Abstract 5753: Multi-omic analysis links neighborhood disadvantage to elevated stress hormones and tumorigenic markers in ER+ breast cancer patient plasma and tumor samples

Intro: Estrogen receptor positive (ER+) breast cancer (BC) patients living in disadvantaged neighborhoods experience worse survival compared with patients in advantaged neighborhoods. Chronic stress, indicated by elevated cortisol levels, may mediate this disparity by dysregulating inflammatory responses driving BC tumorigenesis. However, the role of cortisol in ER+ BC remains underexplored. Objective: To explore associations between pre-treatment plasma cortisol, inflammatory proteins, tumoral gene expression changes, and neighborhood disadvantage in women with primary ER+ BC compared to cancer-free controls. Methods: Pretreatment plasma samples were collected from women with primary ER+ BC (n=98) and cancer-free controls (n=144). Tumor samples were obtained from a subset of cases (n=77). Samples were from three Chicago hospitals serving disadvantaged or advantaged neighborhoods, as determined by Community Needs Assessment reports. Plasma samples were analyzed via a steroid hormone metabolomics assay and Olink Proteomic’s inflammatory proteins panel. Gene expression in tumor samples was analyzed via the Breast Cancer 360 Nanostring panel. Mixed models, adjusted for age and BMI, compared: plasma samples from disadvantaged cases (n=48) vs. controls (n=114), advantaged cases (n=50) vs. controls (n=27), advantaged (n=27) vs. disadvantaged (n=117) controls, and advantaged (n=50) vs. disadvantaged (n=48) cases, and tumor samples from advantaged (n=44) vs. disadvantaged (n=33) cases. Results: Thirteen steroid hormones, 85 plasma proteins, and 759 tumor tissue genes were detected. Among cases vs. controls, cortisol-related metabolites (cortisol/cortisone ratio, 11-deoxycortisol, 17a-OH-progesterone, androstenedione) were elevated in cases (p<0.05). The cortisol/cortisone ratio remained significantly elevated in disadvantaged cases vs. controls (p<0.01) but not advantaged cases vs. controls. In disadvantaged individuals, 62 inflammatory proteins were elevated (p<0.05). Forty overlapped between controls-only and cases-only analyses, while 21 were unique to cases, including five weakly correlated with the cortisol/cortisone ratio (p<0.05). Seventy-six genes were upregulated in tumors from disadvantaged vs. advantaged cases, including those involved in cell cycle regulation, proliferation, and HIF-1 signaling. Motif analyses showed NFKB as a top motif (p<0.01), suggesting dysregulated cortisol signaling. Of the 45 downregulated genes, many were involved in anti-inflammatory pathways (p<0.05). Conclusion: BC diagnosis in disadvantaged individuals is associated with elevated cortisol, potentially contributing to elevated circulating inflammatory proteins and intratumoral gene expression changes that promote tumor progression. Citation Format: Hannah Heath, Oana C. Danciu, Garth Rauscher, Natalie Pulliam, Elona Liko-Hazizi, Sarah Friedewald, Seema Khan, Julie Kim, William Gradishar, Jonna Frasor, Kent F. Hoskins, Zeynep Madak-Erdogan. Multi-omic analysis links neighborhood disadvantage to elevated stress hormones and tumorigenic markers in ER+ breast cancer patient plasma and tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5753.