What question did this study set out to answer?

To evaluate how polygenic risk scores and clinical risk factors interact to predict breast cancer risk in Black women.

February 22, 2026

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

Key Result

MA-385 polygenic risk score predicted breast cancer with OR=1.38 (95% CI 1.32-1.45) in Black/African women, with no significant interaction with clinical risk factors.

Key Points

To evaluate how polygenic risk scores and clinical risk factors interact to predict breast cancer risk in Black women.
Examined clinical and genetic records from self-reported Black women referred for hereditary cancer testing.
Used multivariable logistic regression models to test interactions of MA-385 and individual SNPs with clinical risk factors.
Included interaction terms in models to evaluate effect modification by clinical factors.
Identified 39,817 eligible women, with 22.1% diagnosed with invasive breast cancer.
MA-385 was a significant predictor of breast cancer (OR=1.38; 95% CI 1.32-1.45).
No significant interactions found between MA-385 or SNPs and clinical risk factors.
Strongest interaction evidence was for hormone replacement therapy status, but not statistically significant post-adjustment.

Structured PICO

Does the MA-385 polygenic risk score predict invasive breast cancer risk and interact with clinical risk factors in women of Black/African ancestry?

Population

39,817 self-reported Black/African women referred for hereditary cancer testing with a multigene panel and tested negative for pathogenic variants in BC-associated genes.

Intervention

Multiple-ancestry polygenic risk score (MA-385) and 5 individual BC-associated SNPs

Outcome

Invasive breast cancerhard clinical

The MA-385 polygenic risk score significantly predicts invasive breast cancer in Black/African women independently of clinical risk factors, with no significant interactions observed.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

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 p0.05). 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 p0.05). 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.

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