Abstract P3-02-10: Evaluation of a polygenic risk score as a predictor of breast cancer, triple-negative breast cancer, and early-onset disease in Hispanic women

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Abstract Background: Hispanic women in the U.S. have a lower incidence of breast cancer (BC) when compared to non-Hispanic white (NHW) women. However, Hispanic women diagnosed with BC tend to be younger, have more advanced disease at presentation, and have a higher risk of BC mortality compared to NHW women. Some studies have suggested that these differences may be due, in part, to a higher prevalence of aggressive subtypes, including triple-negative BC (TNBC). More accurate risk prediction methods are urgently needed to identify young Hispanic women with elevated risk of BC. Incorporating polygenic risk scores (PRS) into clinical models can substantially improve risk assessment, but most PRS have demonstrated poor performance among non-European ancestries. We previously described a multiple-ancestry PRS (MA-PRS) based on 56 ancestry-informative and 329 BC-associated single-nucleotide polymorphisms (SNPs). MA-PRS predicts overall BC risk for diverse populations by characterizing genetic ancestry at each BC SNP and applying ancestry-specific SNP risks and frequencies. Here, we evaluated the extent to which MA-PRS improves upon clinical factors for the prediction of overall BC, TNBC, and early-onset (< 50 years of age) disease in a large, independent cohort of self-reported Hispanic women. Methods: We examined clinical and genetic records from self-reported Hispanic women referred for hereditary cancer testing from 8/22 – 9/23 and negative for pathogenic variants in BC-associated genes. The association of MA-PRS with overall BC, TNBC and early-onset disease was analyzed using multivariable logistic regression adjusted for personal and family cancer history, age, and genetic ancestry. Analyses were conducted within the full cohort and the subpopulation of patients < 50 years old. Odds ratios (OR) are reported per standard deviation (SD) with 95% confidence intervals (CI). Results: 12,384 Hispanic women met the study eligibility criteria. A total of 2,071 (16.7%) were diagnosed with BC. Of those, 876 (42.3%) were diagnosed with early-onset BC, 196 (9.5%) were diagnosed with TNBC, and 86 (4.2%) were diagnosed with early-onset TNBC. Most (59.7%) of those diagnosed with BC had no family history of breast or ovarian cancer.MA-PRS significantly improved upon clinical factors for the prediction of overall BC (OR 1.63; 95% CI 1.53-1.73), early-onset BC (OR 1.62; 95% CI 1.49-1.76), TNBC (OR 1.42; 95% CI 1.22-1.67) and early-onset TNBC (OR 1.48; 95% CI 1.18-1.86). This effect of MA-PRS on risk stratification compares favorably to the 1.4 OR per SD reported in the current literature for mammographic density, which is widely recognized as an important risk factor. Conclusions: MA-PRS substantially improved upon clinical factors for the prediction of overall BC, TNBC and early-onset disease in a large cohort of Hispanic women. Incorporation of MA-PRS into BC risk assessment has the potential to improve BC survival through more accurate identification of women at high risk. Citation Format: Holly Pederson, Matthew Kucera, Eudora Hu, Brooke Hullinger, Timothy Simmons, Elisha Hughes. Evaluation of a polygenic risk score as a predictor of breast cancer, triple-negative breast cancer, and early-onset disease in Hispanic women [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-02-10.

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