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

Importance: 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. Objective: To evaluate how many PV carriers in a risk-based breast cancer screening trial would have been recommended for high-risk screening based on clinical risk or clinical plus polygenic risk. Design, Setting, and Participants: 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. WISDOM participants aged 40 to 74 years who tested positive for a PV as part of risk-based screening were included. Data were collected from September 2016 to February 2023, with follow-up to September 2025. Data were analyzed from January to May 2026. Main Outcomes and Measures: Concordance between actual (considering participants' PV status) and hypothetical screening assignments based on a clinical (Breast Cancer Surveillance Consortium) risk model or a clinical model plus polygenic risk score. Results: Of 712 included women with a PV, the median (IQR) 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. There was little overlap between actual screening assignments based on PV status and hypothetical assignments based on a clinical model plus polygenic risk score. Among high-penetrance PV carriers (a group recommended high-risk screening with magnetic resonance imaging alternating with mammography every 6 months), 2 of 232 (0.9%) would have received the same screening assignment based on clinical plus polygenic risk. 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. Results were similar when comparing assignments based on a clinical model alone. Conclusions and Relevance: In this cohort study, 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02620852.