Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials

Abstract

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.

Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.

Design, setting, and participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.

Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.

Main outcomes and measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.

Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).

Conclusions and relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

Figure 1.. Kaplan-Meier Estimates for the Association of Menopausal Hormone Therapy With Invasive Breast Cancer During Cumulative Follow-up

The overall median length of follow-up for participants receiving conjugated equine estrogen (CEE) alone was 16.2 years (interquartile range [IQR], 9.1-20.8 years) and 20.7 years (IQR, 19.7-21.7 years) for those participating in extension II; for participants receiving CEE plus medroxyprogesterone acetate (MPA), the overall median length of follow-up was 18.9 years (IQR, 10.5-21.0 years) and was 20.7 years (IQR, 19.8 − 21.7) for those participating in extension II. Summary statistics are from a Cox proportional hazards regression model stratified by 5-year age group, randomization status in the dietary trial, prior hormone therapy use, race/ethnicity, randomization year, and study phase (time-dependent). The P value corresponds to a 2-sided stratified score (log-rank) test. HR indicates hazard ratio.

Figure 2.. Plot of Cumulative Hazard Ratios From Randomization Through Increasingly Longer Periods of Cumulative Follow-up

There were 10 739 women in the trial evaluating conjugated equine estrogen (CEE) alone and 16 608 in the trial evaluating CEE plus medroxyprogesterone acetate (MPA). Follow-up data were updated until all cases in both trials were included. Treatment durations varied due to the trial designs because randomization occurred from 1993 to 1998; box plots (for the CEE-alone trial on February 29, 2004, [minimum, 5.4 years; quartile 1, 6.6 years; median, 7.3 years; quartile 3, 8.2 years; and maximum, 10.2 years] and for the CEE-plus-MPA trial on July 7, 2002 [minimum, 3.7 years; quartile 1, 4.9 years; median, 5.6 years; quartile 3, 6.5 years; and maximum, 8.6 years]). Consequently, the intervention period and postintervention periods partially overlap. Summary statistics are derived from Cox regression models described in Figure 1. Dots represent cumulative hazard ratios (HRs), illustrating the temporal trend for each 3-month cumulative follow-up; whiskers, 95% CIs; horizontal bars in the colored boxes, period-specific HRs.

Figure 3.. Association of Hormone Therapy With Breast Cancer Incidence by Baseline Subgroups During Cumulative Follow-up

Data were missing. See Figure 1 for statistical details. Not applicable (NA), indicates too few participants.

Figure 4.. Association of Hormone Therapy With Tumor Characteristics and Breast Cancer Mortality During Cumulative Follow-up

Data were missing from all categories for both trials. Definitions of summary statistics and P values are described in the Figure 1 legend.

Figure 5.. Plot of Stratified Score (Log-Rank) Statistics Updated Annually Based on Cumulative Data

Data accumulated from randomization for breast cancer–related events in the trials evaluating conjugated equine estrogen (CEE) alone (n = 10 739) and evaluating CEE plus medroxyprogesterone acetate (MPA) (n = 16 608) during cumulative follow-up. Test statistics are 2 sided, correspond to the stratified score (log-rank) test obtained from the Cox regression model described in Figure 1, and were updated until all observed cases were included.