Polygenic Risk Score Enhances Comprehensive Breast Cancer Risk Assessment and Modifies Clinical Actionability in Carriers of a Pathogenic Variant

Abstract Purpose Breast cancer risk varies widely among women with a pathogenic variant (PV) in a breast cancer susceptibility gene; however, follow-up and prevention strategies are often homogeneous. Polygenic risk scores (PRS) may refine risk stratification. We evaluated changes in breast cancer risk categories and clinical actionability after incorporating PRS into classical risk factors in unaffected carriers. Methods This nationwide multicenter study conducted across Spain included unaffected women carrying a germline PV in a breast cancer susceptibility gene. Ten-year and lifetime breast cancer risk categories were estimated using the BOADICEA model before and after incorporation of the PRISMA-268 PRS. Risk categories were defined according to the NICE thresholds. The primary outcome was change in breast cancer risk category and clinical actionability. Results Among 1,205 women, 577 were non- BRCA1/2 carriers and 628 were BRCA1/2 carriers. PRS incorporation resulted in lifetime-risk reclassification in 31% of non- BRCA1/2 carriers compared with 12% of BRCA1/2 carriers. After PRS integration, 29%, 35%, and 36% of non- BRCA1/2 carriers were classified as having average, moderate, and high lifetime breast cancer risk, respectively. At age 30 years, 61% of non- BRCA1/2/PALB2 carriers would be eligible to initiate breast cancer surveillance. Conclusions Incorporating PRS into multifactorial breast cancer risk assessment significantly modifies risk stratification, particularly among non- BRCA1/2/PALB2 carriers, and provides clinically relevant information to guide personalized prevention and screening strategies.