Distinct implications of different BRCA mutations: efficacy of cytotoxic chemotherapy, PARP inhibition and clinical outcome in ovarian cancer

Abstract

Approximately a fifth of ovarian carcinoma (OC) is associated with inherited germline mutations, most commonly in the DNA repair genes BRCA1 or BRCA2 (BRCA). BRCA1- and BRCA2-associated OCs have historically been described as a single subgroup of OC that displays a distinct set of characteristics termed the “BRCAness” phenotype. The hallmarks of this phenotype are superior clinical outcome and hypersensitivity to platinum-based chemotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors. However, growing evidence suggests that BRCA1- and BRCA2-associated OCs display distinct characteristics, most notably in long-term patient survival. Furthermore, recent data indicate that the site of BRCA1 mutation is important with regard to platinum and PARP inhibitor sensitivity. Here, we summarize the body of research describing the BRCAness phenotype and highlight the differential implications of different BRCA mutations with regard to clinicopathologic features, therapy sensitivity and clinical outcome in OC.

Keywords:

• ovarian cancer
• BRCA1
• BRCA2
• BRCAness

Acknowledgments

We would like to extend our thanks to the Nicola Murray Foundation for their generous support of the Nicola Murray Centre for Ovarian Cancer Research.

Disclosure

RLH and MC report no conflicts of interest in this work. CG discloses the following conflicts of interest: AstraZeneca (advisory board attendance, lecture fees and research funding); Clovis (advisory board attendance); Tesaro (advisory board attendance), Novartis (research funding), Nucana (advisory board attendance and research funding) and Aprea (research funding).