Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study

Abstract

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.

Figure 1.

Invasive breast cancer incidence by estrogen plus progestin use at baseline. Analyses were adjusted for age, race or ethnic group, body mass index, education, smoking status, alcohol use, self-reported health, level of physical activity, presence or absence of a family history of breast cancer, estimated breast-cancer risk based on the Gail model, and bilateral oophorectomy and stratified by baseline age group. All statistical tests were two-sided. CI = confidence interval; HR = hazard ratio.

Figure 2.

Invasive breast cancer incidence by estrogen plus progestin use at baseline modified by time-from-menopause to hormone therapy initiation (gap time). Nonparametric spline fit for the hazard ratio (HR) (95% confidence interval [CI] in shaded region) of the effect of estrogen plus progestin by gap time. The smoothness of the fit was chosen objectively by generalized cross-validation. P values corresponds to a test of whether the effect of estrogen plus progestin changes with gap time. Analyses were adjusted for age, race or ethnic group, body mass index, education, smoking status, alcohol use, self-reported health, level of physical activity, presence or absence of a family history of breast cancer, estimated breast-cancer risk based on the Gail model, and bilateral oophorectomy and stratified by baseline age group. All statistical tests were two-sided.

Figure 3.

Survival after breast cancer diagnosis by estrogen plus progestin use at baseline. Analyses were adjusted for age, race or ethnic group, body mass index, education, smoking status, alcohol use, self-reported health, level of physical activity, presence or absence of a family history of breast cancer, estimated breast-cancer risk based on the Gail model, bilateral oophorectomy, and age at diagnosis and stratified by baseline age group. All statistical tests were two-sided. CI = confidence interval; HR = hazard ratio.

Figure 4.

Breast cancer mortality by estrogen plus progestin use at baseline. Panels depict (A) deaths from breast cancer (deaths directly attributed to the cancer) and (B) deaths after breast cancer (deaths from all causes after the cancer). Analyses were adjusted for age, race or ethnic group, body mass index, education, smoking status, alcohol use, self-reported health, level of physical activity, presence or absence of a family history of breast cancer, estimated breast-cancer risk based on the Gail model, and bilateral oophorectomy. All statistical tests were two-sided. CI = confidence interval; HR = hazard ratio.