Abstract B86: Estrogen metabolism and postmenopausal breast cancer risk in the B∼FIT cohort
Authors: Dallal Cher M. , Tice Jeffrey A. , Buist Diana S.M. , Bauer Douglas C. , Lacey James V. , Cauley Jane A. , Hue Trisha F. , LaCroix Andrea , Falk Roni , Pfeiffer Ruth , Fuhrman Barbara J. , Veenstra Timothy D. , Xu Xia , Brinton Louise A. 
Published: January 2014

Abstract
Background: While elevated circulating estrogens are consistently associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. Estrogen metabolism occurs via hydroxylation at the C-2,-4, or -16 positions, resulting in metabolites with potentially different genotoxic and mitogenic effects. To date, only two prior studies have examined comprehensive estrogen metabolism profiles in relation to postmenopausal breast cancer risk.
Methods: We conducted a case-cohort study within B∼FIT (n=15,595), the Breast and Bone Follow-up to the Fracture Intervention Trial, to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites in relation to postmenopausal breast cancer risk. Participants included 387 breast cancer cases diagnosed during the 10-year follow-up and a subcohort of 492 women randomly selected from the cohort within 10-year age and geographical strata. At the screening visit (1992-1993), female volunteers ages 55-80 completed a baseline questionnaire and provided a blood sample. For cases, the average (SD) time between blood draw and diagnosis was 6 years (3.0). Serum concentrations of estrogens and estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression with robust variance adjustment. Exposures were categorized in quintiles (Q) based on the subcohort distribution; multivariable models were adjusted for study design variables (age, geographical site, and trial participation status). Known breast cancer risk factors were not included in the final models as additional adjustment did not alter the results. Estrogens were analyzed individually, as metabolic pathways (C-2, -4, or -16), and as ratios relative to the parent estrogens (estradiol and estrone).
Results: Elevated circulating estradiol was significantly associated with increased breast cancer risk (HRQ5vsQ1=1.70; 95% CI: 1.08-2.69), although no dose-response was observed (p-trend=0.12). No significant associations were observed in the analysis of individual metabolites or the 2- and 4-hydroxylation pathways. However, women in the highest quintile of the 16-hydroxylation pathway were significantly more likely to develop breast cancer as compared to those in the lowest (HRQ5vsQ1=1.59; 95% CI: 1.02-2.48; p-trend=0.09). When analyzing each hydroxylation pathway relative to the parent estrogens, the ratio of the 2-hydroxylation pathway (HRQ5vsQ1=0.76; 95% CI: 0.50-1.17; p-trend=0.06), 4-hydroxylation pathway (HRQ5vsQ1=0.69; 95% CI: 0.45-1.06; p-trend=0.03) and 16-hydroxylation pathway (HRQ5vsQ1=0.72; 95% CI: 0.47-1.10; P-trend=0.29) to parent estrogens was suggestive of inverse associations. Additionally, a higher ratio of the 2- to 16-hydroxylation pathways was significantly associated with reduced risk (HRQ5vsQ1=0.66; 95% CI: 0.43-0.99; p-trend=0.009).
Conclusions: Our results suggest that women with increased 2- or 4-hydroxylation, relative to their circulating parent estrogens, may be at lower risk of postmenopausal breast cancer. Analyses of metabolic pathways, in addition to individual metabolites, may help elucidate the role of estrogen metabolism in breast carcinogenesis.
Citation Format: Cher M. Dallal, Jeffrey A. Tice, Diana S.M. Buist, Douglas C. Bauer, James V. Lacey, Jane A. Cauley, Trisha F. Hue, Andrea LaCroix, Roni Falk, Ruth Pfeiffer, Barbara J. Fuhrman, Timothy D. Veenstra, Xia Xu, Louise A. Brinton. Estrogen metabolism and postmenopausal breast cancer risk in the B∼FIT cohort. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B86.