Abstract
Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.
Highlights
Prostate cancer (PCa) is the second most common neoplasm in men worldwide and the second leading cause of cancer deaths in Western countries [1]
PCa patients live most of their natural history of disease in the castration-resistant setting, and in the last decade, the approval of six novel treatments for the management of metastatic castration-resistant prostate cancers, spanning from chemotherapy agents, androgen-receptor signalling inhibitors (ARSi, i.e., enzalutamide and abiraterone), vaccines, and bone-seeking radiopharmaceuticals, has dramatically changed the management of mCRPC [4]
Despite the development of several treatment options for mCRPC patients, metastatic PCa remains a lethal disease with poor prognosis [4]
Summary
Prostate cancer (PCa) is the second most common neoplasm in men worldwide and the second leading cause of cancer deaths in Western countries [1]. PCa is one of the most heritable human tumors [5]; the integrative analysis of advanced prostate cancer has revealed that approximately 90% of mCRPC patients harbor clinically actionable germline and somatic alterations [6] In this scenario, DNA damage repair defects (DDR) represent 25% of these alterations, with BRCA2 mutations representing the most. Ese findings suggested that the use of prostate biopsy might be useful to profile patients for DDR mutations, avoiding rebiopsies of metastatic lesions that are potentially dangerous and timeconsuming These data supported the testing for DDR defects in earlier stages of PCa as many of these alterations are already present during the initial phases of PCa development. Mateo et al found no difference in PFS on firstline ARSi (8.3 months in both groups) between gDDR carriers (n 330) and noncarriers (n 60) [22]
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