Improving a polygenic risk score (PRS) for breast cancer (BC) risk assessment in diverse ancestries.

10533 Background: Accurate BC risk assessment is essential to identify women for whom screening and preventive interventions may be lifesaving. Incorporation of PRS into clinical models can improve risk prediction, but most PRS have shown suboptimal performance among non-Europeans. We previously described a multiple-ancestry PRS (MA-149) based on 56 ancestry-informative and 93 BC-associated single-nucleotide polymorphisms (SNPs). MA-149 achieved accuracy for diverse populations by characterizing genetic ancestry at each SNP in terms of fractions attributable to reference ancestries (African, East Asian, European) and applying ancestry-specific risks and frequencies. MA-149 significantly outperformed the Tyrer-Cuzick (TC) model, and integration of MA-149 with TC improved predictive accuracy by roughly two-fold over TC alone. Here, we aimed to improve MA-149 by expanding the set of BC SNPs and refining ancestry-specific risks. Methods: We developed a novel stepwise regression methodology accounting for linkage disequilibrium to select an optimal set of BC SNPs. Women referred for hereditary cancer testing and negative for pathogenic variants in BC genes were divided into consecutive cohorts to (1) refine ancestry-specific SNP risks ( N=58,191 Black/African; N=27,160 East Asian), (2) develop the PRS ( N=184,322), and (3) conduct independent validation ( N=146,110). Predictive accuracy and calibration of the new PRS were evaluated in the full cohort and subpopulations of different ancestries. Odds ratios (OR) from multivariable regression are reported per standard deviation. Results: A set of 385 SNPs (56 ancestry, 329 BC) was selected for the new PRS (MA-385). MA-385 improved upon clinical factors and outperformed MA-149 within each ancestry (Table). Among non-Europeans, MA-385 was a better BC risk predictor (OR=1.47, 95% CI: 1.42-1.52) than MA-149 (OR=1.40, 95% CI: 1.35-1.45). The strongest associations were observed in Ashkenazi Jewish and Hispanic women (Table). MA-385 identified more women at >2-fold increased risk than MA-149 (6.5 % vs 2%). Goodness-of-fit tests showed that MA-385 was well-calibrated while a 385-SNP PRS with European weights was miscalibrated for non-Europeans. Conclusions: MA-385 was well-calibrated, improved upon clinical factors, and outperformed existing PRS in all tested ancestries. Incorporation of MA-385 into risk assessment could improve the early detection and prevention of BC. [Table: see text]