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One hundred and fifty men with prostate cancer that had spread and stopped responding to hormones had their tumours biopsied and sequenced prospectively. Nine in ten had a genetic change that a drug could in principle be aimed at, and one in five had a broken DNA repair gene.
Dan Robinson, Arul Chinnaiyan, Charles Sawyers, Johann de Bono and the Stand Up To Cancer-Prostate Cancer Foundation Dream Team built a multi-institutional clinical sequencing infrastructure and prospectively whole-exome and transcriptome sequenced bone or soft tissue biopsies from 150 men with metastatic castration-resistant prostate cancer.
The single most consequential number is 19.3 percent: aberrations of BRCA2, BRCA1 and ATM at substantially higher frequency than in primary prostate cancer. That figure, together with Pritchard's germline result the following year, is why every man with metastatic prostate cancer should now be offered DNA repair testing. The paper also documented what castration resistance looks like at the genomic level: androgen receptor aberrations in 62.7 percent, and enrichment of TP53 and androgen receptor alterations relative to primary disease.
The genomic definition of advanced prostate cancer, and the evidence that made molecular testing standard in it. The 19.3 percent DNA repair figure is the direct ancestor of PROfound, TRITON3, PROpel and TALAPRO-2, and the 8 percent germline figure is why a tumour result in this disease has implications for a man's relatives.
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.
The evidence that made germline testing standard for every man with metastatic prostate cancer, whatever his family history. It changes his treatment, because PARP inhibitors and platinum work better in these tumours, and it changes his relatives' screening, because BRCA2 carries breast, ovarian and pancreatic risk as well.
The reference classification of prostate cancer as it presents, and the source of the two numbers that drive most molecular treatment decisions in the disease: a quarter with a PI3K or MAPK lesion, which is the rationale for capivasertib in PTEN-deficient disease, and a fifth with DNA repair inactivation, which is the rationale for PARP inhibitors.
The explanation for why prostate cancer has so few targeted drugs outside the hormone axis and the DNA-repair genes: it is a quiet genome with structural rather than point-mutational damage, and the recurrent changes sit in the machinery that reads DNA rather than in kinases.
Shares Arul M. Chinnaiyan, University of Michigan Rogel Cancer Center, TCGA: the molecular taxonomy of primary prostate cancer, ERG and the tag prostate-evidence.
Shares Charles L. Sawyers, The mutational landscape of lethal castration-resistant prostate cancer, TCGA: the molecular taxonomy of primary prostate cancer, ERG and the tag prostate-evidence.
Shares Inherited DNA-repair gene mutations in men with metastatic prostate cancer, Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later, ATM and the tag prostate-evidence.
Shares TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer, Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later, Homologous recombination deficiency (HRD), 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 and the tag prostate-evidence.
Shares The mutational landscape of lethal castration-resistant prostate cancer, ERG, Cell, Next-generation sequencing (NGS) and the tag prostate-evidence.
Shares Charles L. Sawyers, Castration-resistant prostate cancer (CRPC), 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, Androgen receptor and the tag prostate-evidence.
Shares Johann de Bono, The Royal Marsden, Castration-resistant prostate cancer (CRPC), 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 and the tag prostate-evidence.
Shares Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, Next-generation sequencing (NGS), Castration-resistant prostate cancer (CRPC), 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 and the tag prostate-evidence.