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Original Investigation
July 28, 2020

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

Author Affiliations
  • 1Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
  • 2Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington
  • 3Division of Public Health Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
  • 4Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California
  • 5Department of Epidemiology, University of Washington, Seattle, Washington
  • 6Department of Epidemiology, School of Public Health, University of Pittsburgh, Pennsylvania
  • 7Department of Oncology, Karmanos Cancer Institute at Wayne State University, Detroit, Michigan
  • 8Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York
  • 9Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis
  • 10Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
  • 11College of Public Health, The Ohio State University, Columbus
  • 12Division of General Internal Medicine, University of Florida Health Internal Medicine, Gainesville
JAMA. 2020;324(4):369-380. doi:10.1001/jama.2020.9482
Key Points

Question  What is the association of estrogen plus progestin or estrogen alone with breast cancer incidence and breast cancer mortality?

Findings  In long-term follow up of 2 placebo-controlled randomized clinical trials involving 27 347 postmenopausal women, prior randomized use of conjugated equine estrogen (CEE), compared with placebo, among women with prior hysterectomy was significantly associated with lower risk of breast cancer (annualized incidence, 0.30% vs 0.37%; hazard ratio [HR], 0.78); and breast cancer mortality (annualized mortality, 0.031% vs 0.046%; HR, 0.60), whereas prior randomized use of CEE plus medroxyprogesterone acetate (MPA), compared with placebo, among women with an intact uterus, was significantly associated with higher risk of breast cancer (annualized incidence, 0.45% vs 0.36%; HR, 1.28) and no significant difference in breast cancer mortality (annualized mortality, 0.045% vs 0.035%; HR, 1.35).

Meaning  Among postmenopausal women, prior randomized use of CEE in women with prior hysterectomy was significantly associated with a lower risk of breast cancer incidence and mortality, whereas prior randomized use of CEE plus MPA in women with an intact uterus was significantly associated with a higher risk of breast cancer incidence and no significant difference in breast cancer mortality.

Abstract

Importance  The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.

Objective  To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women’s Health Initiative clinical trials.

Design, Setting, and Participants  Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.

Interventions  In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years’ median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years’ median intervention duration.

Main Outcomes and Measures  The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.

Results  Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).

Conclusions and Relevance  In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

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