Relevance of DNA damage repair in the management of prostate cancer

Recent insights into the genomic aberrations that underlie and drive prostate cancer have redoubled efforts to molecularly stratify treatments based on predictive markers. Approximately 23% of patients with metastatic castration-resistant prostate cancer exhibit somatic or germline aberrations in genes implicated in DNA repair, such as BRCA2, BRCA1, ATM, CHEK2, and PALB2, as well as mismatch repair genes. At least 10% of men with advanced disease have germline mutations in DNA-repair genes (DRG). The enrichment of DRG defects in metastatic disease compared with localized, primary tumors suggests a possible role in carcinogenesis, disease progression, and potentially accounts for a more aggressive phenotype. Germline BRCA2-mutant prostate cancer is more likely to present with advanced disease, higher Gleason score, and exhibit poorer survival than noncarriers. Very little is currently known about the clinicopathological features of prostate cancer associated with rarer DRG variants. It is currently unknown whether germline carriers of DRG mutations would benefit from additional screening strategies or more intensive treatment of localized prostate cancer. Defective DNA repair may have profound therapeutic implications for advanced disease, conferring tumor-specific vulnerability to poly(ADP-ribose) polymerase inhibitors, platinum chemotherapy, or immunotherapy that can be exploited for clinical benefit. Pertinent issues regarding cancer risk, screening recommendations and risk reduction strategies for carriers of poorly characterized DRG variants remains to be defined. We review the prevalence and potential clinical implications of DNA damage repair defects in prostate cancer. The broader promise and challenge of implementing this knowledge into clinical practice is also discussed.