Metabolite profiles reflect the integrated impact of the genome and exogenous exposures on the metabolic state and may provide insight into biologic mechanisms contributing to breast cancer development. To better understand this, we explored the association between pre-diagnostic plasma metabolites (N=307) and breast cancer among women in the Nurses' Health Study. Plasma metabolites were profiled for cases and controls via liquid chromatography tandem mass spectrometry (LC-MS) using samples taken ≥10 years prior to diagnosis (distant, N=939 cases), and <10 years prior to diagnosis (proximate, N=592 cases). Multivariable conditional logistic regression adjusting for standard breast cancer risk factors was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for a one standard deviation change in metabolite level, using the number of effective tests to account for testing multiple correlated hypotheses. Metabolite set enrichment analysis (MSEA) was used to group molecularly-similar metabolites based on pre-defined classes; triacylglycerides (TAGs) were further separated by double bond content (≥3 or <3 double bonds) (N classes=17). Weighted gene co-expression network analysis (WGCNA) identified data-driven metabolite modules based on their interconnectedness; associations between resulting module scores and breast cancer risk were examined. Multiple testing in GSEA and WGCNA was accounted for using the false discovery rate.Though no individual metabolites were significantly associated with breast cancer risk, several patterns emerged. At the distant timepoint, cholesterol esters were inversely associated with risk [e.g.: C22:5 CE OR = 0.82, 95% CI=0.75-0.9]. TAGs with ≥3 double bonds were inversely associated with breast cancer at the proximate timepoint [e.g.: C58:7 TAG OR=0.81, 95% CI=0.72-0.92]. MSEA showed negative enrichment (corresponding to an inverse association with breast cancer) of cholesterol esters at both distant (normalized enrichment score (NES)=-2.38, padj=0.02) and proximate (NES=-2.0, padj=0.02) timepoints. Though positive enrichment of TAGs with <3 double bonds was observed at both time points, TAGs with ≥3 double bonds were significantly inversely associated with breast cancer at the proximate time point (NES=-2.92, padj=0.02). At the proximate time point, a module characterized by essential amino acids (positively weighted) and TAGs with high number of double bonds (inversely weighted) was significantly associated with breast cancer risk (OR=1.21, 95% CI=1.06-1.37, padj=0.04). Overall, the results suggest that cholesterol esters may be inversely related to early development of breast cancer, while TAGs with many double bonds appear inversely associated with development of breast cancer closer to diagnosis. Analyses of metabolite differences between each time point and by ER status are ongoing to better understand the biologic mechanisms contributing to breast cancer risk.

Citation Format: Kristen D. Brantley, Oana A. Zeleznik, Rulla Tamimi, Bernard Rosner, Julian Avila-Pacheco, Clary B. Clish, A Heather Eliassen. Circulating plasma metabolites and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 745.