LAUSR

Background: Metabolomics has become a powerful tool to systematically examine metabolic pathways involved in carcinogenesis. Although several epidemiological studies examined the association between metabolites and breast cancer risk, metabolomic biomarkers of breast cancer measured in premenopausal women are still understudied. Herein, we prospectively investigated the associations between pre-diagnostic metabolomic signatures and subsequent risk of developing breast cancer among predominantly premenopausal women at blood collection. Methods: In the Nurses’ Health Study II, 29,611 healthy women (80% premenopausal) donated blood samples in 1996-1999. Between blood collection and 2011, 1,055 women were diagnosed with breast cancer, and each was matched with healthy control. Lipids, carbohydrates, and organic acid-related metabolites were profiled with liquid chromatography-tandem mass spectrometry. Multivariable (including adiposity) adjusted conditional logistic regression was used to estimate odds ratios (ORs) of breast cancer and 95% confidence intervals (CIs). Associations of metabolite groups with breast cancer were evaluated using metabolite set enrichment analysis and network analysis. All analyses were corrected for multiple comparisons. Results: Although no individual metabolites were statistically significantly associated with breast cancer risk after multiple comparisons correction, several individual metabolites were identified as nominally significant: taurodeoxycholate (OR=1.15; 95%CI=1.04-1.28), C16:1 cholesteryl ester (OR=0.88; 95%CI=0.79-0.97), C32:1 phosphatidylcholine (PC) (OR=0.88; 95%CI=0.79-0.98), C34:1 PC (OR=0.87; 95%CI=0.78-0.98), and C34:3 PC (OR=0.88; 95%CI=0.79-0.98). In analyses of grouped metabolites, triglycerides (TAGs) with <3 double bonds (DBs) (normalized enrichment score (NES)= -2.54; Padj<0.00001) and PCs (NES= -2.13; Padj=0.02) were significantly inversely associated with risk of overall breast cancer, with no obvious differences observed by menopausal or BMI status. Significant inverse associations of TAGs with ≥3 DBs were only observed among premenopausal women or among those with high BMI. Opposite enrichments of phospholipids, amino acids, and carbohydrate-related metabolites were observed by estrogen receptor (ER) status. Conclusions: In this prospective study of predominately premenopausal women, we found that the association between TAGs and breast cancer risk was dependent on the number of DBs. Notably, TAGs with <3 DBs, which have been associated with higher risk of type 2 diabetes, were strongly inversely associated with risk of developing breast cancer. Variations of associations with other metabolites were observed by menopausal, obesity, and ER status. Further validation of our findings in independent cohorts of premenopausal women is warranted. Citation Format: Tengteng Wang, Oana Zeleznik, Emma E. McGee, Kristen D. Brantley, Raji Balasubramanian, Bernard A. Rosner, Walter C. Willett, Clary B. Clish, A. Heather Eliassen. Prospective study of circulating metabolomic signatures and breast cancer incidence among predominantly premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3022.