JAMA Netw Open. 2026 Jun 1;9(6):e2619285. doi: 10.1001/jamanetworkopen.2026.19285.
ABSTRACT
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.
PMID:42307944 | DOI:10.1001/jamanetworkopen.2026.19285
