A study investigating the long-term influence of estrogen plus progestin compared with estrogen alone on breast cancer incidence in postmenopausal women has found that the menopausal hormone therapies had opposite effects on breast cancer incidence. While estrogen alone decreased breast cancer incidence and death, with persistent results after a decade of discontinuing use, estrogen/progestin increased breast cancer incidence, with persistent results after discontinuing use. The study by Chlebowski et al was presented at the 2019 San Antonio Breast Cancer Symposium (Abstract GS5-00).

Study Methodology

This current study updates earlier findings from two randomized Women’s Health Initiative (WHI) clinical trials on breast cancer incidence and mortality in women aged 50 to 79 with no prior history of breast cancer and with mammogram clearance. The studies took place at 40 centers in the United States from 1993 to 1998, with follow-up through 2016.

The randomized, placebo-controlled trials included:

• 8,506 women with a uterus who were treated with conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) vs 8,102 women with a uterus treated with placebo for a median of 5.6 years
• 5,310 women with prior hysterectomy treated with CEE alone vs 5,429 women with prior hysterectomy treated with placebo for a median of 7.2 years.

Annual mammography was mandated through the originally specified completion date in both trials (March 31, 2005). Incidence of breast cancer was verified by medical record review. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards models.

The primary outcome for these analyses was time-specific invasive breast cancer incidence rates. In each trial, participants were instructed to stop all study treatments coincident with the publication of each trial’s results—in 2002 and 2004, respectively.

Study Results

After 16.1 years of cumulative follow-up, among those women who received CEE alone, the researchers found there were 520 incidences of breast cancer. CEE-alone use continued to significantly reduce breast cancer incidence (HR = 0.77, 95% confidence interval [CI] = 0.6–0.92, P = .005), whereas subgroup differences were attenuated and were no longer statistically significant. During the intervention period, with 360 incident breast cancers, CEE plus MPA use significantly increased breast cancer incidence (HR = 1.26, 95% CI = 1.02–1.56, P = .04), with the increase in breast cancer incidence greater in women with prior hormone therapy use (interaction P = .02) and women with a gap time < 5 years (interaction P = .002).

Postintervention, through 18.3 years cumulative follow-up, with 1,003 incident breast cancers, CEE plus MPA continued to significantly increase breast cancer incidence (HR = 1.29, 95% CI = 1.14–1.47, P < .001), whereas subgroup differences were attenuated and were no longer statistically significant.

“CEE alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence [in the] long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence [in the] long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions, all postmenopausal women with prior hysterectomy using CEE alone have the potential benefit of experiencing a reduction in breast cancer incidence, while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence,” concluded the study authors.

Clinical Relevance

“In the two randomized, placebo-controlled Women’s Health Initiative (WHI) clinical trials involving 27,347 postmenopausal women, CEE plus MPA significantly increased breast cancer incidence, with these adverse effects persisting over a decade after discontinuing use,” said lead study author Rowan T. Chlebowski, MD, PhD, Chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center, in a statement. “And in contrast to decades of observational study findings, in the WHI trial, CEE alone significantly reduced breast cancer incidence and significantly reduced deaths from breast cancer, with these favorable effects persisting over a decade after discontinuing use.”

He continued, “While there are differences in characteristics of participants in the observational studies compared with those in the WHI randomized trials, the discordance between the randomized clinical trial findings with respect to estrogen-alone use and observational findings are difficult to reconcile.”

Disclosure: The WHI program is supported by the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services; and the National Cancer Institute. For full disclosures of the study authors, visit abstractsonline.com.