title: Estrogen metabolism and breast cancer risk among postmenopausal women: a case-cohort study within B~FIT.
abstract: Although 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 the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992-93, 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 EMs were measured by liquid chromatography-tandem mass spectrometry. EMs (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) was 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.
authors.affiliation: Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics and.
authors.forename: Cher M
authors.initials: CM
authors.lastname: Dallal
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Tice
authors.forename: Diana S M
authors.initials: DS
authors.lastname: Buist
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Bauer
authors.forename: James V
authors.initials: JV
authors.lastname: Lacey
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Trisha F
authors.initials: TF
authors.lastname: Hue
authors.forename: Andrea
authors.initials: A
authors.lastname: Lacroix
authors.forename: Roni T
authors.initials: RT
authors.lastname: Falk
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Fuhrman
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D015519:Bone Density; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D004967:Estrogens / Q000378:metabolism*; D004970:Estrone / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D053719:Tandem Mass Spectrometry
chemical_list: D014408:Biomarkers, Tumor; D004967:Estrogens; D004970:Estrone