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 Breast Health Study, a population-based case-control study of 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(2), 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 = 0.002). Similar association patterns were found for ER(+), ER(+)PR(+), 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(2)) 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 interaction = 0.057). Similar associations were seen for virtually all breast cancer subtypes, although interaction tests were statistically significant for ER(+) 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.