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Wendy Y. Chen, MD, MPH; JoAnn E. Manson, MD, DrPH; Susan E. Hankinson, ScD; Bernard Rosner, PhD; Michelle D. Holmes, MD, DrPH; Walter C. Willett, MD, DrPH; Graham A. Colditz, MD, DrPH

Arch Intern Med. 2006;166:1027-1032.

Background  Although short-term unopposed estrogen use does not seem to increase breast cancer risk, the effect of longer-term estrogen use remains unclear. We sought to assess the relationship between longer-term use of unopposed estrogen and the risk of invasive breast cancer over an extended follow-up period.

Methods  Within the Nurses' Health Study, a prospective cohort study, we observed 11 508 postmenopausal women who had a hysterectomy and reported information on estrogen use at baseline (1980). The study population was expanded every 2 years to include women who subsequently became postmenopausal and had a hysterectomy, so that 28 835 women were included in the final follow-up period (2000-2002). Estrogen use was assessed from self-reported data on biennial questionnaires. The main outcome was invasive breast cancer.

Results  A total of 934 invasive breast cancers were included in the analysis. Breast cancer risk increased with duration of unopposed estrogen use among longer-term users with the highest risk seen in cancers positive for estrogen receptor (ER+) and progesterone receptor (PR+). The multivariate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer with current use of unopposed estrogen for less than 5 years, 5 to 9.9 years, 10 to 14.9 years, 15 to 19.9 years, and 20 years or longer were, respectively, 0.96 (95% CI, 0.75-1.22), 0.90 (95% CI, 0.73-1.12), 1.06 (95% CI, 0.87-1.30), 1.18 (95% CI, 0.95-1.48), and 1.42 (95% CI, 1.13-1.77) (P for trend <.001). The risk of ER+/PR+ breast cancers was noted to be statistically significant after 15 years of current use (RR, 1.48; 95% CI, 1.05-2.07).

Conclusion  Users of unopposed estrogen were at increased risk of breast cancer but only after longer-term use.

Author Affiliations: Channing Laboratory (Drs Chen, Manson, Hankinson, Rosner, Holmes, Willett, and Colditz) and Division of Preventive Medicine (Dr Manson), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; Department of Medical Oncology, Dana Farber Cancer Institute (Dr Chen), Boston; and Departments of Epidemiology (Drs Hankinson, Willett, and Colditz) and Nutrition (Dr Willett), Harvard School of Public Health, Boston.

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