Abstract A90: Relationship of serum estrogens and estrogen metabolites with postmenopausal breast cancer risk
Authors: Falk Roni T. , Gierach Gretchen L. , Xu Xia , Dorgan Joanne F. , Veenstra Timothy D. , Brinton Louise A. 
Published: June 2012

Abstract
Background: Elevated levels of circulating estrogens are linked to breast cancer risk among postmenopausal women; however, little is known about the importance of patterns of estrogen metabolism and the role of specific estrogen metabolites (EM). Estrogen metabolism entails hydroxylation at sites C2, C4 or C-16, and conjugation (predominantly via methylation, sulfation or glucuronidation). Recent research, primarily laboratory studies, has focused on the possible carcinogenic role for 4-hydroxyestrogens (4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2)) and 16-alpha-hydroxyestrone (16 - OHE1), and an anti-carcinogenic role for 2-methoxyestradiol (2-MeOE2). Further, the catechol estrogen 2-hydroxyestrone (2-OHE1) has been postulated to be either weakly estrogenic or antiestrogenic. The recent development of sophisticated laboratory methods to measure these metabolites in sera from large epidemiologic studies may provide clues to breast carcinogenesis and potentially help identify women who would benefit from chemopreventive endocrine therapies.
Study Design and Methods: We analyzed a panel of 15 EM in bloods drawn from participants in the Columbia Missouri Serum Bank Cohort who were identified for a nested case-control study of postmenopausal breast cancer. Between 1977 and 1987, 7224 women provided blood samples, and were followed for incident breast cancer through December 2004. We included 197 breast cancer cases and 215 frequency matched controls who were postmenopausal at blood draw and not using exogenous hormones. Analysis of variance models were used to evaluate mean differences in logarithmically-transformed hormone levels. Correlations between EM were evaluated by Pearson's rho. In addition, logistic regression models, which controlled for matching factors and known breast cancer risk factors, were used to calculate quartile-specific relative risks (RRs) and 95% confidence intervals (CIs). To adjust for potential confounding effects of the parent estrogens (E1, E2 and E3)), which comprise &gt;65% of the total EM, RRs were also calculated based on percent of the total EM.
Results: Overall, total EM (the sum of all of the individual EM) did not vary between cases and controls. Absolute levels of individual EM did not differ significantly between cases and controls, although the methoxyestrogens tended to be lower in cases, with levels of 2-methyoxyestrone-3-methyl ether (3-MeOE1) and 2-MeOE2 being of borderline significance (p=0.06 and 0.09, respectively). Levels of estrone (E1) and estradiol (E2) were slightly but not significantly higher among cases. Compared to women in the lowest quartile of 3-MeOE1, women in each of the remaining quartiles had a significant 50% reduction in breast cancer risk (RR were 0.51, 0.52 and 0.47 for moderate through high levels), but no trend was evident. For 2-MeOE2, risk was reduced in women in the highest v lowest quartile, with RR=0.49, 95% CI-0.26–0.91. There was some evidence that women in the upper three quartiles of E1, E2 and estriol (E3) had higher risks than women in the lowest quartiles, but no consistent trends in risk were noted, and except for the quartile of moderately high E3, none of the risk estimates were statistically significant. For 2-OHE1, no pattern of risk was evident for the absolute levels; however, based on the percent of total EM, RRs declined with increasing levels (p=0.08). As expected, correlations between EM and their respective parent estrogens (E1 and E2) were high (Pearson's rho varied from 0.62–0.85).
Conclusions: Preliminary analyses of metabolic patterns suggest that women with high levels of circulating methyoxestrogens and low catechol estrogens may have a reduced risk of postmenopausal breast cancer. Efforts are ongoing to disentangle the unique and potentially competing effects of these highly correlated hormones.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A90.