Tumour-specific synthetic lethality: Targeting BRCA dysfunction in ovarian cancer

The inheritance of mutations in either BRCA1 or BRCA2 genes is associated with an estimated lifetime risk of developing ovarian cancer of up to 40-50% for BRCA1 mutation carriers and 10-20% for BRCA2 carriers The analysis of BRCA1 and BRCA2 function in DNA repair is leading to new approaches to antitumour therapy for such patients, including the use of poly(ADP)-ribose polymerase (PARP) inhibitors. Such novel agents are selectively lethal to cells lacking functional BRCA1 or BRCA2, with minimal toxicity to cells with normal BRCA function. Early clinical trials have confirmed this finding and shown that PARP inhibitors are well tolerated with substantial antitumour efficacy in ovarian cancer patients with BRCA mutations. The increased understanding of BRCA dysfunction, particularly in high-grade serous ovarian cancers has now led to the testing of these novel therapeutics in broader groups of women with this disease. The stage is now set for this tumour-specific synthetic lethal approach to have a positive impact on women in the gynae-oncology clinic.