung cancer treatment.
Twenty-five years of trying to make chemotherapy hit only cancer cells, from the unstable first ADC to today's third-generation blockbusters and the fourth generation now in trials.
Breast medical oncologist and Deputy CEO for clinical operations at the National Cancer Centre Singapore, an international leader in triple-negative breast cancer trials.
Led ASCENT, the trial that made sacituzumab govitecan the first ADC for triple-negative breast cancer, and the EMERALD trial of elacestrant.
Leads Dana-Farber's breast oncology division and many of the trials that moved ADCs and de-escalated therapy into breast cancer care.
Gilead owns Trodelvy (via the $21B Immunomedics deal) and the Kite CAR-T franchise.
AstraZeneca is the most ADC-committed large pharma, co-owner of Enhertu and Datroway, with deep targeted-therapy and radiopharma bets.
Daiichi Sankyo is the Japanese company whose DXd payload technology created the best ADC platform in the industry.
An antibody that finds the tumour, carrying a tiny dose of very strong chemotherapy that is released only inside it.
Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life.
About a third of triple-negative tumours are HER2-low and so eligible for trastuzumab deruxtecan, but the difference between a HER2 score of 0 and 1+ is the one pathologists agree on least, and most triple-negative tumours were scored before the label mattered. Re-scoring archived slides with digital help when a patient relapses would find the eligible third.
Radovich (2020) showed ctDNA after neoadjuvant chemotherapy in 142 residual-disease patients carried a distant relapse hazard ratio of 2.99 and a death hazard ratio of 4.16. The UK c-TRAK TN trial (2023) then tested acting on it: 27 percent of 161 women turned ctDNA-positive within a year, but 72 percent of those already had metastases on staging and none of five given pembrolizumab cleared their DNA, so later designs test earlier, with tumour-informed assays, and use drugs with more single-agent activity. Meanwhile the residual cancer burden score, validated across 5,161 patients (Yau 2022), became the entry criterion for antibody-drug conjugate trials after neoadjuvant therapy: ASCENT-05 (sacituzumab govitecan with pembrolizumab, 1,514 patients) and TROPION-Breast03 (datopotamab deruxtecan with or without durvalumab, 1,174 patients).
In 196 women with triple-negative breast cancer left with residual tumour after pre-surgery chemotherapy, finding tumour DNA in the blood after surgery tripled the risk of distant relapse and quadrupled the risk of death; at two years 56 percent versus 81 percent were free of distant disease.
The UK trial that watched 161 women with early triple-negative breast cancer by three-monthly blood tests for tumour DNA: 27 percent tested positive within a year, but by then nearly three quarters already had visible metastases, and none of the five who started pembrolizumab cleared the DNA. The lesson was to test earlier and more sensitively.
A pooled analysis of 5,161 patients from 12 European and US institutions and trials confirming that the residual cancer burden score predicts relapse in every breast cancer subtype, and proposing it become part of standard pathology reporting after pre-surgery chemotherapy.
Tests whether giving a TROP2 ADC after surgery can cure more of the triple-negative patients whose cancer survived pre-surgery chemo-immunotherapy.
TROPION-Breast03 is the Dato-DXd counterpart to ASCENT-05: an ADC, with or without immunotherapy, for triple-negative patients with leftover cancer at surgery.
Circulating tumour DNA (ctDNA) consists of fragments of DNA shed by tumour cells into the blood, detectable with sensitive sequencing.
Cancer still present after treatment but too small to see on scans, detected by blood or marrow tests.
A pathology score for how much cancer remains in the breast and lymph nodes after pre-surgery treatment, from 0 (none) to III (a large amount), combining tumour bed size, cellularity and nodal involvement. RCB-II or III after neoadjuvant therapy predicts a high risk of relapse and defines who enters escalation trials.
A blood test that reads fragments of DNA shed by the tumour, so you can genotype or monitor cancer without a needle in the tumour.
An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would.
Signatera is Natera's tumour-informed blood test that tracks 16 mutations from each patient's own tumour to detect residual or returning cancer after surgery. Medicare covers it in colorectal, breast, bladder, lung and ovarian cancer and for immunotherapy monitoring, and in 2026 it selected the bladder cancer patients for the first approval based on circulating tumour DNA.
