Abstract PS3-01-03: Interactions between polygenic variants and clinical factors as predictors of breast cancer risk in women of self-reported Black/African ancestry

Abstract Background Polygenic risk scores (PRSs) combine information from single-nucleotide polymorphisms (SNPs) across the genome to explain a substantial portion of genetic breast cancer (BC) susceptibility. In previous studies, a multiple-ancestry PRS (MA-385) based on 56 ancestry-informative and 329 BC-associated SNPs was accurate for diverse populations and ranked among the most significant factors affecting the risk of BC development. However, medical guidelines discourage the routine clinical use of PRS, citing a need for studies to evaluate potential interactions between SNPs and environmental and hormonal risk factors in diverse populations. Here, we investigate interactions of MA-385 and individual BC-associated SNPs with clinical risk factors in the widely used Tyrer-Cuzick (TC) model in a large cohort of self-reported Black/African women. Methods We examined clinical and genetic records from self-reported Black/African women who were referred for hereditary cancer testing with a multigene panel and tested negative for pathogenic variants in BC-associated genes. Multivariable logistic regression models adjusted for age, personal/family cancer history, and genetic ancestry were used to test individual TC risk factors, MA-385, and 5 individual BC SNPs with the greatest impact on BC risk for women of Black/African ancestry. Effect modification of MA-385 and individual SNPs by TC risk factors was evaluated by including interaction terms in the models. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported per standard deviation of MA-385. Significance tests were performed using two-sided p-values based on likelihood-ratio test statistics. Results We identified 39,817 women who met study eligibility criteria. 8,802 (22.1%) women had been diagnosed with invasive BC prior to hereditary cancer testing. 17,529 women, independent of previous MA-385 development studies, were included in analyses of MA-385. Individual SNPs and clinical TC risk factors were examined in women with complete risk factor information. All 39,817 women had complete information for age and BC family history; sample sizes for other clinical risk factors ranged from 1,795 for breast density to 29,486 for height. The MA-385 was a highly significant predictor of invasive BC after accounting for clinical factors (OR=1.38; 95% CI 1.32-1.45, p=4.2 x 10-45). We found no evidence of interaction of MA-385 with any individual TC factor (all Bonferroni-adjusted p>0.05). The strongest evidence of interaction was for hormone replacement therapy status (unadjusted p=0.04; Bonferroni-adjusted p=0.66). The 5 SNPs with the greatest impact on BC risk for women of Black/African ancestry were distinct from those previously identified as having the greatest impact on BC risk for women of European ancestry. We found no evidence of interaction between these individual SNPs and TC risk factors (all Bonferroni-adjusted p>0.05). The strongest evidence for interaction was between a SNP on chromosome 19 (rs2363956) and BMI category (unadjusted p=0.04; Bonferroni-adjusted p=1). Conclusions In a large cohort of Black/African women, MA-385 was a highly significant predictor of BC and substantially improved risk prediction over clinical risk factors. In contrast, interactions of MA-385 and individual BC SNPs with clinical risk factors were not statistically significant. These findings suggest that TC factors have a minimal, if any, impact on the strength of the association between the MA-385 PRS and invasive BC in women of Black/African ancestry. Citation Format: T. Simmons, E. Hughes, M. Kucera, A. Gutin. Interactions between polygenic variants and clinical factors as predictors of breast cancer risk in women of self-reported Black/African ancestry [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-03.