Germline mutations and prostate cancer: is it time to change treatment algorithms?

Prostate cancer is the most commonly diagnosed non-skin cancer in men. Although early disease can be cured or remain indolent, advanced castration-resistant disease remains a significant cause of morbidity and mortality. One approach to precision screening may be the use of germline genetic testing. Mutations in high-risk genes such as BRCA 2 are rare however polygenic risk scores could potentially limit screening to only those at higher risk, improving the benefit-to-harm ratio. The National Comprehensive Cancer Network (NCCN) Prostate Cancer guidelines have recently recommended testing for germline mutations in patients diagnosed with high-risk or metastatic prostate cancer, regardless of family history. New therapeutic options are emerging for genomically-defined subsets of patients; germline or somatic mutations in homologous recombination repair genes suggest potential susceptibility to PARP inhibitors and platinum-based chemotherapy, whereas mutations in DNA mismatch repair genes may confer susceptibility to immune checkpoint inhibitors. Current barriers to genetic testing include cost, limited access to genetic counseling for those found to have germline mutations and lack of clear guidelines on the clinical applicability of results. Work is ongoing in three key areas: Using germline genetic testing to improve screening, establishing treatment algorithms for patients with known pathogenic germline or somatic mutations diagnosed with localized disease, and the use of genomic biomarkers to define treatment-selection for patients with advanced prostate cancer.