Abstract ES1-1: Management of non-BRCA breast cancer predisposition
Authors: Robson M 
Published: May 2016

In the years since the discovery of BRCA1 and BRCA2, researchers have extended our understanding of the genetic architecture of breast cancer risk. Breast cancer has been described as a component tumor or a number of high penetrance autosomal dominant predisposition syndromes, such as Li-Fraumeni, Cowden Syndrome, Hereditary Diffuse Gastric Cancer, Peutz-Jeghers Syndrome, and possibly Lynch Syndrome. These are rare, but have clear clinical relevance once identified. At the other end of the spectrum, a series of genome-wide association studies (GWAS) identified over 80 common variants (SNPs) associated with breast cancer risk in the general population. The risk of an individual SNP is very low. An individual inheriting a significant number of risk alleles, however, may be a a clinically relevant degree of risk, even without a family history. An individual polygenic risk score can be calculated and correlates with risk, although how to apply this clinically is uncertain. Lastly, mutations in a number of moderate penetrance genes have been found that confer average relative risks of 2-3, with even higher risks in the setting of a family history. These genes include CHEK2, ATM, PALB2, and possibly others such as NBN. Other genes such as BARD1 and MRE11A have also been suggested to be moderate penetrance predisposition genes, but evidence of clinical validity is lacking. None of these are clearly linked to ovarian cancer risk. Genes such as BRIP1 and RAD51B/C/D appear to be moderate penetrance ovarian cancer predisposition genes, but their association with breast cancer is uncertain.

Cancer genetics professionals had not been routinely testing patients for moderate penetrance predispositions before next generation sequencing facilitated the development of multi-gene panel testing. Since the commercial deployment of panel testing, hundreds (even thousands) of individuals, mainly women, have been identified as carriers of mutations in these genes. The appropriate management of these predispositions remains unclear, as guidelines developed for those with high penetrance mutations are not appropriate for most of those with more moderate risks. The effectiveness (and cost-effectiveness) of incremental MRI screening for women at moderate risk is unclear, although the lifetime risks associated with several moderate penetrance mutations cross the 20% threshold proposed by the American Cancer Society and American College of Radiology. There is no consensus, however, as to the age at which to begin this screening. Preventive mastectomy is probably not appropriate for most women with moderate penetrance mutations without a substantial family history. Risk-reducing sapling-oophorectomy may be appropriate for women with BRIP1 and RAD51B/C/D mutations, but the procedure can probably be delayed until around the time of natural menopause in most women, unless they have a significant family history of ovarian cancer.

Moderate penetrance mutations can best be thought of as risk factors, which interact with other genetic (e.g. Family history) and non-genetic factors to influence an individual's breast or ovarian cancer risk. This is different from the situation with high penetrance mutations, where the mutation is causative in isolation. Management should be directed by this concept, tailored to the family history.

Citation Format: Robson M. Management of non-BRCA breast cancer predisposition. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES1-1.