Abstract PS3-07-30: Genomic Drivers of Racial Disparity in HR-Positive Early Breast Cancer

Abstract Background: Nearly all breast cancer disparities research has focused on the higher incidence of triple-negative breast cancer (TNBC) among Black women despite the fact that hormone receptor-positive (HR+) breast cancer is three times more common than TNBC, and Black women with HR+, early-stage breast cancer (EBC) are 80% more likely to die and 30% more likely to have biologically aggressive HR+ tumors compared with Non-Hispanic White (NHW) women (Hoskins et al, JAMA Oncol 2021). Genomic subtyping studies of HR+ EBC reveal that compared with NHW women, Black women have a higher prevalence of the aggressive luminal B and HR+ basal subtypes, but the molecular mechanisms underlying this racial difference are unknown. We analyzed genomic profiles of HR+/HER2- primary tumors in a diverse cohort of EBC patients in order to identify molecular drivers of the aggressive HR+ tumor phenotype that disproportionately affects Black women. Methods: A series of cases of HR+/HER2- EBC treated at the University of Illinois Chicago (UIC) between 2018-2021 underwent NGS profiling of the primary tumor in the Laboratory of Genomic Medicine at UIC for DNA and RNA somatic driver alterations with the Oncomine Comprehensive Assay v3 (OCAv3), which includes 161 driver genes and detects SNVs, CNVs, indels, and gene fusions. Enrichment of alterations according to self-identified race was tested with Fisher’s exact tests and odds ratios with 95% confidence intervals (CI). Publicly available TCGA data was downloaded from the Genomic Data Commons portal (https://portal.gdc.cancer.gov) to validate findings. Indicators of neighborhood disadvantage were obtained by geocoding residential addresses and linking to census tract measures of the social and environmental context to examine associations between tumor genomic profile and neighborhood contextual factors. Results: In total, 128 primary tumors were evaluated (Black, n=72; non-Black, n=56). Results for the most prevalent alterations are presented in the table. Inactivating SNVs and indels in ARID1A and ATM were more common in tumors from Black patients. Results of analyses for survival and for associations between neighborhood- and individual-level indicators of disadvantage and tumor genomic profile, and validation with TCGA data will be presented. Conclusion: Inactivation of ARID1A (a key component of the SWI/SNF chromatin remodeling complex) in HR+ breast cancer cells leads to loss of luminal identity, switch to an estrogen-independent basal-like phenotype, and resistance to endocrine therapy (Xu et al. Nature Genetics 2020). Enrichment of ARID1A somatic driver mutations in HR+/HER2- tumors from Black patients with EBC provides a mechanistic explanation for the higher rate of HR+ basal tumors in that population. This finding along with the higher rate of ATM alterations can inform development of targeted therapeutic strategies designed to mitigate racial disparity in EBC survival. Citation Format: J. Vu, J. Gor, Y. Simons, G. E. Chlipala, M. W. Geise, A. Ibraheem, O. C. Danciu, V. K. Gadi, M. Singh, K. F. Hoskins, G. Mohapatra. Genomic Drivers of Racial Disparity in HR-Positive Early Breast Cancer 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 PS3-07-30.