Estrogen Plus Progestin and Breast Cancer Incidence

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Abstract and Introduction


Background In the Women's Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.

Methods We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided.

Results After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers.

Conclusions Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.


In the Women's Health Initiative (WHI) randomized, placebo-controlled clinical trial, estrogen plus progestin increased breast cancers not limited to tumors with favorable prognosis and increased breast cancer mortality. These findings were similar to observational study results regarding incidence (4) but differ from most reports regarding tumor characteristics and clinical outcome, in which a decrease, in deaths after breast cancer is commonly, but not universally, seen.

To explain these patterns, variation in study populations, including difference in time from menopause to first hormone therapy use (gap time) and differential mammography, have been invoked. Pursuant to this question, Prentice and colleagues combined WHI randomized trial results with WHI observational study results after 5.6 years of follow-up and suggested that estrogen plus progestin initiation with shorter gap time was associated with greater breast cancer risk. We now extend those findings in the WHI observational study by examining associations between estrogen plus progestin and breast cancer incidence, now with 11.3 years of mean follow-up, and, for the first time, with breast cancer mortality, in analyses adjusting for gap time, ongoing mammography, estrogen plus progestin use, and prior hormone therapy use before cohort entry.


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