Importance: Validating polygenic risk scores (PRSs) as a breast cancer (BC) risk stratification tool in high-risk clinical settings is essential for potential clinical implementation. Objective: To evaluate the performance of African-ancestry PRSs for overall BC and triple-negative BC (TNBC) in an independent African American cohort at elevated familial risk. Design, Setting, and Participants: This case-control study was conducted among women with self-reported African ancestry in a clinical hereditary cancer genetic testing setting who had negative results for pathogenic or likely pathogenic variants in known BC-associated genes between 2016 to 2024. Analyses were performed from September 2025 to April 2026. Exposure: Six African-ancestry PRSs and a European-ancestry PRS (PRS-313). Main Outcomes and Measures: Performance of the PRSs was measured with covariate-adjusted area under the receiver operating characteristic curve (AUC) and adjusted odds ratio (OR) per 1 SD from logistic regression adjusting for age, top 10 genetic principal components, and family history. Results: This study included 31 522 women (mean SD age, 47.1 13.3 years): 12 067 women with BC (2311 with TNBC) and 19 455 women unaffected by BC. Women unaffected by BC were younger at testing than women with BC at diagnosis (mean SD age, 42.1 11.7 years vs 55.2 11.8 years) and were more likely to report a first- and second-degree family history of BC than women with BC (14 524 women 74.7% vs 6483 women 53.7%). For overall BC, PRS-313 showed an AUC of 0.567 (95% CI, 0.560-0.574) and an OR of 1.28 (95% CI, 1.25-1.31) per 1 SD of individuals unaffected by BC. In comparison, the African overall BC models 1 (2 324 063-variant model) and 2 (175 173-variant model) performed better, with AUCs of 0.588 (95% CI, 0.580-0.595) and 0.584 (95% CI, 0.576-0.591) and ORs of 1.39 (95% CI, 1.35-1.43) and 1.37 (95% CI, 1.34-1.41) per 1 SD of individuals unaffected by BC, respectively. Importantly, for TNBC, one 162-variant PRS consistently outperformed all other models, with an AUC of 0.609 (95% CI, 0.596-0.622) and an OR of 1.47 (95% CI, 1.40-1.55) per 1 SD of individuals unaffected by BC. Conclusions and Relevance: In this clinically ascertained case-control study of self-reported Black or African American women, the PRSs demonstrated good performance among women with a strong family history of BC, reflecting populations in whom early PRS testing is most relevant. The high accuracy of the 162-variant TNBC PRS supported its potential as a cost-effective risk assessment tool to promote equitable care.
Sun et al. (Wed,) studied this question.