Breast cancer after use of estrogen plus progestin in postmenopausal women

Abstract

Background: Following the release of the 2002 report of the Women's Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial.

Methods: We analyzed the results of the WHI randomized clinical trial--in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily and another group received placebo--and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use.

Results: In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged.

Conclusions: The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.

Figure 1. Effects over Time of Estrogen plus Progestin on the Incidence of Breast Cancer in the WHI Clinical Trial

Time-varying linear hazard ratios and 95% confidence intervals (solid and dashed lines, respectively) are shown for the effect of conjugated equine estrogens plus medroxyprogesterone acetate on the risk of breast cancer as compared with placebo during the intervention and postintervention phases of the study. The shaded areas indicate the overall mean and 95% confidence intervals for the hazard ratios in the intervention and postintervention phases. The I bars show hazard ratios and 95% confidence intervals according to an analysis based on events accumulated at 6-month intervals. The P value of 0.28 for a difference in trend is for the comparison of the hazard-ratio slopes in the two study phases in the primary, unadjusted analysis, and the P value of 0.005 is for a difference in trend from an analysis adjusted for adherence status, with censoring of events that occurred 6 months after a woman became nonadherent (defined as consuming <80% of study pills or starting hormone therapy). The thin solid lines show the adherence-adjusted, time-varying linear hazard ratios.

Figure 2. Effects over Time of Estrogen plus Progestin on the Risk of Breast Cancer in the WHI Observational Study

Smoothed time-varying, multivariable-adjusted hazard ratios and 95% confidence intervals (solid and dashed blue lines, respectively) for the comparison of participants who were taking estrogen plus progestin at study entry with those who were not are shown with the corresponding multivariable-adjusted hazard ratios and 95% confidence intervals from an analysis based on accumulated events at 6-month intervals (I bars). The variables used in this analysis are listed in the Methods section. The vertical line indicates the announcement of the results of the clinical trial in July 2002. The bar graph shows the year-to-year percentages of participants who were taking hormones and those who were not.

Figure 3. Adherence-Adjusted Effects over Time of Estrogen plus Progestin on the Risk of Breast Cancer in the WHI Observational Study

Time-varying linear hazard ratios and 95% confidence intervals for the risk of breast cancer (solid and dashed lines, respectively) are shown for a multivariable-adjusted proportional-hazards model comparing women who were using hormones at study entry with those who were not, with censoring of follow-up data for women whose status with regard to hormone use changed after enrollment and before July 2002. The I bars show hazard ratios and 95% confidence intervals according to the use or nonuse of hormones in an analysis based on events accumulated at 6-month intervals. Inverse probability weights according to time were used to adjust for changing characteristics of the study sample over time. The vertical line indicates the announcement of the results of the clinical trial in July 2002.