Germline and Somatic Mutations in Prostate Cancer for the Clinician

Abstract

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.

Clinical Implications of Germline Testing in Newly Diagnosed Prostate Cancer

“…Germline testing (GT) for men with prostate cancer (PCa) is rapidly expanding and impacting clinical care across the stage and risk spectrum [1][2][3][4]. A major context for which to consider integration of GT is men with newly diagnosed PCa, given the expansion of GT guidelines and the growth of precision medicine [1][2][3][4][5][6]. Approximately 4% of men aged <75 yr present with metastatic PCa, with the remainder presenting at an earlier stage [7].…”

Optimizing the management of castration‐resistant prostate cancer patients: A practical guide for clinicians

“…However, for those with an identified germline mutation, their risk of developing mPC increases. For example, for those with pathogenic germline BRCA2 mutations, the relative risk of developing PC by age 65 is estimated to be 2.5‐ to 8.6‐fold compared with noncarriers 1‐3 …”

Towards precision oncology in advanced prostate cancer

“…Owing to a high frequency of germline alterations (in up to 12% of men with advanced prostate cancer, even patients unselected for age or family history) 58 , germline testing is now recommended by the National Comprehensive Cancer Network for all patients with metastatic prostate cancer 59 . This high frequency of mutations has important implications not only for men with prostate cancer, but also for their family members, as they are at increased risk of developing certain other cancers 60 .…”