Blood carries fragments of tumour DNA. This roadmap follows the tests that read them, from the first sighting in 1948 to blood tests that now choose a drug, spare chemotherapy, or screen for many cancers at once, and it lists the readouts to watch next.
Breast cancer researcher who turned ctDNA into a tool for choosing treatment, leading SERENA-6 and CAPItello-291.
The Royal Marsden was the world's first hospital dedicated to cancer (1851) and is paired with the Institute of Cancer Research.
After a 'successful' treatment, cells can sleep for years then relapse. We can barely detect them and cannot target them.
After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run.
The de-escalation trials are large and slow: OptimICE-pCR (pembrolizumab versus observation after pathological complete response, 1,295 estimated, primary completion May 2033) and SCARLET (anthracycline-free chemo-immunotherapy, 2,400 estimated, March 2033). The escalation trials report sooner: ASCENT-05 (June 2027) and TROPION-Breast03 (September 2027) for residual disease. First-line combinations follow: TROPION-Breast05 (datopotamab deruxtecan with durvalumab against chemotherapy with pembrolizumab in PD-L1-positive disease, 625 estimated, July 2027), IZABRIGHT-Breast01 (izalontamab brengitecan first line in immunotherapy-ineligible disease, 600, March 2028) and the PD-L1 and VEGF bispecific PM8002 with nab-paclitaxel (392, July 2027). KEYNOTE-522 completed on the registry in October 2025; OlympiA's study completion is listed for May 2029.
Asks whether patients whose cancer completely disappeared before surgery still need a year of immunotherapy afterwards.
Tests whether the anthracycline can be dropped from TNBC pre-surgery treatment without losing effect.
Tests whether giving a TROP2 ADC after surgery can cure more of the triple-negative patients whose cancer survived pre-surgery chemo-immunotherapy.
TROPION-Breast03 is the Dato-DXd counterpart to ASCENT-05: an ADC, with or without immunotherapy, for triple-negative patients with leftover cancer at surgery.
Tests whether Dato-DXd plus a PD-L1 blocker beats today's immunotherapy-chemotherapy standard.
IZABRIGHT-Breast01 is the global first-line trial of the EGFR×HER3 bispecific ADC in triple-negative breast cancer.
A phase 3 trial testing PM8002 in triple-negative breast cancer, active and no longer recruiting.
The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival.
Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations.
Giving less treatment to patients who are doing well and more to those who are not, using a marker such as scan response, ctDNA or MRD to decide. The aim is to cure the same number of people with less harm.
Two thirds of women treated on the KEYNOTE-522 regimen have no tumour left at surgery and about 92 percent of them are alive without relapse at five years, yet all receive nine more cycles of pembrolizumab. Trials are now testing whether the best responders can stop early, skip the anthracycline, or in lymphocyte-rich stage I tumours skip chemotherapy altogether.
After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run.
Four things the trials have not settled. PD-L1 assays disagree on a quarter of patients and only one, 22C3 combined positive score of 10, has an approved drug attached. Two TROP2 antibody-drug conjugates and trastuzumab deruxtecan share a topoisomerase I payload and no randomised trial has asked which to give first or whether the second works after the first. Brain metastases occur in about half of metastatic patients (Lin 2008) and most trials exclude active brain disease. And the disease is twice as common in Black women in the United States, with worse survival in the UK POSH cohort despite equal access, yet trial enrolment does not reflect it. Each has an idea on this page; the UK-specific gaps are set out on the UK and NHS page for triple-negative breast cancer.
Three different PD-L1 tests run on the same 614 IMpassion130 tumours called 46, 75 and 73 percent of them positive and agreed with each other only about 69 percent of the time; the benefit of atezolizumab was concentrated in the tumours all three called positive.
A 2008 Dana-Farber series of 116 women with metastatic triple-negative breast cancer in which 46 percent developed brain metastases before death, median survival after spread was 13.3 months and after a brain diagnosis 4.9 months.
A count of 1.15 million US breast cancers from 2010 to 2014 in which Black women had 2.27 times the odds of a triple-negative diagnosis and women under 40 nearly twice the odds, confirming the disparity at national scale.
The UK cohort of 2,915 women diagnosed with breast cancer at 40 or younger in which Black women had more triple-negative tumours (26 versus 19 percent) and worse survival despite the same access to care and the same use of chemotherapy.
