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||Estrogen metabolism and breast cancer risk among postmenopausal women: a case-cohort study within B~FIT.
||Dallal CM, Tice JA, Buist DS, Bauer DC, Lacey JV, Cauley JA, Hue TF, Lacroix A, Falk RT, Pfeiffer R, Fuhrman BJ, Veenstra TD, Xu X, Brinton LA
||2013 Nov 8
||BB, EBP, HREB
||While elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case-cohort study within B~FIT, the Breast and Bone Follow-up to the Fracture Intervention Trial, to assess serum estrogens and estrogen metabolites (EM) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992-1993, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EM were measured by liquid chromatography tandem mass spectrometry. EM (quintiles, Q), were analyzed individually, as metabolic pathways (C-2, -4, or -16), and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HRQ5vsQ1=1.86; 95% CI: 1.19-2.90; p-trend=0.04). An elevated ratio of the 2-hydroxylation pathway (HRQ5vsQ1=0.69; 95% CI: 0.46-1.05; p-trend=0.01) and 4-hydroxylation pathway (HRQ5vsQ1=0.61; 95% CI: 0.40-0.93; p-trend=0.004) to parent estrogens (estradiol and estrone) were inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HRQ5vsQ1=0.60; 95% CI: 0.40-0.90; p-trend=0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.