Abstract 1603: Estrogen metabolites and colorectal cancer risk in postmenopausal women in the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT)
Authors: Falk Roni T. , Dallal Cher M. , Lacey James V. , Bauer Douglas C. , Buist Diana S. , Cauley Jane A. , Hue Trisha F. , LaCroix Andrea , Tice Jeffrey A. , Pfeiffer Ruth M. , Xu Xia , Veenstra Timothy D. , Brinton Louise A. 
Published: May 2015

Abstract
Background: A role for estrogen in colon carcinogenesis is suggested by the lower incidence of colorectal cancer (CRC) in women than men; the protective effect of exogenous hormones on risk; and reduced levels of estrogen receptor beta (ERβ) expression, the predominant ER in the colon, in cancerous compared to healthy colonic tissue. Nonetheless, the few cohort studies of endogenous hormones have not found reduced risks associated with circulating estradiol or estrone levels in postmenopausal women. We hypothesized that specific metabolites in the estrogen metabolic pathway may preferentially bind to and activate colonic ERβ, and analyzed a panel of 15 estrogen metabolites (EM), including estradiol and estrone, in a case-cohort study of CRC.
Methods: We prospectively followed 15,595 women enrolled in B∼FIT (Breast and Bone Follow-up to the Fracture Intervention Trial (FIT)) who had completed questionnaires and donated blood between 1992 and 1993 for incident CRC through December 2004. Using liquid chromatography-tandem mass spectrometry, EM were measured in serum from 197 CRC cases and a subcohort of 491 women who were not using exogenous hormones at the time of blood draw. EM were examined individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring), and by ratios of the groupings. Cox proportional hazard regression models adjusted for clinical site and age (grouped in ten year intervals) were used to calculate quartile-specific hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: Significant risks were not observed for individual EM, and HR for quartiles of total EM (sum of all EM) were elevated but not significant (HRQ4 v Q1=1.23, 95% CI=0.8-2.0, ptrend=0.53). No associations were seen for estrone (HRQ4 v Q1=1.05, 95% CI=0.6-1.7) or estradiol (HRQ4 v Q1=0.90. 95% CI=0.5-1.5). When represented as a ratio to the parent estrogens (estrone and estradiol), risks of CRC for women with higher levels of 2-pathway EM or 4-pathway EM were reduced in each quartile, but neither HR nor trends were significant (ratio 2-pathway: parent, HRQ4 v Q1=0.88, 95 CI=0.6-1.4 ptrend=0.56; ratio 4-pathway: parent, HRQ4 v Q1=0.92, 95% CI=0.6, 1.5 ptrend=0.46).
Conclusions: Levels of circulating estrone and estradiol and their metabolites are not associated with CRC risk in the B∼FIT cohort.
Citation Format: Roni T. Falk, Cher M. Dallal, James V. Lacey, Douglas C. Bauer, Diana SM Buist, Jane A. Cauley, Trisha F. Hue, Andrea LaCroix, Jeffrey A. Tice, Ruth M. Pfeiffer, Xia Xu, Timothy D. Veenstra, Louise A. Brinton. Estrogen metabolites and colorectal cancer risk in postmenopausal women in the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1603. doi:10.1158/1538-7445.AM2014-1603