Cancer Genomics for Oncologists: Cancer Risk and Management of BRCA1 and BRCA2 Carriers

Abstract

The rise of routine integration of genetic testing into oncological pathways, through initiatives such as mainstream testing, is making it increasingly important for oncologists to understand more about the wider implications of inherited mutations in cancer susceptibility genes. This is vital to facilitate accurate information-giving by oncologists, taking informed consent for testing, and to ensure they are referring patients appropriately for risk reduction strategies such as screening. In this review, the most relevant information for oncologists discussing and consenting patients will be discussed. Kuchenbaecker et al. (JAMA 317(23):2402-2416, 2017) have provided updated risk estimates for BRCA1 and BRCA2 carriers, from a large meta-analysis of international cohorts. For those considering risk-reducing interventions, we have evidence now from the POSH study to suggest that those diagnosed < 40 years have a 12% risk of carrying a mutation, with no detrimental effect from undergoing risk-reducing surgery. The role of chemotherapy for BRCA carriers with breast cancer was further assessed in cohorts from The Netherlands, MSKCC and the GeparSixto studies, assessing both overall survival and breast cancer–specific survival. For those considering surgical intervention, Metcalfe et al. (JAMA oncology 1(3):306-313, 2015) reported a survival advantage in BRCA cancers diagnosed with breast cancer undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). The use of ovarian screening for BRCA carriers continues to be investigated by Rosenthal et al. (J Clin Oncol 35(13):1411-1420, 2017), who reported phase II of the UK FOCSS study, looking at their CA-125 algorithm and trans-vaginal ultrasound scanning. Whilst there is still no reduction in mortality for ovarian cancer, the studies of PSA screening for prostate cancer in BRCA carriers look more promising from the IMPACT study. The role of inherited gene mutations in ovarian cancer susceptibility outside of BRCA and Lynch was assessed by Song et al. (J Clin Oncol 33(26):2901-2907, 2015) in two different studies, investigating the role of BRIP1, RAD51C, RAD51D, RAD51B, BARD1, PALB2 and NBN. They concluded a causative role can only be confirmed for RAD51C, RAD51D and BRIP1. Work continues on identifying the best way to find and test patients with germline genetic mutations, and the best way to manage carriers. These studies provide updated information on risk and the screening and management of individuals carrying these mutations to ensure they receive optimal care stratified by genetic risk.