Abstract A038: Interrogating the immune and tumor signatures underlying endometrial cancer disparities in Black/African American women

Abstract Endometrial cancer (EC) is the sixth most common gynecological malignancy globally, with an increasing incidence over the last two decades. Black/African American (BAA) women are disproportionately affected, experiencing higher rates of high-grade EC and increased mortality compared to Non-Hispanic White (NHW) women. Notably, BAA women are 2–3 times more likely to be diagnosed with aggressive, high-grade EC and have significantly higher mortality rates. These disparities are likely driven by complex interactions between systemic inequities, social determinants of health, physiology, and biological differences within the tumor microenvironment. To improve outcomes, there is an urgent need to address these disparities through both biological and community-informed research. Uterine EC disparities are influenced by heterogeneous tumor ecosystems with distinct genotypes, phenotypes, and spatial transcriptomic profiles. There are four molecular subtypes of EC: POLE-ultramutated, copy number high, copy number low, and microsatellite instable. The molecular subtypes contribute to the heterogeneity and complexities that are housed within these tumors. Hence, the biological diversity of EC particularly among tumors arising in BAA women presents challenges for therapeutic targeting and contributes to poorer outcomes. This study focuses on uncovering the genomic and transcriptomic drivers of EC disparities in BAA women by characterizing the tumor microenvironment using paired genomic and spatial technologies. Our cohort includes primary, metastatic, and adjacent normal uterine tissues, with cases spanning endometrioid adenocarcinoma across multiple tumor grades. To dissect the tumor microenvironment, we utilized spatial transcriptomics to map gene expression across cellular niches within tumor sections. This analysis uncovered two distinct stromal niches where some tumors exhibited reactive stroma characterized by fibroblast-enriched, ECM-remodeling programs, while others contained hypoxic stroma with upregulated stress and metabolic pathways. Importantly, samples with myometrial invasion displayed two distinct immune response patterns—one marked by robust cytotoxic infiltration and another by immune exclusion and suppression—suggesting variable immunogenicity even within histologically similar tumors. Whole exome and RNA-sequencing is underway to further characterize these cases for known and novel molecular events potentially contributing to distinct patterns of tumor heterogeneity in EC. Together, these findings offer a nuanced view of the tumor-stromal interplay and highlight possible unique biological features of EC among BAA women. This integrative approach represents a critical step toward uncovering the mechanistic underpinnings of EC disparities. Ultimately, this work aims to inform the development of precision diagnostics and equitable therapeutic strategies that reduce mortality and improve outcomes in historically underserved and understudied populations. Citation Format: Danyelle Paine, Yuxin Jin, Javier Arias-Stella III, David Craig, Rania Bassiouni, John Carpten. Interrogating the immune and tumor signatures underlying endometrial cancer disparities in Black/African American women abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A038.