BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

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.

Diagnostic Strategies for Treatment Selection in Advanced Prostate Cancer

“…BRCA2 was reported to have the highest relative risk of metastases when compared with men who do not have PCa [ 31 ]. DNA damage repair defects (DDR) represent 25% of these alterations, with BRCA2 mutations being the most frequently observed [ 6 ]. A second analysis by Dall’Era et al looked at both somatic and germline DNA alterations in men with both localized and metastatic disease.…”

“…It can also have family implications if a germline mutation is identified. Germline BRCA2 mutations are associated with higher risk of PCa development, risk of local treatment failures and mortality [ 6 ]. More importantly, these alterations are clinically actionable and can be therapeutically targeted with Poly (adenosine diphosphate ribose) polymerase (PARP) inhibition or by immune checkpoint inhibition.…”

“…The worldwide PCa burden is expected to grow to almost 2.3 million new cases and 740,000 deaths by 2040 simply due to the growth and aging of the population [ 3 ] making it an expanding global health concern. In addition to age, ethnicity (e.g., African American), heredity (e.g., family history) and mutations in DNA-repair genes such as BRCA2 are risk factors for PCa [ 4 , 5 , 6 ]. A variety of environmental factors have been discussed as being associated with the risk of developing PCa [ 4 ].…”

Narrative review: predicting future molecular and clinical profiles of prostate cancer in the United States

“…Furthermore, a growing body of evidences suggest that germline and somatic mutations on DNA repair genes should be investigated in patients with prostate cancer due to the development of PolyAdenosine Diphosphate (ADP)-Ribose Polymerase (PARP) inhibitors (16). It has been estimated that alterations in DNA Damage Repair (DDR) genes can be found in approximately 11% of prostate cancers (17).…”

A comprehensive mechanistic basis of prostate cancer advancement & its personalized implementation-bridging the gap: present state and future prospect

“…Towards identification of patient specific optimal sequences for these future therapeutic measures, there is a growing requirement for identification of suitable biomarkers to guide effective treatment selection and characterization of treatment responses [24]. Recently, a number of genomic aberrations have been proposed as predictive biomarker for evaluation of treatment response profiles like cyclin-dependent kinase 12 (CDK12) and DNA damage repairs (DDR) associated breast cancer gene 1 (BRCA1) as well as ataxia telangiectasia mutated (ATM) in CRPC patients [142,143]. It has been suggested that the biallelic loss of CDK12 are prevalent in around 5% of metastatic CRPCs and intrinsically associated with immunosuppression through massive infiltration of CD4 + FOXP3 − T lymphocytes in prostate TME, which strongly urges for the interventions with immunotherapeutic approaches [142].…”