Women’s Health Initiative Update on Menopausal Hormone Therapy and Breast Cancer Incidence/Mortality

By Manijeh “Mani” Berenji

Over the last 30 years, there have been many studies (randomized control trials as well as observational) looking at the effects of menopausal hormonal therapy on breast cancer incidence and mortality. The Women’s Health Initiative, which has conducted one of the most comprehensive analyses to-date, recently provided an update on the long-term ramifications of menopausal hormonal therapy on breast cancer incidence and mortality over 20 years of follow-up. Study authors Chlebowski and colleagues looked at the follow-up data of randomized control trials assessing (i) conjugated equine estrogen (CEE) plus medroxyprogresterone acetate (MPA) in post-menopausal women with an intact uterus and (ii) CEE-alone in post-menopausal women with prior hysterectomy (1). The CEE+MPA trial started in 1997 and was stopped 5.6 years into the trial (on July 7, 2002) because of positive association and statistically-significant risk of breast cancer in the test group. The CEE-alone trial started in 1997 was stopped 7.2 years into the trial (on February 29, 2004) for similar reasons.

For the follow-up analyses, Chlebowski and fellow researchers identified the breast cancer incidence as the primary study outcome. Secondary outcomes included beast cancer mortality and non-breast cancer mortality.

These two trials enrolled 27,347 post-menopausal women aged 50–79 from 40 centers across the U.S. For the CEE+MPA trial, there were 8,506 women who received both the hormones and 8,102 women who received placebo. For the CEE-alone trial, women with hysterectomy were randomized to CEE treatment arm (n=5,310) or placebo arm (n=5,429). These women had no prior breast cancer diagnosis and were negative for any breast pathology at baseline screening mammogram. The women were enrolled from 1993–1998 and then followed-up every 6 months through 2005 and then yearly from 2006 through 2017. These women completed self-report questionnaires describing their demographics (including race and ethnicity), medical history, breast cancer risk factors, and lifestyle. Trained interviewers gathered more detailed information on past hormone therapy use.

Of the 27,347 women, those in the CEE-alone trial had a higher percentage of African-Americans, a greater number of obese women, and more prior hormone therapy reported compared to the CEE+MPA trial. The actual follow-up time for those in the CEE-alone trial was 16.2 years and 18.9 years in the CEE+MPA trial and the times differed from the expected 20 years because of variation in participant consent.

When analyzing the data for the CEE+MPA trial, Chlebowski and associates found that those who had received CEE+MPA had a statistically-significant higher breast cancer incidence in the cumulative follow-up. This amounted to a breast cancer incidence of 0.45% risk per year in the CEE+MPA group as compared to a breast cancer incidence of 0.36% per year in the placebo group (p=0.005). But use of CEE+MPA was not statistically-significantly associated with death from breast cancer compared to placebo. When analyzing the CEE-only data, the researchers found that those who had received CEE had a statistically lower breast cancer incidence in the cumulative follow-up. This amounted to a breast cancer incidence of 0.30% per year in the CEE-only group as compared to a breast cancer incidence of 0.37% in the placebo group (p=0.005). CEE-alone was associated with statistically-significant less deaths from breast cancer compared to placebo. The study authors made sure to explain that despite this association, the reduction is modest and should be interpreted as such. This follow-up study made good use of the data from the randomized controlled trials with a diverse study population and robust study methodology (including mammogram clearance and routine mammograms, review of all positive breast cancer cases, and thorough follow-up).

References:

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020;324(4):369–380.