Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?

Abstract

The relationship between menopausal hormone therapy (HT) and breast cancer is complex and further complicated by misinformation, perception, and overgeneralization of data. These issues are addressed in this mini-review through the lens of the Women's Health Initiative (WHI) that has colored the view of HT and breast cancer. In the WHI, unopposed conjugated equine estrogen (CEE) reduced breast cancer risk and mortality. In the WHI CEE plus continuously combined medroxyprogesterone acetate (MPA) trial, although the hazard ratio (HR) was elevated it was statistically non-significant for an association between CEE + MPA and breast cancer. In fact, the increased HR was not due to an increased breast cancer incidence rate in women randomized to CEE + MPA therapy but rather due to a decreased and unexpectedly low breast cancer rate in the subgroup of women with prior HT use randomized to placebo. For women who were HT naïve when randomized to the WHI, the breast cancer incidence rate was not affected by CEE + MPA therapy relative to placebo for up to 11 years of follow-up. The current state of science indicates that HT may or may not cause breast cancer but the totality of data neither establish nor refute this possibility. Further, any association that may exist between HT and breast cancer appears to be rare and no greater than other medications commonly used in clinical medicine.

Keywords: Hormone therapy; Women’s Health Initiative; breast cancer; estrogen.

Figure 1.

Breast cancer incidence in the Women’s Health Initiative trial of conjugated equine estrogen plus medroxyprogesterone acetate (E+P in figure) versus placebo, stratified by prior use of hormone therapy showing similar trends for all the subgroups except for women with prior hormone therapy use randomized to placebo where breast cancer incidence unexpectedly sharply diverges without explanation. It is the divergence in the trend line for women with prior hormone therapy use randomized to placebo that accounts for the elevated hazard ratio for breast cancer falsely giving the impression that breast cancer incidence was increased in the trial due to conjugated equine estrogen plus medroxyprogesterone acetate where in fact the elevated hazard ratio was due to a DECREASED breast cancer incidence In the PLACEBO treated group.