title: Estrogen Metabolism and Risk of Postmenopausal Endometrial and Ovarian Cancer: the B ∼ FIT Cohort.
abstract: Estrogen metabolites may have different genotoxic and mitogenic properties yet their relationship with endometrial and ovarian cancer risk remains unclear. Within the Breast and Bone Follow-up to the Fracture Intervention Trial (B ∼ FIT, n = 15,595), we conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Participants included 66 endometrial and 67 ovarian cancer cases diagnosed during follow-up (∼ 10 years) and subcohorts of 346 and 416 women, respectively, after relevant exclusions. Serum concentrations were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. Exposures were categorized in tertiles (T) and analyzed individually, as metabolic pathways (C-2, -4, or -16) and as ratios to parent estrogens (estradiol, estrone). Estradiol was significantly associated with increased endometrial cancer risk (BMI-adjusted HRT3vsT1 = 4.09, 95% CI 1.70, 9.85; p trend = 0.003). 2-Hydroxyestrone and 16α-hydroxyestrone were not associated with endometrial risk after estradiol adjustment (2-OHE1:HRT3vsT1 = 1.97, 95% CI 0.78, 4.94; 16-OHE1:HRT3vsT1 = 1.50, 95% CI 0.65, 3.46; p trend = 0.16 and 0.36, respectively). Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment (2-pathway catechols-to-methylated: HRT3vsT1 = 4.02, 95% CI 1.60, 10.1; 4-pathway catechols-to-methylated: HRT3vsT1 = 4.59, 95% CI 1.64, 12.9; p trend = 0.002 for both). Estrogens and estrogen metabolites were not associated with ovarian cancer risk; however, larger studies are needed to better evaluate these relationships. Estrogen metabolism may be important in endometrial carcinogenesis, particularly with less extensive methylation of 2- or 4-pathway catechols associated with elevated endometrial cancer risk.
authors.affiliation: Department of Epidemiology and Biostatistics, University of Maryland School of Public Health, College Park, MD, 20742, USA. cdallal@umd.edu.|Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. cdallal@umd.edu.
authors.forename: Cher M
authors.initials: CM
authors.lastname: Dallal
authors.affiliation: Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: James V
authors.initials: JV
authors.lastname: Lacey
authors.affiliation: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Department of Epidemiology and Biostatistics, University of San Francisco, San Francisco, CA, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Bauer
authors.affiliation: Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Roni T
authors.initials: RT
authors.lastname: Falk
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: Diana S M
authors.initials: DS
authors.lastname: Buist
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.affiliation: Department of Epidemiology and Biostatistics, University of San Francisco, San Francisco, CA, USA.
authors.forename: Trisha F
authors.initials: TF
authors.lastname: Hue
authors.affiliation: Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, CA, USA.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: LaCroix
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Tice
authors.affiliation: C2N Diagnostics, Saint Louis, MO, USA.|Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MA, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.affiliation: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MA, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
mesh_terms: D000368:Aged; D002853:Chromatography, Liquid / Q000379:methods; D016889:Endometrial Neoplasms / Q000097:blood* / Q000209:etiology*; D004967:Estrogens / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000209:etiology*; D017698:Postmenopause; D016016:Proportional Hazards Models; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry
chemical_list: D004967:Estrogens