Germline and Somatic Mutations in Prostate Cancer for the Clinician

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It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.

Submitted January 30, 2019; accepted for publication April 2, 2019.

Disclosures: Dr. Cheng has disclosed that she receives grant/research support from Clovis Oncology, Janssen, Medivation, Sanofi, and Astellas. Dr. Sokolova has disclosed that she has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Schaeffer has disclosed that he is a scientific advisor for AbbVie and Opko. Dr. Small has disclosed that he has stock options in Fortis Therapeutics and Harpoon Therapeutics; and receives honoraria from Janssen; and is a scientific advisor for Janssen and Fortis. Dr. Higano has disclosed that she receives grant/research support from Aragon, Astellas, AstraZeneca, Bayer, Emergent Biosolutions, Medivation, Hoffman LaRoche, and Pfizer, and is a scientific advisor for Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova, and Janssen.

Correspondence: Heather H. Cheng, MD, PhD, Division of Medical Oncology, University of Washington, 825 Eastlake Avenue East, Seattle, WA 98109. Email: hhcheng@uw.edu

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