Abstract 590: Circulating estrogen metabolites and risk of postmenopausal breast cancer in the Nurses’ Health study
Authors: Brantley Kristen D. , Ziegler Regina G. , Hankinson Susan E. , Eliassen A. Heather 
Published: August 2019

The positive association between endogenous estrogen levels and breast cancer risk in postmenopausal women has been well established. However, evidence for whether irreversible hydroxylation of the parent estrogens (estrone and estradiol) at the 2- or 16-position plays an important role in breast cancer etiology among postmenopausal women remains limited.

We performed a nested case-control study within the Nurses’ Health Study to examine plasma estrogens and estrogen metabolites (jointly referred to as EM) among postmenopausal women not using menopausal hormone therapy at blood draw (in 1989-1990). Breast cancer cases (N=341) were diagnosed between 1996 and 2004. Controls (N=679) were individually matched to cases. Total concentrations of each EM, including conjugated and unconjugated forms, were measured by liquid chromatography-tandem mass spectrometry.

Multivariate conditional logistic regression, adjusting for breast cancer risk factors, was used to estimate the relative risk (RR) and 95% confidence interval (CI) of breast cancer comparing highest v. lowest quintiles of individual EM, summed 2-hydroxylation catechols, summed 16-hydroxylation pathway, and pathway ratios. Secondary analyses included adjustment for unconjugated and total estradiol and estrone. Unconditional logistic regression with adjustment for batch, matching factors, and breast cancer risk factors was performed to estimate the RR by breast tumor subtype, defined by estrogen receptor (ER) and progesterone receptor (PR) status.

Higher concentrations of both total estradiol and total estrone were associated with increased risk of breast cancer overall (both p-trend&lt;0.0001) and among ER+/PR+ tumors [estradiol overall RR=2.7, 95% CI (1.6-4.4); ER+/PR+ RR=3.7, 95% CI (1.9-7.4)]. A positive association was observed between 2-hydroxylation pathway catechols and overall breast cancer [RR=2.7; 95% CI (1.5-4.6); p-trend&lt;0.0001], which remained significant, though attenuated, after adjusting for total estradiol and estrone [RR=2.0; 95% CI (1.1-3.6)]. This association remained consistent among ER+/PR+ tumors [RR=2.4; 95% CI (1.3, 4.5)], with slight attenuation following adjustment for parent EM. Though there was a suggestive positive association between the 16-hydroxylation pathway and overall breast cancer [RR =1.5, 95% CI (0.9-2.5)], it was not maintained after adjustment for total estradiol and estrone. However, one 16-hydroxylation EM, 17-epiestriol, was associated with risk of overall breast cancer even after adjustment for total estradiol and estrone [RR=1.8, 95% CI (1.0-3.0)].

The 2-hydroxylation of parent estrogens to 2-catechols was associated with a higher risk of overall breast cancer, independent of parent estrogens. This pathway may provide etiologic insight and targets for further research into risk assessment and prevention.

Citation Format: Kristen D. Brantley, Regina G. Ziegler, Susan E. Hankinson, A. Heather Eliassen. Circulating estrogen metabolites and risk of postmenopausal breast cancer in the Nurses’ Health study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 590.