Breast cancer incidence decreased by oestrogen alone but increased by adding progestin

Long-term results showed that conjugated equine oestrogens (CEE) alone significantly decreased breast cancer incidence, whilst CEE plus medroxyprogesterone acetate (MPA) use significantly increased breast cancer incidence. Both effects were long-term and persisted over a decade after discontinuing use.

The Women’s Health Initiative is a multi-component study designed to address determinants of major chronic disease in women, including breast cancer [1]. Between 1993 and 1998, postmenopausal women between 50 and 79 years with no prior breast cancer and with mammogram clearance were enrolled in 1 of 2 randomised clinical trials at 40 United States (US) centres. Follow-up continued through September 2016. The randomised, placebo-controlled trial interventions were either CEE 0.625 mg/day plus MPA 2.5 mg/day (n=8,506) versus placebo (n=8,102) for a median of 5.6 years for women with a uterus, or CEE alone (n=5,310) versus placebo (n=5,429) for a median of 7.2 years for women who had had a prior hysterectomy. Annual mammography was mandated through the originally specified completion date in both trials (March 31, 2005), and breast cancers were verified by central medical record and pathology report review. The primary outcome for these analyses was time-specific invasive breast cancer incidence rates. In each trial, participants were instructed to stop all study pills coincident with the publication of each trial’s results, in 2002 and 2004, respectively. See Table 1 for baseline characteristics.

Table 1. Baseline characteristics of the study population [1]



CEE, conjugated equine oestrogens; MPA, medroxyprogesterone acetate;

After 16.1 years of cumulative follow-up, among women who had received CEE alone, there were 520 incidences of breast cancer during the post-intervention period [1]. Compared with women who had received placebo, those who had received CEE alone were 27% less likely to have been diagnosed with breast cancer and 44% less likely to have died from the disease. These positive outcomes are in agreement with earlier findings from this trial during the intervention period. After 18.3 years of cumulative follow-up, among women who were treated with CEE plus MPA, there were 1,003 incidences of breast cancer during the post-intervention period. Compared with women who had received placebo, those who had received CEE plus MPA were 29% more likely to have been diagnosed with breast cancer. This negative outcome is in agreement with earlier findings from this trial during the intervention period. CEE plus MPA was associated with an increased risk for death from breast cancer in the extended analysis, but it did not reach statistical significance (see Table 2).

Table 2. Hormone therapy and breast cancer mortality [1]



CEE, conjugated equine oestrogens; MPA, medroxyprogesterone acetate

These findings led to the conclusion that the use of CEE alone and CEE plus MPA had opposite effects on breast cancer, with CEE alone significantly decreasing breast cancer incidence and deaths from the disease, persisting over decades after discontinuation of use. CEE plus MPA on the other hand significantly increased breast cancer incidence and associated deaths, persisting over a decade after discontinuing its use. Researchers pointed out that a key limitation of the study was the fact that breast cancer mortality analyses were not protocol-specified. Moreover, the study assessed 1 dose and schedule of CEE alone or CEE plus MPA, and it was noted that the results from a particular dose or schedule may not be applicable to other variations in dosing or treatment schedule.

1. Chlebowski RT, et al. GS5-00. SABCS 2019.



Posted on 13 February, 202029 February, 2024