Impact of Population-Based Pathogenic Variant Testing on Risk-Based Breast Screening Recommendations

Risk-based breast cancer screening has emerged as a viable alternative to annual mammography. To guide implementation, knowledge is needed on the contribution of testing for pathogenic variants (PVs) beyond clinical risk factors and common genetic variants for population-based risk stratification. This cohort study used retrospective data from the WISDOM Study, a national clinical trial of risk-based vs annual breast cancer screening, to compare screening assignments informed by PV status vs those based on a clinical risk model alone or a clinical risk model combined with a polygenic risk score. Of 712 included women with a PV, the median age was 53 (46-62) years. A total of 232 PVs (33%) were high penetrance, 278 (39%) were moderate penetrance, and 202 (28%) were CHEK2 low penetrance. Overall, 178 of 279 PV carriers aged 40 to 49 years (63.8%) would have otherwise been recommended to defer screening until age 50 years based on clinical plus polygenic risk, whereas 385 of 433 carriers aged 50 to 74 years (88.9%) would have been recommended biennial mammography. Most participants with PVs in breast cancer genes would not have been recommended for high-risk screening based on their clinical or clinical plus polygenic risk. PV testing therefore may identify different subsets of high-risk women than clinical risk factors and polygenic risk scores. These findings highlight the importance of population-based PV testing in risk-based screening.