Cancer
Cumulative risk of breast cancer in the US population, considering pathogenic variants, family history, and established epidemiologic risk factors Katie O’Brien* Katie O’Brien Dale Sandler Alexander Keil
Background Certain variants of BRCA1, BRCA2, and other genes can greatly increase individuals’ breast cancer risk. Understanding personal risk may help women make decisions about preventive care, but few studies have investigated the role of these pathogenic variants (PVs) in the general population or in the context of family history and other established risk factors.
Methods We estimated breast cancer odds ratios for PVs of 7 genes in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium (n=67,692, including 33,841 cases). We then combined PV data with nationwide incidence and mortality statistics to estimate conditional cumulative risks of breast cancer, standardized to the U.S. population. Additional models also incorporated population-based data and relative risk estimates for established epidemiologic risk factors.
Results PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2 were strongly associated with breast cancer, with estimates for BRCA1 and PALB2 PVs demonstrating evidence of heterogeneity by family history. The estimated cumulative risks of breast cancer incidence by age 50 ranged from 2.4% (95% confidence interval [CI]: 2.4-2.4) in women with no PVs and no family history to 35.5% (CI: 21.6-55.1) in PALB2 PV carriers with a family history. Among those breast cancer-free at age 50, the risk of breast cancer by age 80 ranged from 11.1 % (CI: 11.0-11.2) in non-carriers with no family history to 70.5% (CI: 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race/ethnicity and established breast cancer risk factors.
Discussion We present population-based estimates of cumulative breast cancer risk for established PVs for those with and without a family history, overall and for specific subgroups. Such estimates may be useful for prevention and medical decision-making among known PV carriers.
