Estrogen Metabolism and Risk of Postmenopausal Endometrial and Ovarian Cancer: the B∼FIT Cohort

HORM CANC (2016) 7:49–64 DOI 10.1007/s12672-015-0237-y ORIGINAL PAPER Estrogen Metabolism and Risk of Postmenopausal Endometrial and Ovarian Cancer: the B∼FIT Cohort Cher M. Dallal1,2 & James V. Lacey Jr.3 & Ruth M. Pfeiffer4 & Douglas C. Bauer5,8 & Roni T. Falk2 & Diana S. M. Buist6 & Jane A. Cauley7 & Trisha F. Hue8 & Andrea Z. LaCroix9 & Jeffrey A. Tice5 & Timothy D. Veenstra10,11 & Xia Xu11 & Louise A. Brinton2 & for the B∼FIT Research Group Received: 13 July 2015 /Accepted: 16 October 2015 /Published online: 4 January 2016 # Springer Science+Business Media New York (outside the USA) 2015 Abstract Estrogen metabolites may have different genotoxic estrogens (estradiol, estrone). Estradiol was significantly asso- and mitogenic properties yet their relationship with endome- ciated with increased endometrial cancer risk (BMI-adjusted trial and ovarian cancer risk remains unclear. Within the HRT3vsT1=4.09, 95 % CI 1.70, 9.85; p trend=0.003). 2- Breast and Bone Follow-up to the Fracture Intervention Trial Hydroxyestrone and 16α-hydroxyestrone were not associated (B∼FIT, n=15,595), we conducted a case-cohort study to with endometrial risk after estradiol adjustment (2- evaluate 15 pre-diagnostic serum estrogens and estrogen me- OHE1 :HRT3vsT1=1.97, 95 % CI 0.78, 4.94; 16- tabolites with risk of incident endometrial and ovarian cancer OHE1:HRT3vsT1=1.50, 95 % CI 0.65, 3.46; p trend=0.16 among postmenopausal women not on hormone therapy. Par- and 0.36, respectively). Ratios of 2- and 4-pathway catechol- ticipants included 66 endometrial and 67 ovarian cancer cases to-methylated estrogens remained positively associated with diagnosed during follow-up (∼10 years) and subcohorts of endometrial cancer after BMI or estradiol adjustment (2-path- 346 and 416 women, respectively, after relevant exclusions. way catechols-to-methylated: HRT3vsT1=4.02, 95 % CI 1.60, Serum concentrations were measured by liquid 10.1; 4-pathway catechols-to-methylated: HRT3vsT1=4.59, chromatography-tandem mass spectrometry. Hazard ratios 95 % CI 1.64, 12.9; p trend=0.002 for both). Estrogens and (HRs) and 95 % confidence intervals (CIs) were estimated estrogen metabolites were not associated with ovarian cancer using Cox proportional hazard regression. Exposures were risk; however, larger studies are needed to better evaluate categorized in tertiles (T) and analyzed individually, as meta- these relationships. Estrogen metabolism may be important bolic pathways (C-2, -4, or -16) and as ratios to parent in endometrial carcinogenesis, particularly with less extensive Electronic supplementary material The online version of this article (doi:10.1007/s12672-015-0237-y) contains supplementary material, which is available to authorized users. * Cher M. Dallal 5 Department of Medicine, University of California, San [email protected] Francisco, CA, USA 6 Group Health Research Institute, Seattle, WA, USA 1 Department of Epidemiology and Biostatistics, University of 7 Department of Epidemiology, Graduate School of Public Health, Maryland School of Public Health, College Park, MD 20742, USA University of Pittsburgh, Pittsburgh, PA, USA 8 2 Hormonal and Reproductive Epidemiology Branch, Division of Department of Epidemiology and Biostatistics, University of San Cancer Epidemiology and Genetics, National Cancer Institute, Francisco, San Francisco, CA, USA National Institutes of Health, Bethesda, MD, USA 9 Division of Epidemiology, Department of Family and Preventive 3 Division of Cancer Etiology, Department of Population Sciences, Medicine, University of California, San Diego, CA, USA Beckman Research Institute of City of Hope, Duarte, CA, USA 10 C2N Diagnostics, Saint Louis, MO, USA 4 Biostatistics Branch, Division of Cancer Epidemiology and Genetics, 11 Cancer Research Technology Program, Leidos Biomedical Research, National Cancer Institute, National Institutes of Health, Inc., Frederick National Laboratory for Cancer Research, Bethesda, MD, USA Frederick, MA, USA 50 HORM CANC (2016) 7:49–64 methylation of 2- or 4-pathway catechols associated with ele- early pregnancy sex steroids in relation to maternal epithelial vated endometrial cancer risk. cancer risk by histological subtype [26]. No prior studies have examined the role of serum estrogen metabolites. Given the lack of studies, we conducted a case-cohort study within the Introduction Breast and Bone Follow-up to the Fracture Intervention Trial [22, 27], to evaluate associations between 15 pre-diagnostic Endometrial cancer has long been considered an estrogen- serum estrogens and estrogen metabolites and endometrial driven malignancy due to observed positive associations with and ovarian cancer risk among postmenopausal women not circulating estrogen [1], the use of unopposed estrogen