Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Breast Cancer Risk Prediction Among Asian Women.

Importance: Polygenic risk scores (PRSs) have shown promise in breast cancer risk prediction; however, limited studies have been conducted among Asian women. Objective: To develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors. Design, Setting, and Participants: This diagnostic study included women of Asian ancestry from the Asia Breast Cancer Consortium. PRSs were developed using data from genomewide association studies (GWASs) of breast cancer conducted among 123 041 women with Asian ancestry (including 18 650 women with breast cancer) using 3 approaches: (1) reported PRS for women with European ancestry; (2) breast cancer-associated single-nucleotide variations (SNVs) identified by fine-mapping of GWAS-identified risk loci; and (3) genomewide risk prediction algorithms. A nongenetic risk score (NGRS) was built, including 7 well-established nongenetic risk factors, using data of 416 case participants and 1558 control participants from a prospective cohort study. PRSs were initially validated in an independent data set including 1426 case participants and 1323 control participants and further evaluated, along with the NGRS, in the second data set including 368 case participants and 736 control participants nested within a prospective cohort study. Main Outcomes and Measures: Logistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% CIs and area under the receiver operating characteristic curve (AUC). Results: A total of 126 894 women of Asian ancestry were included; 20 444 (16.1%) had breast cancer. The mean (SD) age ranged from 49.1 (10.8) to 54.4 (10.4) years for case participants and 50.6 (9.5) to 54.0 (7.4) years for control participants among studies that provided demographic characteristics. In the prospective cohort, a PRS with 111 SNVs developed using the fine-mapping approach (PRS111) showed a prediction performance comparable with a genomewide PRS that included more than 855 000 SNVs. The OR per SD increase of PRS111 score was 1.67 (95% CI, 1.46-1.92), with an AUC of 0.639 (95% CI, 0.604-0.674). The NGRS had a limited predictive ability (AUC, 0.565; 95% CI, 0.529-0.601). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and NGRS were at a 3.84-fold (95% CI, 2.30-6.46) and 2.10-fold (95% CI, 1.22-3.62) higher risk of breast cancer, respectively. The prediction model including both PRS111 and NGRS achieved the highest prediction accuracy (AUC, 0.648; 95% CI, 0.613-0.682). Conclusions and Relevance: In this study, PRSs derived using breast cancer risk-associated SNVs had similar predictive performance in Asian and European women. Including nongenetic risk factors in models further improved prediction accuracy. These findings support the utility of these models in developing personalized screening and prevention strategies.