Development of a Breast Cancer Risk Prediction Model Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Korean Women

Abstract

Background: To develop a breast cancer prediction model for Korean women using published polygenic risk scores (PRS) combined with nongenetic risk factors (NGRF).

Methods: Thirteen PRS models generated from single or multiple combinations of the Asian and European PRSs were evaluated among 20,434 Korean women. The AUC and increase in OR per SD were compared for each PRS. The PRSs with the highest predictive power were combined with NGRFs; then, an integrated prediction model was established using the Individualized Coherent Absolute Risk Estimation (iCARE) tool. The absolute breast cancer risk was stratified for 18,142 women with available follow-up data.

Results: PRS38_ASN+PRS190_EB, a combination of Asian and European PRSs, had the highest AUC (0.621) among PRSs, with an OR per SD increase of 1.45 (95% confidence interval: 1.31-1.61). Compared with the average risk group (35%-65%), women in the top 5% had a 2.5-fold higher risk of breast cancer. Incorporating NGRFs yielded a modest increase in the AUC of women ages >50 years. For PRS38_ASN+PRS190_EB+NGRF, the average absolute risk was 5.06%. The lifetime absolute risk at age 80 years for women in the top 5% was 9.93%, whereas that of women in the lowest 5% was 2.22%. Women at higher risks were more sensitive to NGRF incorporation.

Conclusions: Combined Asian and European PRSs were predictive of breast cancer in Korean women. Our findings support the use of these models for personalized screening and prevention of breast cancer.

Impact: Our study provides insights into genetic susceptibility and NGRFs for predicting breast cancer in Korean women.

Figure 1.

Study flow chart. Previously reported breast cancer SNPs were validated among Korean women using various published PRSs, and absolute breast cancer risks were evaluated using the PRS with the highest accuracy (left). Prediction models incorporating PRSs and NGRFs were constructed using a different cohort (right). After evaluating the predictive performance of the models, the absolute breast cancer risk was estimated.

Figure 2.

AUC for various PRS models and NGRFs predicting the breast cancer risk. The AUC was compared among NGRFs, PRSs, and integrated (PRS+NGRF) models for women. A, Age <50 years. B, ≥50 years.

Figure 3.

Estimation of the absolute breast cancer risk by seven percentiles. The absolute risk of developing breast cancer is predicted using the integrated model (PRS_{38_ASN}+PRS_{190_EB}+NGRF). The dotted lines represent the average risks. A, Lifetime absolute risk. B, 5-year absolute risk.

Figure 4.

Density plot of breast cancer absolute risk at age 80. The absolute risk was stratified by seven PRS percentiles. A, Multiple PRS model. B, Integrated model.