Human Cancer Biology Interactions of Hormone Replacement Therapy, Body Weight, and Bilateral Oophorectomy in Breast Cancer Risk

Purpose: To examine potential modifying effects of body weight and bilateral oophorectomy on the association of hormone replacement therapy (HRT) with risk of breast cancer, overall and by subtypes according to status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) among postmenopausal women. Experimental Design: This analysis included 2,510 postmenopausal white women recruited in the Nashville BreastHealth Study, a population-based case–control studyof breast cancer.Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) for associations between HRT use and risk of breast cancer overall and by subtypes, adjusted for age and education. Results: Among women with natural menopause and body mass index (BMI) < 25 kg/m, ever-use of HRT was associated with increased breast cancer risk (OR, 1.95; 95%CI, 1.32–2.88). Risk was elevated with duration of HRT use (P for trend 1⁄4 0.002). Similar association patterns were found for ERþ, ERþPRþ, and luminal A cancer subtypes but not ER , ER PR , and triple-negative cancer. In contrast, ever-HRT use in overweight women (BMI 25 kg/m) showed no association with risk of breast cancer overall or by subtypes; interaction tests for modifying effect of BMI were statistically significant. Ever-HRT use was associated with decreased breast cancer risk (OR, 0.70; 95% CI, 0.38–1.31) among women with prior bilateral oophorectomy but elevated risk (OR, 1.45; 95% CI, 0.92–2.29) among those with hysterectomy without bilateral oophorectomy (P for interaction1⁄4 0.057). Similar associations were seen for virtually all breast cancer subtypes, although interaction tests were statistically significant for ERþ and luminal A only. Conclusion: Body weight and bilateral oophorectomy modify associations between HRT use and breast cancer risk, especially the risk of hormone receptor–positive tumors. Clin Cancer Res; 1–10. 2014 AACR.