Abstract 3631: The role of distress-related metabolic dysfunction in ovarian cancer development

Abstract Background: Ovarian cancer has few known risk factors and most of them are not easily modifiable on a population level. Thus, there is an urgent need to identify novel and modifiable risk factors for ovarian cancer. Growing evidence suggests chronic stress and subsequent distress influence ovarian cancer etiology. Metabolites represent the end-products of metabolism, reflect genetic and environmental influences, and are associated with chronic distress. Here, we evaluated the association of a 20-metabolite distress score (MDS) and its constituting metabolites with ovarian cancer risk. Methods: Our study includes two 1:1 matched case-control studies, one (N=594) nested within the Nurses’ Health Studies (NHS and NHSII) and another (N=348) nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Metabolites were measured 3-27 years before diagnosis using liquid-chromatography tandem mass spectrometry in two batches. We calibrated and pooled metabolite values across two studies. Of the 20 MDS metabolites, we aligned 19 across batches, which were used in calculating the MDS. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer corresponding to a one standard deviation (SD) increase in MDS and the individual metabolites using unconditional logistic regression, adjusting for matching factors and menopausal status, race, tubal ligation, oral contraceptive use, and family history of breast/ovarian cancer. Results: A 1-SD increase in MDS was not associated with ovarian cancer risk, however, point estimates were consistent across studies and in the expected directions (Overall: OR 1.07; CI 0.97-1.19, p=0.17; NHS: OR 1.07; CI 0.94-1.21, p=0.31; PLCO: OR 1.09; CI 0.90-1.31, p=0.39). We observed heterogeneity in the MDS-ovarian cancer association by menopausal status, where a 1-SD increase in MDS was associated with a 19% (OR 1.19; CI 0.98-1.14, p=0.08) increased ovarian cancer risk in pre-menopausal women and 3% (OR 1.03; CI 0.91-1.17, p=0.62) increased risk in post-menopausal women. Conclusion: Pooling two independent studies, higher circulating MDS levels were associated with a modest increase in ovarian cancer risk, consistent with our hypothesis. Further, the MDS-ovarian cancer association was more pronounced among pre-menopausal women, consistent with the previously reported association between depression and ovarian cancer risk. Additional analyses investigating heterogeneity in the MDS-ovarian cancer association by lifestyle and behavior factors is ongoing. Our findings suggest that metabolic dysregulation associated with chronic distress may represent a novel risk factor for ovarian cancer. Citation Format: Nan Lin, Raji Balasubramanian, Heather A. Eliassen, Britton Trabert, Mary K. Townsend, Shelley S. Tworoger, Oana A. Zeleznik. The role of distress-related metabolic dysfunction in ovarian cancer development [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 3631.