Risk-Reducing Mastectomy for BRCA Gene Mutation Carriers

Abstract

A family history of early-onset breast cancer in multiple relatives is an important breast cancer risk factor that should prompt efforts to define and manage cancer risk. Genetic testing is the most powerful tool we have for precisely determining who in these families is at increased risk and who is not. With the advent of massive parallel sequencing or next-generation sequencing and the commercialization of multigene panels, we have incrementally expanded the proportion of families that can be understood and managed from a genetic perspective. Nevertheless, BRCA1 and BRCA2 remain the most commonly identified genes affected by deleterious mutations. The next largest fraction includes PALB2, CHEK2, and ATM, but it is estimated that even with whole-genome sequencing, we are explaining only about 35 % of apparent inherited breast cancer predisposition. 1 The first task after receiving a ‘‘deleterious’’ or ‘‘likely deleterious’’ genetic test result is to estimate cancer risks. This requires knowledge about the mutated gene, about the specific mutation, and about the extended cancer family history. It is common, but not accurate, to see a BRCA1 mutation and immediately assume that the lifetime breast cancer risk is 80 %. Slight differences in the way we code for other genes (polymorphisms) can influence the cancer probabilities associated with mutations in major predisposition genes. Different families have different risk profiles, even with the same mutation. This has been observed for BRCA1 for which lifetime breast cancer risk has been estimated at 26–87 % depending on the associated family history. It also is true for the newer ‘‘modest penetrance’’ genes such as ATM, for which the lifetime risk appears to be as high as 60 % in some families. 2 Attention to the three-generation cancer family history during post-test counseling cannot be emphasized enough. Once cancer risks have been estimated, the focus shifts to developing a risk management strategy that considers the magnitude of the risk, the risks and effectiveness of possible interventions, and individual risk tolerance and preferences. The options to consider include lifestyle interventions, enhanced surveillance, chemoprevention, and risk-reducing surgery.