Abstract

     ۵-۱۰% of all breast cancers are associated with mutations in hereditary breast cancer genes several of which are involved in the DNA damage response.

     BRCA1 and BRCA2 mutation is not associated with poor prognosis in breast cancers, but infact better prognosis when treated with chemotherapy in comparison to similar non BRCA mutated breast cancers.

    Treatment with the small molecule PARP inhibitor olaparib after chemotherapy improves overall survival in patients with early breast cancer and germline BRCA1 or BRCA2 mutations.

     Platinum based chemotherapy is highly active in those with germline BRCA1 or BRCA2 mutations but cross resistance between platinum agents and PARP inhibitors can be mediated by somatic “reversion mutations” in BRCA1 or BRCA2 and is a clinical challenge.

     Understanding the underlying mechanisms of overlapping or distinctive resistance is vital to therapy development in this evolving area of translational medicine.

Introduction

     Approximately 5% to 10% of the 2.3 million breast cancer cases diagnosed annually are associated with a mutation in a known hereditary breast cancer predisposition gene such as BRCA1 or BRCA2.1,2 The integration of genomics into the standard diagnostic pathways for breast cancer patients and the availability of targeted treatment approaches for those with hereditary breast cancer predisposition gene mutations means that the management of these patients is now distinct to that a decade ago. In this review, we discuss the recent advances made in systemic treatments for hereditary breast cancer and highlight future challenges that must be addressed for improvements in clinical outcomes to be achieved in this distinct subgroup.

Hereditary Breast Cancer Genes

     Many of the germline mutations associated with hereditary breast cancer occur in “caretaker” tumor suppressor genes (genes whose normal function is to maintain the integrity of the genome and whose dysfunction leads to genome instability) and include BRCA1, BRCA2, PALB2, ATM, CHEK2, and p53.3 For example, germline deleterious mutations in BRCA1 (gBRCA1m) or BRCA2 (gBRCA2m), which play key roles in DNA repair by homologous recombination (HR), are associated with an increased lifetime risk of developing breast, ovarian, prostate and pancreatic cancer.2,4,5 gBRCA1m carriers have a cumulative lifetime breast cancer risk of 46% to 60% and when diagnosed with breast cancer typically have the basal-like, triple negative (B-L, TNBC), subtype of the disease. gBRCA2m carriers have a cumulative lifetime breast cancer risk of 43% to 55% and tend to develop estrogen receptor-positive (ER+), luminal B subtype, breast cancers (significantly more so than for gBRCA1m carriers).6, 7, 8, 9 gBRCA1/2m breast cancers in those who have a strong family history are usually detected at a younger age than sporadic breast cancers.

Disclosure

     E.H.-J. is a clinical PhD fellow funded by Cancer Research UK and AstraZeneca. A.T. is a consultant for AstraZeneca, Merck KGaA, Artios, Pfizer, Vertex, GE Healthcare, Inbiomotion, MD Anderson Cancer Centre; has received grant/research support from AstraZeneca, Myriad, Medivation, and Merck KGaA; and is a stockholder in Inbiomotion. Stands to gain from the use of PARP inhibitors as part of the ICR’s “rewards to inventors” scheme. C.J.L. makes the following disclosures: receives and/or has received research funding from: AstraZeneca, Merck KGaA, Artios. Received consultancy, SAB membership or honoraria payments from: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics. Has stock in: Tango, Ovibio, Enedra Tx., Hysplex, Tesselate. C.J.L. is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR “Rewards to Inventors” scheme.