{"entity":{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","kind":"paper","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","aka":["Chung 2019","FoundationOne prostate 3476","real-world prostate genomic profiling"],"tldr":"The largest routine-practice picture of what is broken in prostate tumours. Across 3,476 samples sent for commercial sequencing, TP53 was altered in 44 percent and PTEN in 32 percent, and just over half carried something a drug is being developed against.","summary":"Jon Chung, Jeffrey Ross and colleagues at Foundation Medicine analysed 3,476 clinically advanced prostate tumours sent for comprehensive genomic profiling, 1,660 from primary sites and 1,816 from metastases in unmatched patients, and reported both gene-level alterations and genome-wide signatures: loss of heterozygosity, microsatellite instability and tumour mutational burden.\n\nThis is the real-world counterpart to TCGA and the SU2C cohort, and it is the right citation for what a clinician actually sees on a report. It also makes two points the research cohorts do not. Median tumour mutational burden is low at 2.6 mutations per megabase and only 3 percent of tumours are high, of which 71 percent are also microsatellite-unstable, which is why immunotherapy fails in this disease. And CDK12-altered tumours, unlike BRCA and ATR-altered ones, are infrequently high for genome-wide loss of heterozygosity, so they are not homologous recombination deficient in the sense PARP inhibitors need.","asOf":"2026-09-25","links":[{"label":"JCO Precis Oncol 2019","url":"https://doi.org/10.1200/po.18.00283"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31218271/"},{"label":"Europe PMC","url":"https://europepmc.org/article/MED/31218271"}],"tags":["prostate-evidence"],"related":["paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-antonarakis-keynote-199-pembrolizumab-jco-2020","paper-fizazi-triton3-rucaparib-nejm-2023","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc","prostate-mhspc"],"sections":["diagnostics","targeted-therapy"],"technologies":[],"targets":["tp53","pten","erg","tmprss2","androgen-receptor","brca","cdk12","rb1","pik3ca"],"drugs":[],"companies":["foundation-medicine"],"institutions":[],"pathways":[],"terms":["hrd","tmb","msi","ngs","genome-wide-loss-of-heterozygosity","chromoplexy"],"trials":[],"people":[],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response","b-real-world-evidence"],"keyPapers":[],"journals":["jco-precision-oncology"],"dependsOn":[],"notes":[],"journal":"JCO Precision Oncology","year":2019,"doi":"10.1200/po.18.00283","pmid":"31218271","authors":"Chung JH, Dewal N, Sokol E, et al.","paperType":"real-world","findings":["Frequently altered genes across 3,476 tumours were TP53 (44 percent), PTEN (32 percent), TMPRSS2-ERG (31 percent) and the androgen receptor (23 percent).","DNA repair pathway alterations included homologous recombination repair (23 percent), Fanconi anaemia (5 percent), CDK12 (6 percent) and mismatch repair (4 percent).","BRCA1 and BRCA2, ATR and FANCA alterations were associated with high genome-wide loss of heterozygosity, whereas CDK12-altered tumours were infrequently loss-of-heterozygosity high.","Median tumour mutational burden was low at 2.6 mutations per megabase; 3 percent of cases were tumour mutational burden high, of which 71 percent also had high microsatellite instability.","Metastatic site tumours were enriched for the 11q13 amplicon (CCND1, FGF19, FGF4, FGF3) and for alterations in the androgen receptor, LYN, MYC, NCOR1, PIK3CB and RB1 compared with primary tumours; alterations that are investigational biomarkers for targeted therapies were identified in 57 percent of cases."],"whatItMeans":"What a prostate cancer sequencing report looks like in practice, and the numerical basis for two clinical rules: do not expect checkpoint immunotherapy to work unless the tumour is mismatch repair deficient, and do not treat a CDK12 alteration as if it were a BRCA alteration.","caveats":["Commercial sequencing referrals, so the cohort is selected by who was tested and cannot give population prevalences.","No clinical outcome data are linked, which the authors name as the study's main limitation.","Primary and metastatic samples come from different, unmatched patients, so the enrichment seen in metastases is a between-group comparison rather than a within-patient evolution."],"changedPractice":false,"participants":3476},"route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/","neighbours":{"paper":[{"id":"paper-antonarakis-keynote-199-pembrolizumab-jco-2020","kind":"paper","name":"KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer","route":"/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/"},{"id":"paper-magnitude-j-clin-oncol-2023","kind":"paper","name":"Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer","route":"/key-papers/paper-magnitude-j-clin-oncol-2023/"},{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","kind":"paper","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/"},{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","kind":"paper","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","route":"/cancers/prostate-mhspc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"cdk12","kind":"target","name":"CDK12","route":"/targets/cdk12/"},{"id":"erg","kind":"target","name":"ERG","route":"/targets/erg/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tmprss2","kind":"target","name":"TMPRSS2","route":"/targets/tmprss2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"company":[{"id":"foundation-medicine","kind":"company","name":"Foundation Medicine (Roche)","route":"/companies/foundation-medicine/"}],"term":[{"id":"chromoplexy","kind":"term","name":"Chromoplexy","route":"/terms/chromoplexy/"},{"id":"genome-wide-loss-of-heterozygosity","kind":"term","name":"Genome-wide loss of heterozygosity (gLOH)","route":"/terms/genome-wide-loss-of-heterozygosity/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-real-world-evidence","kind":"bottleneck","name":"Weak real-world evidence and registries","route":"/bottlenecks/b-real-world-evidence/"}],"journal":[{"id":"jco-precision-oncology","kind":"journal","name":"JCO Precision Oncology","route":"/journals/jco-precision-oncology/"}],"idea":[{"id":"idea-prostate-hrr-testing-at-metastatic-diagnosis","kind":"idea","name":"Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later","route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/"},{"id":"idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine","kind":"idea","name":"Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it","route":"/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/"}]}}