Breast Cancer Risk Assessment and Genetic Testing: Complexities, Conundrums, and Community

Abstract

This special issue of Breast Disease is a testament to how far the field of genetic counseling for breast cancer susceptibility has advanced since the mid-1990s, following the cloning of two major breast (and ovarian) cancer susceptibility genes, BRCA1 and BRCA2. Although perhaps not fully appreciated at the time, individuals who pursued genetic testing shortly after it became available were truly pioneers. They were seeking important, indeed life-changing information, when in fact few specifics about several key issues could be provided. For example, the only available data regarding cancer risks in mutation carriers were derived from the highest risk families, most of which were not representative of the families seen in clinical practice. Then, largely due to the discovery of three founder mutations in Ashkenazi Jews, population-based data revealed a range of breast and ovarian cancer risks in carriers. Subsequently, additional information about mutation penetrance, genetic epidemiology, and risk modifiers, some of which is now integrated into routine clinical counseling, has also facilitated the development of elaborate models to predict the likelihood that an individual will test positive for a BRCA1/2 mutation. For women who test positive, several recent studies confirm what we suspected early on – namely that prophylactic mastectomy and oophorectomy confer significant protection against the development of breast and ovarian cancer. In premenopausal women, the benefits of oophorectomy are particularly significant, given the associated risk reduction for both breast and ovarian cancer. In addition, for those women who opt against prophylactic mastectomy, screening with a combination of mammography and magnetic resonance imaging appears to frequently detect breast cancer at an early stage. Effective screening strategies for ovarian cancer, however, remain elusive. Ongoing research to develop better screening measures for ovarian cancer is especially critical now given the substantial number of women who are identified by BRCA1/2 positive status as being at high risk for this disease – a risk not necessarily intuitive based on their family history, which often does not include ovarian cancer. Perhaps one of the most unanticipated findings subsequent to the identification of BRCA1 and BRCA2 was the number of high-risk families who do not harbor a detectable mutation in these genes. Recently, the availability of testing for large rearrangements in BRCA1 and BRCA2 has increased the sensitivity of commercial testing; however, the overall yield of deleterious mutations detected with this new method is small. In other high risk families, rare hereditary cancer syndromes may be implicated. Although these syndromes often have a distinct phenotype, they may be underrecognized by clinicians. In addition, we are learning more about other genetic contributions to familial breast cancer risk – including low penetrance gene mutations, SNPs (single nucleotide polymorphisms), and mutations in modifier genes. Given that no other ma-