Sex hormone levels, breast cancer risk, and cancer receptor status in postmenopausal women: The ORDET cohort

Background: Endogenous sex hormone levels have been associated with increased breast cancer risk in postmenopausal women in several prospective studies. However, it remains unclear to what extent serum hormone-breast cancer associations differ with receptor status. Methods: Associations between serum sex hormone levels and breast cancer risk were assessed in a nested case-control study on postmenopausal women of the ORDET cohort. After a median follow-up of 13.5 years, 165 women developed breast cancer. Relative risks of developing breast cancer were estimated by conditional logistic regression. Results: Total and free testosterone levels were directly associated with breast cancer risk [relative risk, 3.28 (95% confidence interval, 1.93-5.55) and 2.86 (95% confidence interval, 1.66-4.94), respectively, for highest versus lowest quartile]. When relations between hormone level and risk of breast cancer expressing various receptor combinations were assessed, high total testosterone was significantly associated with increased risk of estrogen receptor-positive cancers, irrespective of progesterone receptor status. High total testosterone was also associated with increased risk of both human epidermal growth factor receptor 2 (HER2)-negative (HER2^-) and HER2⁺ cancers. High estradiol tended to be associated with increased risk of HER2^- cancer and inversely associated with HER2⁺ cancer, with significant (P = 0.027) heterogeneity between HER2⁺ and HER2^- cancers. However, there were relatively few HER2⁺ cases. Conclusions: This study provides further evidence that high levels of circulating testosterone increase the risk of developing breast cancer in postmenopausal women. The cancers that develop are mainly estrogen receptor positive. Although HER2 ⁺ and HER2^- breast cancers were both associated with high total testosterone, they showed opposing associations with estrogen.