Risk-Reducing Surgery for Breast Cancer

Abstract

In recent years, there has been an upsurge of interest in identifying women with genetic predisposition and this has been facilitated by enhanced understanding of the genetic basis for breast cancer susceptibility derived from genome-wide linkage analysis and mutational screening. The focus has shifted from high-penetrance genes to intermediate and low penetrance mutations that confer lower levels of risk individually but collectively are more significant. There has been frenzied public interest in genetic testing and risk reduction strategies following revelations in the New York Times in May 2013 that the famed actress Angelina Jolie had chosen to undergo bilateral prophylactic mastectomy due to carriage of a BRCA-1 gene mutation. Genetic counseling and testing for breast cancer predisposition have been formally implemented in many countries, and the number of women seeking genetic testing continues to rise. Nonetheless, despite these advances in genetics, approximately 30% of familial breast cancer risk remains unaccounted for by mutations in currently known genes. Moreover, genetic changes do not necessarily have a causative association with a diseased state, and phenotypic manifestations of cancer are variable. The clinical management of women with an asymptomatic mutation in BRCA1 and BRCA2 or carriage of a mutation in other high-risk genes such as TP53, PALB2, or pTEN is increasingly complex. Approaches include screening, chemoprevention, and risk-reducing surgery but the outcomes of these different interventions for risk reduction remain variable in terms of accuracy of data and levels of certainty. In particular, although an intervention may reduce the chance of developing breast cancer, this may not translate into a reduction in mortality with gains in both breast cancer-specific and overall survival. No randomized trials have addressed the impact of these risk-reducing strategies on either incidence or survival outcomes with much of the evidence for efficacy derived from observational studies that are prone to systematic biases. It important that women with a hereditary predisposition are fully informed about the limitations of the existing knowledge base relating to risk-reducing interventions for breast cancer.