The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload.
Giving a second ADC with the same kind of payload straight after the first often does not work well.
Tumour deposits that have travelled to the brain from a cancer elsewhere, ten times more common than cancers that start in the brain, mostly from lung, breast, melanoma and kidney cancer. Because the blood-brain barrier excludes most drugs, whether a medicine reaches and shrinks them now decides which drug is chosen, and trials report intracranial progression separately.
Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.
Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
The blood-brain barrier's tight junctions and efflux pumps keep antibodies, antibody-drug conjugates and most kinase inhibitors out of the brain, so glioblastoma treatment has barely changed since 2005 and brain metastases, which develop in about a fifth of adults with cancer, are usually left to radiotherapy alone.
Older, Black, Hispanic, Asian, rural, poor and multimorbid patients are under-represented, so results may not apply to them.
Three PD-L1 tests run on the same tumours called 46, 75 and 73 percent of them positive and agreed only 69 percent of the time. With atezolizumab withdrawn, pembrolizumab's test (22C3, combined positive score of 10) is the only one that matters, yet laboratories still run whichever kit they have. One assay, one score and a proficiency scheme would end answers that vary by postcode.
Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life.
Nearly half of women with metastatic triple-negative breast cancer develop brain metastases and survive under five months after the diagnosis, yet the trials that set the standard mostly exclude active brain disease. Requiring a brain metastasis cohort in every phase 3, with intracranial response as an endpoint, would answer whether the new drugs reach the brain.
Black women in the United States have about twice the odds of a triple-negative diagnosis and, in the UK POSH cohort, worse survival than White women despite equal chemotherapy use. The pivotal trials enrolled few of them. Enrolment targets tied to incidence, reported by ethnicity in every primary paper, would make the evidence match the disease.
The one UK study to look found young Black women had more triple-negative breast cancer and worse survival than White women despite equal chemotherapy, but it ended in 2008 and covered women under 41. Routine cancer statistics could report triple-negative incidence, stage and survival by ethnicity every year; at present they do not.
Answers the two questions that hung over adjuvant olaparib, durability and late leukaemia, in its favour; the remaining question is whether carriers who also received pembrolizumab or capecitabine, whom the trial did not study, get the same benefit.
The first-line overall survival result that made an antibody-drug conjugate the standard for PD-L1-negative or immunotherapy-ineligible metastatic triple-negative disease, and the reason the sequencing question (which TROP2 drug first, what after it) is now urgent.
The latest in a line of negative targeted-therapy trials in triple-negative disease (EGFR, VEGF, iniparib, now AKT): a modest delay in progression that did not translate into survival, in the same year that an antibody-drug conjugate did. It is why the roadmap treats pathway-targeted small molecules as the road not taken.
NCCN is the source of the category grades on the triple-negative breast cancer page and the first major guideline to place an antibody-drug conjugate first line for the disease.
Platinum and immunotherapy are now consensus for early triple-negative disease; the open votes have moved to who can safely receive less.
A second publication from the KEYNOTE-522 trial, later than the first and described in its title as an update or longer-term analysis. Read it with the primary publication linked from the trial page; the record was linked automatically and its figures have not been checked by hand.
The evidence behind the stage I de-escalation statement on the triple-negative page: an ordinary haematoxylin and eosin slide identifies a fifth of patients whose outcome without chemotherapy matches treated cohorts. A prospective trial of chemotherapy omission is the missing step.
This is the European standard the UK page for triple-negative breast cancer is compared against; NICE guidance covers the same ground with a narrower set of funded drugs.
The first prospective test of acting on ctDNA in triple-negative disease, and a negative one: with a quarterly, single-mutation assay the window between detectable DNA and visible metastasis was too short to intervene. Later designs use tumour-informed assays, earlier sampling and drugs with more single-agent activity.
The external validation the 2017 paper asked for; it is why residual cancer burden is reported in UK and European pathology and used as a trial entry criterion rather than an MD Anderson curiosity.
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.
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.
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.
This is the paper Europe PMC returns for registry id NCT03125902 with the most citations, so it is the natural first reading for anyone following the IMpassion131 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
The clearest demonstration that PD-L1 positive in triple-negative breast cancer means different things depending on the kit; with atezolizumab withdrawn, pembrolizumab's 22C3 combined positive score of 10 is the surviving standard, and roughly a quarter of patients get a different answer depending on which assay their laboratory runs.
