Palmer, Julie R

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

Abstract Background The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. Methods Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. Results Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to &gt;100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. Conclusions The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.