Abstract P2-02-17: Race and outcomes in HR+/HER2- breast cancer: how tissue morphology and molecular pathways contribute to worse outcomes in Black women

Abstract Background: Black women with breast cancer (BC) have a 40% higher relative risk of BC death than White women. Previous analyses from the RxPonder study have shown that differences in tumor biology, particularly higher proliferation axis scores in tumors from Black women, may contribute to these poorer outcomes (Abdou et al. ASCO24). However, a comprehensive understanding of the underlying tumor biology necessitates further investigation. To this end, we conducted an in-depth analysis of tissue morphology and molecular pathways in Black and White women with early-stage hormone receptor-positive (HR+) BC, aiming to elucidate the biological factors driving these disparities. Methods: We used the SIMBIOSYS PhenoScope Discovery software suite to investigate (HR+) BCs using paired MRIs and gene expression data from the ISPY-2 trial (N = 309 patients, 272 White and 37 Black). PhenoScope Discovery uses an AI-based algorithm to automatically segment tumors and surrounding tissues from MRIs and calculates morphological features associated with tumor biology. These morphological features, including features describing the tumor size, shape, and vascularity are then integrated via a machine learning model into a composite score called the the TumorSight Risk score, which has been shown to be prognostic of event-free survival (EFS) in early-stage breast cancer. Additionally, PhenoScope Discovery uses genome-scale metabolic modeling to simulate tumor metabolic pathway usage and dependency from gene expression data. We integrated the multi-scale outputs of PhenoScope Discovery to compare tumor morphology, simulated metabolism, and risk of recurrence amongst Black and White patients. Results: We used the TumorSight Risk score to stratify patients based on their tumor morphology characteristics into recurrence high-risk and low-risk groups. We found Black women with (HR+) BC are more likely to have high-risk tumors than White women with (HR+) BC – 43% of tumors in Black women were high-risk; compared to only 29% of tumors in White women. Furthermore, integrating results from our metabolic modeling, we found that high-risk tumors were more likely to be dependent on mitochondrial fatty acid metabolism, suggesting a mechanistic connection between recurrence risk and breast adiposity. We also directly compared tumor metabolism simulated from our metabolic model between Black and White women. We found that the tumors in Black women had a higher proliferation rate than tumors in White women (p = 0.001), indicating more aggressive tumors in Black women. This increased proliferation rate was driven by an increase in Warburg metabolism (characterized by higher glucose uptake, more use of the glycolysis pathway, and higher lactate secretion in tumors in Black women). Conclusions: In this cohort of patients with (HR+) BC, tumors in Black women had a higher proliferation rate and a higher likelihood of being classified as high-risk of recurrence (using TumorSight Risk). Additional analyses of cellular signaling, tumor vascularity, and tumor perfusion are underway to try to further understand these disparities. Citation Format: Daniel Cook, Zach Cacini, John A. Cole, Kimberly A. Kelly, Yara Abdou. Race and outcomes in HR+/HER2- breast cancer: how tissue morphology and molecular pathways contribute to worse outcomes in Black 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 P2-02-17.