thera- currently using postmenopausal estrogens. py [2], and estrogen-related exposures such as obesity [3, 4]. Although the postulated relationship between estrogen and ovarian cancer remains less clear [5], recent findings from a Materials and Methods reanalysis of epidemiological data suggest an elevated risk of ovarian cancer, specifically serous or endometroid tumors, We conducted a prospective case-cohort study within B∼FIT, with estrogen only or estrogen and progesterone therapy [6]. a longitudinal cohort of participants screened for the Fracture Despite prior research on endogenous and exogenous estro- Intervention Trial (FIT), which has previously been described gens in relation to gynecological cancers, little is known re- [27]. The case-cohort design was selected to assess the rela- garding the relationship between estrogen metabolism and the tionship between estrogen metabolism and multiple cancer risk of endometrial [7, 8] or ovarian cancer. endpoints. The metabolism of estradiol or estrone begins with irre- In brief, FIT was a randomized, placebo-controlled trial versible hydroxylation at the C-2, -4, or -16 positions of the designed to test the efficacy of alendronate an oral steroid ring [9], resulting in metabolites (Online Resource 1) bispohosphonate, in reducing the rate of fractures in women with potential genotoxic and mitogenic properties [10, 11]. with low bone mineral density [27]. In 1992–1993, 22,695 Earlier research suggested an elevated ratio of two estrogen postmenopausal women (ages 55–80) were screened for par- metabolites, 2-hydroxyestrone (2-OHE1) and 16α- ticipation at 11 clinical centers in the USA. Potential partici- hydroxyestrone (16α-OHE1), may be inversely related to pants underwent a bone mineral density scan (dual-energy X- estrogen-mediated cancer risk [12, 13]. Both metabolites bind ray absorptiometry), donated a baseline serum sample, provid- to the estrogen receptor, however, with different affinities. ed clinical examination data including measured anthropomet- Based on laboratory studies, 16α-OHE1 is suggested to cova- rics, and completed an extensive health history questionnaire lently bind to the estrogen receptor [14], induce cell prolifer- that ascertained information on demographic, lifestyle, hor- ation [15, 16], and subsequently, increase cancer risk. Addi- monal, and reproductive factors. Serum samples were origi- tionally, estrogen metabolism may lead to genotoxic deriva- nally stored at −20 °C for 3 years and then transferred to tives [10], as hydroxylation at the C-2 and C-4 positions of the −70 °C for long-term storage. Primary results from FIT were steroid ring produces catechol estrogens (2-OHE1,2- reported in 1996 [27] and 1998 [28], and a subset of partici- hydroxyestradiol (2-OHE2), and 4-hydroxyestrone (4- pants who had used alendronate for at least 3 years were in- OHE1)), characterized by the addition of a second hydroxyl vited to participate in the FIT Long-Term Extension Trial group. Oxidation of these catechol estrogens can lead to the (FLEX) [29]. formation of mutagenic quinone products [17] while methyl- B∼FIT (N=15,595) is comprised of female volunteers orig- ation prevents this process [18]. Given these biological prop- inally screened for FIT at 10 of the original 11 FIT clinical erties, an elevated ratio of catechol to methylated catechols is centers; one clinic declined to participate in the follow-up hypothesized to increase cancer risk. study. Women who refused or withdrew were excluded (n= Most epidemiological studies have explored these hypoth- 7100). Vital status and cause of death was determined using eses in relation to breast cancer and not other estrogen- the National Death Index Plus (NDI+). From 2001 to 2004, mediated cancers [19–23]. To date, only one prospective study surviving women were contacted by mail and/or telephone has evaluated circulating 2-OHE1 and 16α-OHE1, as mea- and invited to complete a follow-up questionnaire (64 % of sured by enzyme immunoassay, in relation to endometrial eligible women completed the BFIT questionnaire), which cancer risk among postmenopausal women [7]. Additionally, asked about cancer diagnoses, other health outcomes and re- two case-control studies [8, 24] have reported differences in productive surgeries that occurred since they were screened estrogen metabolite profiles when comparing endometrial for FIT, family history of cancer, detailed hormone use, and cancer patients with healthy controls. With regard to ovarian preventive screening procedures. Women who reported an cancer, only one prior prospective study [25] has evaluated incident cancer or fracture were asked to give permission for associations with circulating estrone among pre- and postmen- medical record review of those events. In addition, all

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