Baseline Endogenous Estradiol and the Association of Hormone Therapy with Breast Cancer Risk, the Women's Health Initiative Clinical Trials.
Authors: Farhat G. , Parimi N. , Vittinghoff E. , Lee J. , Huang A. , Grady D. , Jackson R. , Cummings S. 
Published: December 2010

Abstract
Background: The effect of exogenous hormones on breast cancer risk may depend on baseline endogenous levels of estradiol (E2). We investigated whether women with lower E2 levels will have the greatest increase in breast cancer risk during treatment with estrogen plus progestin ((E+P); combined conjugated equine estrogens (CEE) plus medroxyprogesterone acetate) or estrogen-alone ((E-alone); CEE) therapy. Additionally, we examined whether the risk of breast cancer varies by untreated levels of endogenous E2.Methods: We performed an ancillary study within the Women's Health Initiative E+P and E-alone clinical trials. We used a case-only design to test for interactions between untreated levels of E2 and hormone therapy (E+P or E-alone) on breast cancer risk. We measured baseline levels of bioavailable E2 in 346 cases of invasive breast cancer from the E+P trial and 231 cases from the E-alone trial. To estimate the risk of breast cancer by endogenous E2 levels (expressed as quartiles), we used a case-cohort design which included the cases described above in addition to a randomly selected comparison group (N=387; 203 from the E+P and 184 from the E-alone trial). Incident breast cancer cases were identified over an average follow-up of 4.1 years in the E+P trial and 5.4 years in the E-alone trial. All analyses were performed separately for the E+P and the E-alone trials.Results: In the case-only study, the effect of E+P therapy on breast cancer risk did not seem to vary by endogenous E2 quartiles (p-heterogeneity= 0.16). Breast cancer risk associated with E-alone treatment tended to be greater among women with the lowest E2 levels; however this association was not significant (hazard ratio (HR)= 1.44, 95% confidence interval (CI)= 0.79-2.59).Table 1. Effects of E+P and E-alone treatments on breast cancer risk (HR (95% CI)) by quartiles of baseline estradiol: case-only results E+PE-aloneEstradiol Quartile 11.20 (0.80-1.80)1.44 (0.79-2.59)Quartile 20.88 (0.58-1.34)0.98 (0.58-1.67)Quartile 31.27 (0.81-2.00)0.79 (0.47-1.33)Quartile 40.67 (0.43-1.06)0.92 (0.57-1.49)P-heterogeneity0.160.51P-trend0.160.20 In the case-cohort analysis, higher endogenous E2 levels were associated with increased breast cancer risk (p-trend= 0.01), independent of hormone therapy.Table 2. Effects of baseline estradiol and hormone therapy (E+P vs. E-alone) on breast cancer risk (HR (95% CI)): case-cohort results E+PE-aloneHormone therapy treatment (Reference= placebo group)1.01 (0.96-1.07)0.84 (0.56-1.26) Estradiol Quartile 1 (Reference)1.001.00Quartile 21.22 (0.75-2.00)1.30 (0.77-2.17)Quartile 31.41 (0.87-2.32)1.32 (0.77-2.27)Quartile 41.85 (1.12-3.03)2.38 (1.32-4.35)P-trend0.010.01 Conclusion: The risk of breast cancer increases with higher levels of untreated endogenous E2. However, untreated E2 level does not modify the effect of E+P or E-alone therapy on breast cancer risk. Estradiol measurement is unlikely to identify women where hormone therapy may substantially increase the risk of breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 906.