Associations of Vitamins and Related Cofactor Metabolites with Mammographic Breast Density in Premenopausal Women

Background: Identifying biological drivers of mammographic breast density (MBD), a strong risk factor for breast cancer, could provide insight into breast cancer etiology and prevention. Studies on dietary factors and MBD have yielded conflicting results. There are, however, very limited data on the associations of dietary biomarkers and MBD. Objective: We aimed to investigate the associations of vitamins and related cofactor metabolites with MBD in premenopausal women. Methods: We measured 37 vitamins and related cofactor metabolites in fasting plasma samples of 705 premenopausal women recruited during their annual screening mammogram at the Washington University School of Medicine, St. Louis, MO. Volpara was used to assess volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV). We estimated the least square means of VPD, DV, and NDV across quartiles of each metabolite, as well as the regression coefficient of a metabolite in continuous scale from multiple covariate-adjusted linear regression. We corrected for multiple testing using the Benjamini-Hochberg procedure to control the false discover rate (FDR) at a 5% level. Results: Participants' mean VPD was 10.5%. Two vitamin A metabolites (beta-cryptoxanthin and carotene diol 2) were positively associated, and one vitamin E metabolite (gamma-tocopherol) was inversely associated with VPD. The mean VPD increased across quartiles of beta-cryptoxanthin (Q1 = 7.2%, Q2 = 7.7%, Q3 = 8.4%%, Q4 = 9.2%; P-trend = 1.77E-05, FDR P value = 1.18E-03). There was a decrease in the mean VPD across quartiles of gamma-tocopherol (Q1 = 9.4%, Q2 = 8.1%, Q3 = 8.0%, Q4 = 7.8%; P -trend = 4.01E-03, FDR P value = 0.04). Seven metabolites were associated with NDV: 3 vitamin E (gamma-CEHC glucuronide, delta-CEHC, and gamma-tocopherol) and 1 vitamin C (gulonate) were positively associated, whereas 2 vitamin A (carotene diol 2 and beta-cryptoxanthin) and 1 vitamin C (threonate) were inversely associated with NDV. No metabolite was significantly associated with DV. Conclusion: We report novel associations of vitamins and related cofactor metabolites with MBD in premenopausal women.