SUMMARY Toward development of a precision medicine framework for metastatic, castration resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53 and PTEN were frequent (40–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified novel genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin and ZBTB16/PLZF. Aberrations of BRCA2, BRCA1 and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides evidence that clinical sequencing in mCRPC is feasible and could impact treatment decisions in significant numbers of affected individuals.

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Importance Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. Objective To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. Design, Setting, and Patients Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. Main Outcomes and Measures Feasibility, use of WES for decision making, and identification of novel biomarkers. Results A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95× and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. Conclusions and Relevance The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.

This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society.

PURPOSE We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. PATIENTS AND METHODS Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated. RESULTS Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant. CONCLUSION Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.

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