Polygenic Risk Scores for Prediction of Breast Cancer in Korean women

Background: Polygenic risk scores (PRS) developed in large European GWAS have been shown to predict breast cancer risk in European-ancestry women and perform well in Asian women relative to PRS developed in smaller Asian studies. However, prospective validation of absolute risk predictions from models combining lifestyle and PRS in Asian women is limited. Objectives: Here 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 and GRS-136EUR) and two included sub-genome-wide significant SNPs (PRS-42ASN and PRS-209EUR). We also assessed the improvement in risk prediction and risk stratification by incorporating the PRS into classical risk factor model. 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 in a cohort of 41,031 women from the Korean Cancer Prevention Study-II Biobank: (i) a model using incidence, mortality, and risk factor distributions among U.S. non-Hispanic white women and European-ancestry relative risks; (ii) a recalibrated model, using Korean incidence mortality and risk factor distributions but European-ancestry relative risks; and (iii) a fully Korean-based model using Korean incidence mortality and risk factor distributions and relative risk estimates from the KCPS. Results: All Asian and European PRS improved risk prediction for breast cancer in Korean women under 50 (Qx: AUC=0.65, Qx+PRS-42ASN: AUC=0.68, Qx+PRS-209EUR: AUC=0.69 in Korean-based model for age<50). European PRS had larger effect sizes and greater discrimination than Asian PRS in a Korean population (PRS-42ASN: HR per SD = 1.40, AUC = 0.60 vs. PRS-209EUR: HR per SD = 1.54, AUC = 0.62). 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 PRS into risk models in ancestrally diverse populations.