Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography in Postmenopausal Women with Hysterectomy
Findings from the Women’s Health Initiative (WHI) Estrogen-Alone (E-Alone) trial were published in April 2004. The National Institutes of Health decided to stop this trial early because of an increased risk of stroke and no heart disease benefit in participants assigned to active estrogen pills compared to those assigned to placebo (inactive pills). The E-Alone trial included 10,739 postmenopausal women who were 50-79 years old and already had a hysterectomy when they joined the WHI. In the E-Alone trial, 5,310 women were assigned to take active conjugated equine estrogen pills (CEE or Premarin®) at a dosage of 0.625 mg each day and 5,429 were assigned to take placebo.
The major findings from the trial were that E-alone increased the risk of strokes and blood clots in the legs, decreased the risk of hip fractures, and had no clear effect on heart disease or breast cancer.
For breast cancer, these initial findings suggested that women in the active estrogen (CEE) group had a 23% lower risk of breast cancer compared to those in the placebo group over an average follow-up of 6.8 years. While this difference was not statistically significant, the findings were viewed as surprising, because a significant increase in breast cancer risk was found in the other WHI hormone trial of combined estrogen plus progestin (E+P) in women who had a uterus when they joined the WHI. In the initial E-Alone report, limited data were published from the 218 invasive breast cancers that had been reported. The breast cancer findings in the E-Alone trial, therefore, needed further study.
On April 12, 2006, the Journal of the American Medical Association published the final report of all breast cancers diagnosed before the E-Alone trial was stopped. This report covered an average of 7.1 years of follow-up and analyzed detailed information from all 237 invasive breast cancers that occurred during the trial. Participants in the CEE group had a 20% lower risk of invasive breast cancer compared to those in the placebo group, similar to the findings in the initial report. In this final report, the difference between groups was also not statistically significant, which means the decreased risk could be due to chance.
Another way of looking at these findings is that 104 cases of invasive breast cancer were diagnosed in the CEE group (28 cases per 10,000 women per year) compared to 133 cases in the placebo group (34 cases per 10,000 per year). This observed reduction (6 per 10,000 per year) is not statistically significant, but the data provide evidence that breast cancer risk is not increased for at least 7 years in women 50-79 years who have a prior hysterectomy and take CEE in the dosage studied in the E-Alone trial. Detailed analyses showed no evidence that breast cancer risk shifted during the average 7 years of follow-up in the E-Alone trial. In contrast, in the E+P trial, the increase in risk of breast cancer emerged after 4 years.
About 5-7% of E-Alone participants in both groups stopped taking their study pills each year. More than half (54%) of participants were no longer taking pills by 7 years. When analyses included only women who were still taking study pills (taking at least 80% during the 6 months before reporting on their health), women in the CEE group had a 33% lower risk of breast cancer compared to those in the placebo group.
In order to understand more about how breast cancer is affected by CEE and guide future research, exploratory analyses were done. The effect of CEE on breast cancer, though not significant, was seen mainly in a specific type and stage of disease—CEE reduced risk of ductal carcinoma and early stage disease. CEE reduced breast cancer risk in women who were already at lower risk for this disease (based on risk factors), whereas it tended to increase risk in women already at higher risk. Analyses also suggested that the decreased risk of breast cancer risk associated with CEE may be mainly in women who had never used menopausal hormones before. There was no evidence in these analyses that obesity influenced the CEE effects on breast cancer.
Finally, the new findings show that participants in the CEE group had significantly more abnormal mammograms than those in the placebo group (9.2% versus 5.5% by the first year; 36.2% versus 28.1% over the course of the trial). Most of these abnormalities just required a repeat mammogram in 6 months and were not suspicious for cancer. From the second year onward, women in the CEE group also had more breast biopsies than those in the placebo group.
Findings from the E-Alone trial show that women with prior hysterectomy do NOT have an increased risk of breast cancer for at least 7 years after starting estrogen-alone (CEE). In contrast, findings from the E+P trial show that women with a uterus who used combined estrogen and progestin had an increased risk of breast cancer by 5 years. These findings suggest that CEE alone is safer in regard to breast cancer than combined estrogen plus progestin, at least in the short term for women who have a hysterectomy and, therefore, would not be prescribed a progestin.
A woman’s individual decision about hormone therapy should take into account her risk profile for breast cancer and other diseases that might be affected by hormones (such as stroke, heart disease, blood clots, and hip fractures).