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Original Investigation
June 2015

Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women’s Health Initiative Randomized Clinical Trials

Author Affiliations
  • 1Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California
  • 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
  • 3Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 4Fred Hutchinson Cancer Research Center, Public Health Sciences, Seattle, Washington
  • 5Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville, Jacksonville
  • 6Stanford Prevention Research Center, School of Medicine, Stanford University, Palo Alto, California
  • 7Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, Michigan
  • 8Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis
  • 9Department of Social and Preventive Medicine, State University of New York at Buffalo
  • 10Obstetrics/Gynecology, University of Miami Health System Miami, Florida
  • 11Georgetown Lombardi Comprehensive Cancer Center, Washington, DC
  • 12Department of Biochemistry and Molecular Medicine, University of California, Davis
  • 13Hematology and Medical Oncology, MedStar Washington Hospital Center, Washington, DC
JAMA Oncol. 2015;1(3):296-305. doi:10.1001/jamaoncol.2015.0494

Importance  The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use.

Objective  To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women’s Health Initiative (WHI) randomized clinical trials.

Design, Setting, and Participants  A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010.

Interventions  A total of 16 608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10 739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years.

Main Outcomes and Measures  Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials.

Results  In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95% CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95% CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95% CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95% CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95% CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95% CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95% CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials.

Conclusions and Relevance  In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.