Known modifiable risk factors account for a small fraction of premenopausal breast cancers. We investigated associations between pre-diagnostic circulating amino acid and amino acid-related metabolites (N = 207) and risk of breast cancer among predominantly premenopausal women of the Nurses\u27 Health Study II using conditional logistic regression (1057 cases, 1057 controls) and multivariable analyses evaluating all metabolites jointly. Eleven metabolites were associated with breast cancer risk (q-value \u3c 0.2). Seven metabolites remained associated after adjustment for established risk factors (p-value \u3c 0.05) and were selected by at least one multivariable modeling approach: higher levels of 2-aminohippuric acid, kynurenic acid, piperine (all three with q-value \u3c 0.2), DMGV and phenylacetylglutamine were associated with lower breast cancer risk (e.g., piperine: ORadjusted (95%CI) = 0.84 (0.77-0.92)) while higher levels of creatine and C40:7 phosphatidylethanolamine (PE) plasmalogen were associated with increased breast cancer risk (e.g., C40:7 PE plasmalogen: ORadjusted (95%CI) = 1.11 (1.01-1.22)). Five amino acids and amino acid-related metabolites (2-aminohippuric acid, DMGV, kynurenic acid, phenylacetylglutamine, and piperine) were inversely associated, while one amino acid and a phospholipid (creatine and C40:7 PE plasmalogen) were positively associated with breast cancer risk among predominately premenopausal women, independent of established breast cancer risk factors
