Abstract C090: Detecting epigenetic signatures to prevent avoidable racial inequities in triple-negative breast cancer (desparit): A pilot study

Background: Black women in the United States experience a 40% higher mortality rate from breast cancer compared to White women, a disparity largely attributable to a twofold higher incidence of triple-negative breast cancer (TNBC) among Black women. TNBC is an aggressive subtype with limited treatment options that is more difficult to detect at early stages. Delaware is among the states with the highest incidence of TNBC in the US. We recently identified geographic “hotspots” within the state that have significantly elevated TNBC incidence. These hotspots are characterized by high rates of racial residential segregation but are not fully explained by greater proportions of Black residents. Evidence suggests that neighborhood characteristics that promote greater exposure to potentially modifiable risk factors such as obesity, limited breastfeeding, alcohol use, and environmental toxins contribute to elevated geographic risk for TNBC after adjusting for demographic factors. We hypothesize that the cumulative effect of these exposures drive epigenetic reprogramming of circulating immune cells, creating a pro-inflammatory and immunosuppressive microenvironment that promotes TNBC development. This pilot study aimed to evaluate whether breast cancer patients living in TNBC hotspot regions exhibit distinct epigenetic changes in circulating immune cells compared to those from non-hotspot areas. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 32 treatment-naïve breast cancer patients enrolled at the Helen F. Graham Cancer Center & Research Institute and stratified by residential address into TNBC hotspot (n=16) and non-hotspot (n=16) groups, based on geospatial clustering of TNBC incidence in Delaware. Genomic DNA was extracted and profiled using the Twist Human Methylome Panel, targeting over 3.2 million CpG sites across the genome. Methylation data were analyzed using the nf-core methylseq v2.6.0 pipeline and methylKit v1.25 in R. Results: A total of 12,200 CpG sites showed significant differences in methylation load, with 5,202 hypomethylated and 6,998 hypermethylated sites in patients from hotspot regions compared to those in non-hotspot regions. Principal component analysis (PCA) of differentially methylated genes and promoters (FDR < 0.05; ≥3% methylation difference) revealed clear clustering by geographic hotspot status. Differentially methylated genes included those involved in immunosuppression, inflammation, and cytokine signaling. Conclusions: This pilot study found epigenetic changes in immune-related genes among women residing in TNBC hotspot neighborhoods, supporting a potential link between cumulative exposure and immune reprogramming. Further research is needed to determine the clinical significance of these changes and their role in driving breast cancer disparities. Citation Format: Jennifer Sims-Mourtada, Ross Budziszewski, Lisa Frerichs, Ashely Stewart, Caitlin Mbuakoto, Madolyn L. MacDonald, Shawn W. Polson, Yuchen Zhang, Scott D. Siegel. Detecting epigenetic signatures to prevent avoidable racial inequities in triple-negative breast cancer (desparit): A pilot study [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 C090.