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Journal of the National Cancer Institute Advance Access published online on April 8, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn075
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© The Author 2008. Published by Oxford University Press.

ARTICLES

Conjugated Equine Estrogen and Risk of Benign Proliferative Breast Disease: A Randomized Controlled Trial

Thomas E. Rohan, Abdissa Negassa, Rowan T. Chlebowski, Laurel Habel, Anne McTiernan, Mindy Ginsberg, Sylvia Wassertheil-Smoller, David L. Page

Affiliations of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, AN, MG, SWS); Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA (RTC); Division of Research, Kaiser Permanente, Oakland, CA (LH); Fred Hutchinson Cancer Research Center, Seattle, WA (AM); Department of Pathology, Vanderbilt University Medical School, Nashville, TN (DLP)

Correspondence to: Thomas E. Rohan, MBBS, PhD, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461 (e-mail: rohan{at}aecom.yu.edu).

Background: Estrogens stimulate proliferation of breast epithelium and may therefore increase the risk of benign proliferative breast disease, a condition that is associated with increased risk of breast cancer. We tested the effect of conjugated equine estrogen (CEE) on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial.

Methods: In the WHI CEE trial, 10739 postmenopausal women were randomly assigned to 0.625 mg/d of CEE or to placebo. Baseline and annual breast examinations and mammograms were required. We identified women in the trial who reported breast biopsies that were free of cancer, obtained the associated histological sections, and subjected them to standardized central review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results: A total of 232 incident cases of benign proliferative breast disease were ascertained during follow-up (average duration, 6.9 years), with 155 in the CEE group and 77 in the placebo group. Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease (HR = 2.11, 95% CI = 1.58 to 2.81). For benign proliferative breast disease without atypia, the HR was 2.34 (95% CI = 1.71 to 3.20), whereas for atypical hyperplasia, it was 1.12 (95% CI = 0.53 to 2.40). Risk varied little by levels of baseline characteristics.

Conclusion: Use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease.


CONTEXT AND CAVEATS

Prior knowledge

There is mixed evidence that associates estrogens with risk of benign proliferative breast disease, a condition that may lead to breast cancer. After an average follow-up of 7 years, the Women's Health Initiative (WHI) detected no increase in breast cancer risk among women taking 0.625 mg/d conjugated equine estrogen (CEE) in a randomized controlled trial of 10739 hysterectomized postmenopausal women.

Study design

Histological sections were studied from women from the WHI CEE trial who reported breast biopsies free of cancer. Incidence rates of benign proliferative breast disease in the CEE and placebo groups were compared.

Contribution

After nearly 7 years of follow-up, women who took CEE had approximately twice as much risk of benign proliferative breast disease as women who took a placebo.

Implications

Use of unopposed estrogens appears to increase risk of benign proliferative breast disease, but whether this would translate into an increase in breast cancer is not yet known.

Limitations

Trial participants were treated with only one estrogen regime and dose, and the trial was stopped early. Symptoms and signs induced by CEE might have increased the likelihood of suspected breast lesions and biopsy in the treatment arm.

 
Manuscript received October 4, 2007; revised January 25, 2008; accepted February 14, 2008.


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