Generalizability of PRS313 for breast cancer risk amongst non-Europeans in a Los Angeles biobank

Polygenic risk scores (PRS) summarize the combined effect of common risk variants and are associated with breast cancer risk in patients without identifiable monogenic risk factors. One of the most well-validated PRSs in breast cancer to date is PRS313, which was developed from a Northern European biobank but has shown attenuated performance in non-European ancestries. We further investigate the generalizability of the PRS313 for American women of European (EA), African (AFR), Asian (EAA), and Latinx (HL) ancestry within one institution with a singular EHR system, genotyping platform, and quality control process. We found that the PRS313 achieved overlapping Areas under the ROC Curve (AUCs) in females of Lantix (AUC, 0.68; 95 CI, 0.65-0.71) and European ancestry (AUC, 0.70; 95 CI, 0.69-0.71) but lower AUCs for the AFR and EAA populations (AFR: AUC, 0.61; 95 CI, 0.56-0.65; EAA: AUC, 0.64; 95 CI, 0.60-0.680). While PRS313 is associated with Hormone Positive (HR+) disease in European Americans (OR, 1.42; 95 CI, 1.16-1.64), for Latinx females, it may be instead associated with Human Epidermal Growth Factor Receptor 2 (HER2+) disease (OR, 2.52; 95 CI, 1.35-4.70) although due to small numbers, additional studies are needed. In summary, we found that PRS313 was significantly associated with breast cancer but with attenuated accuracy in women of African and Asian descent within a singular health system in Los Angeles. Our work further highlights the need for additional validation in diverse cohorts prior to clinical implementation of polygenic risk scores.