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.
This is the paper Europe PMC returns for registry id NCT03036488 with the most citations, so it is the natural first reading for anyone following the KEYNOTE-522 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
This is the paper Europe PMC returns for registry id NCT01945775 with the most citations, so it is the natural first reading for anyone following the EMBRACA trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
This is the paper Europe PMC returns for registry id NCT02425891 with the most citations, so it is the natural first reading for anyone following the IMpassion130 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
Established that residual disease after neoadjuvant chemotherapy is a treatable state, the principle behind OlympiA and the post-neoadjuvant antibody-drug conjugate trials; capecitabine remains the option for residual triple-negative disease without a BRCA variant in ESMO, NCCN and UK practice.
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.
The UK's own evidence that the disparity is not only American and not only about access: within the NHS, with equal chemotherapy use, young Black women had more triple-negative disease and worse survival. It anchors the disparities idea on the triple-negative page and the UK and NHS page.
The basis of the US accelerated approval pathway on pathological complete response that KEYNOTE-522 and neoadjuvant trials since have used, together with the warning that a higher response rate in a trial is a promise, not a proof, of longer life.
This is the paper Europe PMC returns for registry id NCT01426880 with the most citations, so it is the natural first reading for anyone following the GeparSixto trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
The vocabulary used on the triple-negative page (basal-like 1 and 2, mesenchymal, luminal androgen receptor, immunomodulatory) comes from this paper; it made triple-negative breast cancer several diseases with several possible drugs rather than one disease with none.
Made pathological complete response the organising endpoint of triple-negative drug development and residual disease its central unsolved problem; every post-neoadjuvant trial from CREATE-X to ASCENT-05 follows from this observation.
Explains why triple-negative trials can use three-year event-free survival, why follow-up is front-loaded, and why survivors past five years are told their risk has largely passed.
One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The paper that made race a biological as well as a social variable in triple-negative breast cancer, and the reason the US disparity is described as roughly twice the incidence in Black women; the UK POSH study later found a smaller but real excess.
The molecular bridge between germline BRCA1 and triple-negative breast cancer; it is why every triple-negative patient under 60 is now offered germline testing and why PARP inhibitors were tried in this disease first.
The origin of the intrinsic subtypes and of the word basal-like; triple-negative breast cancer is the clinical shadow of this molecular group, though the two overlap imperfectly.
Founder mutations make population-level testing feasible because a three-variant panel finds most carriers; the BRCA1 founder variants in particular predispose to basal-like, triple-negative tumours, so ancestry shapes who gets this disease and who is eligible for PARP inhibitors.
Oestrogen receptor, progesterone receptor and HER2 became the three tests every breast cancer gets; the tumours negative for all three were left as a remainder, and it took twenty years for that remainder to acquire a name and a research agenda.
Shares ASCENT, DESTINY-Breast04, HER2-low and HER2-ultralow metastatic breast cancer, HER2-low and HER2-ultralow and the tags tnbc, breast.
Shares IMpassion130, KEYNOTE-355, Combined positive score (CPS), Tumour-infiltrating lymphocytes (TILs) and the tags tnbc, breast.
Shares GeparSixto, Residual cancer burden (RCB), Homologous recombination deficiency (HRD), Pathologic complete response (pCR) and the tags tnbc, breast.
Shares PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer, IMpassion130, KEYNOTE-355, Combined positive score (CPS) and the tags tnbc, breast.
Shares OlympiA, Residual cancer burden (RCB), KEYNOTE-522, Pathologic complete response (pCR) and the tags tnbc, breast.
Shares Residual cancer burden (RCB), Pathologic complete response (pCR), HER2-positive breast cancer, Triple-negative breast cancer (TNBC) and the tags tnbc, breast.
Shares HER2-low and HER2-ultralow, Pathologic complete response (pCR), Triple-negative breast cancer (TNBC), HR-positive / HER2-negative breast cancer and the tags tnbc, breast.
Shares Androgen receptor, Pathologic complete response (pCR), Triple-negative breast cancer (TNBC) and the tags tnbc, breast.