A. Heather Eliassen^1,3, Stacey A. Missmer^1,2,3, Shelley S. Tworoger^1,3 and Susan E. Hankinson^1,3

¹ Channing Laboratory, Department of Medicine, and ² Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School and ³ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.

Requests for reprints: A. Heather Eliassen, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115.

Phone: 617-525-2104; Fax: 617-5252008. E-mail: heather.eliassen@channing.harvard.edu.

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Circulating estrogens are associated with breast cancer risk in postmenopausal women. Given that estrogen metabolites are potentially both mitogenic and genotoxic, it is possible that plasma levels of estrogen metabolites are related to breast cancer risk. We conducted a prospective, nested case-control study within the Nurses' Health Study. Blood samples, collected in 1989 to 1990, were assayed for 2-OH and 16α-OH estrone among 340 cases and 677 matched controls not taking postmenopausal hormones. Multivariate relative risks (RR) and 95% confidence intervals (95% CI) were calculated by conditional logistic regression, adjusting for breast cancer risk factors. Neither 2-OH nor 16α-OH estrone concentrations were significantly associated with breast cancer risk overall (top versus bottom quartile: RR, 1.19; 95% CI, 0.80-1.79; P_trend = 0.40 for 2-OH estrone and RR, 1.04; 95% CI, 0.71-1.53; P_trend = 0.81 for 16α-OH estrone). The ratio between the two metabolites (2-OH:16α-OH estrone) was similarly unrelated to risk overall (1.30; 95% CI, 0.87-1.95; P_trend = 0.35). Although no associations were detected among women with estrogen receptor (ER)–positive/progesterone receptor (PR)–positive tumors, significant positive associations were observed for 2-OH estrone and the 2-OH:16α-OH estrone ratio among women with ERnegative/PR-negative tumors (RR, 3.65; 95% CI, 1.23-10.81; P_trend = 0.01; P_{heterogeneity} = 0.02 for 2-OH estrone; RR, 3.70; 95% CI, 1.24-11.09; P_trend = 0.004; P_{heterogeneity} = 0.005 for 2-OH:16α-OH estrone). These data do not support the hypothesized inverse associations with 2-OH estrone and the 2-OH:16α-OH estrone ratio or the hypothesized positive association with 16α-OH estrone. The significant positive associations with 2-OH estrone and the 2-OH:16-OH estrone ratio among women with ER-negative/PRnegative tumors needs to be replicated in future studies.

(Cancer Epidemiol Biomarkers Prev 2008;17(8):2029–35)