Associations Between Pre-diagnostic Plasma Metabolites and Ovarian Cancer: A Prospective Case-Cohort Analysis in the Cancer Prevention Study-3

BACKGROUND: Ovarian cancer remains a significant health concern among U.S. women, yet its underlying etiology is not fully understood. Untargeted metabolomics enables comprehensive profiling of small molecules that may provide insight into metabolic alterations associated with ovarian cancer risk. METHODS: We conducted a case-cohort study within the Cancer Prevention Study-3, measuring pre-diagnostic plasma metabolites via untargeted metabolomics in 127 ovarian cancer cases and a randomly selected sub-cohort of 1,811 women, one of whom was later diagnosed with ovarian cancer. Median follow-up time was 2.4 years (IQR: 1.2-3.6) among ovarian cancer cases and 3.2 years (IQR: 2.5-5.2) in the sub-cohort. Metabolite associations with ovarian cancer risk were estimated using multivariable Prentice-weighted Cox models, and pathway enrichment analyses were performed. False discovery rate (FDR) correction was applied, considering FDR < 0.2 statistically significant. RESULTS: Among 868 plasma metabolites analyzed, none showed statistically significant associations with ovarian cancer risk after FDR correction. In stratified analyses by menopausal status, five metabolites remained statistically significant after FDR correction among postmenopausal women only. Pathway enrichment analyses identified several lipid-related sub-pathways enriched among metabolites associated with ovarian cancer risk (FDR-adjusted p-value < 0.2), with the strongest positive enrichment observed for primary bile acid metabolism and the strongest negative enrichment for sphingomyelins. CONCLUSIONS: In this prospective metabolomics analysis, individual pre-diagnostic plasma metabolites were not associated with ovarian cancer risk, but lipid-related pathways and possible differences by menopausal status may warrant additional investigation. IMPACT: These findings contribute to the growing untargeted metabolomics literature on ovarian cancer.