Abstract 5903: Polygenic risk scores for prediction of breast cancer in Korean women

Abstract Background: Polygenic risk scores (PRS) developed in large European GWAS have been shown to perform well in Asian women relative to PRS developed in smaller Asian studies. However, prospective validation of absolute risk prediction models combining lifestyle and PRS in Asian women is limited. We evaluate the calibration of four PRS developed using Asian or European training samples; two PRS were restricted to genome-wide significant SNPs (GRS-11ASN, GRS-136EUR) and two included sub-genome-wide significant SNPs (PRS-42ASN, PRS-209EUR). Methods: For each PRS, we compared discrimination (area under the curve [AUC]) and calibration (expected-to-observed ratio [E/O]) of three absolute risk models among 41,031 women from the Korean Cancer Prevention Study-II Biobank: (i) a model using incidence, mortality, and risk factor distributions (reference inputs) among U.S. women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS. Results: All Asian and European PRS improved risk prediction for breast cancer in Korean women (Qx: AUC=0.65, Qx+PRS-42ASN: AUC=0.68, Qx+PRS-209EUR: AUC=0.69 in Korean-based model for age less than 50). We found that the U.S.-based absolute risk models overestimated the risks for women age ≥50 years (PRS-42ASN: E/O=1.93, 95% CI=1.69, 2.19, PRS-209EUR: E/O = 1.92, 95% CI=1.69, 2.19). Our absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS. Conclusions: Incorporation of PRS previously developed in Asian and European-ancestry populations can improve discrimination in Korean women. Our finding suggests that PRS may be useful for prioritizing individuals for targeted intervention on their lifestyle such as alcohol intake and obesity. Larger Asian training samples should improve PRS discrimination among Korean women. Further studies are needed to evaluate the value of incorporating additional information on factors into a model in ancestrally diverse populations. Citation Format: Yon Ho Jee, Weang-Kee Ho, Sohee Park, Douglas Easton, Soo-Hwang Teo, Keum Ji Jung, Peter Kraft. Polygenic risk scores for prediction of breast cancer in Korean women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5903.