BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside.

Abstract

Simple SummaryDNA damage is one of the hallmarks of cancer. Epithelial ovarian cancer (EOC) —especially the high-grade serous subtype—harbors a defect in at least one DNA damage response (DDR) pathway. Defective DDR results from a variety of lesions affecting homologous recombination (HR) and nonhomologous end joining (NHEJ) for double strand breaks, base excision repair (BER), and nucleotide excision repair (NER) for single strand breaks and mismatch repair (MMR). Apart from the EOC, mutations in the DDR genes, such as BRCA1 and BRCA2, are common in prostate cancer as well. Among them, BRCA2 lesions are found in 12% of metastatic castration-resistant prostate cancers, but very rarely in primary prostate cancer. Better understanding of the DDR pathways is essential in order to optimize the therapeutic choices, and has led to the design of biomarker-driven clinical trials. Poly(ADP-ribose) polymerase (PARP) inhibitors are now a standard therapy for EOC patients, and more recently have been approved for the metastatic castration-resistant prostate cancer with alterations in DDR genes. They are particularly effective in tumours with HR deficiency.DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.