Investigation of circulating metabolites associated with breast cancer risk by untargeted metabolomics: a case–control study nested within the French E3N cohort

Background: Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease. Methods: Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression. Results: Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49–0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19–2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18–1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11–2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05–1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women. Conclusions: Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake.