Plasma Metabolomics and Breast Cancer Risk over 20 Years of Follow-up among Postmenopausal Women in the Nurses' Health Study

Background: Metabolite profiles provide insight into biologic mechanisms contributing to breast cancer development. We explored the association between prediagnostic plasma metabolites (N = 307) and invasive breast cancer among postmenopausal women in a nested case-control study within the Nurses' Health Study (N = 1,531 matched pairs). Methods: Plasma metabolites were profiled via LC/MS-MS using samples taken >= 10 years (distant, N = 939 cases) and <10 years (proximate, N = 592 cases) before diagnosis. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) comparing the 90th to 10th percentile of individual metabolite level, using the number of effective tests (NEF) to account for testing multiple correlated hypotheses. Associations of metabolite groups with breast cancer were evaluated using metabolite set enrichment analysis (MSEA) and weightedgene coexpression network analysis (WGCNA), with adjustment for the FDR. Results: No individual metabolites were significantly associated with breast cancer risk. MSEA showed negative enrichment of cholesteryl esters at the distant timepoint [normalized enrichment score (NES) = -2.26; P-adj = 0.02]. Positive enrichment of triacylglycerols (TAG) with <3 double bonds was observed at both time points. TAGs with >= 3 double bonds were inversely associated with breast cancer at the proximate timepoint (NES = -2.91, P-adj = 0.03). Conclusions: Cholesteryl esters measured earlier in disease etiology were inversely associated with breast cancer. TAGs with many double bonds measured closer to diagnosis were inversely associated with breast cancer risk. Impact: The discovered associations between metabolite subclasses and breast cancer risk can expand our understanding of biochemical processes involved in cancer etiology.