Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women

Abstract

Context: In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.

Objective: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.

Design, setting, and participants: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.

Main outcome measures: Invasive breast cancer incidence and breast cancer mortality.

Results: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.

Conclusions: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.

Trial registration: clinicaltrials.gov Identifier: NCT00000611.

Figure 1

Flow of study participants during the intervention, postintervention and extension phases. The post-intervention phase began on July 9, 2002 the day after participants were instructed to stop study medication use (conjugated equine estrogen plus medroxyprogesterone acetate or placebo) use. The post-intervention phase continues thru the original trial completion date (March 31, 2005). The extension phase began on April 1, 2005, and includes follow-up for participants who re-consented (83% of those eligible) thru August 14, 2009.

Figure 2

Incidence of invasive breast cancer in the WHI clinical trial. Intent-to-treat Kaplan Meier cumulative hazard curves for incidence of invasive breast cancer by study group and time since randomization. Hazard ratios (HRs), 95% confidence intervals (CIs) and P values are from Cox regression models, stratified by age (5 year intervals) and randomization assignment in the WHI Dietary Modification trial. Quintiles of duration on study intervention (elapsed time from randomization until the intervention stopped on July 8, 2002) are indicated by the progressive shaded regions. For example, 80%, 60%, 40% and 20% of participants were in the intervention for at least 4.6 years, 5.2 years, 5.8 years and 6.7 years, respectively. All women stopped the intervention by 8.6 years (when shading ends).

Figure 3

Invasive breast cancer incidence by baseline characteristics and study group. Hazard ratios (combined hormone therapy vs. placebo) are from a Cox regression models stratified by age and randomization assignment in the dietary modification (DM) trial. For subgroup analyses, HR are allowed to vary by subgroup, and Cox regression models are stratified by age, randomization assignment in the WHI Dietary Modification trial, and subgroup. P-values are from Cox regression models for a 1-df test for trend. “Current use” refers to those reporting combined hormone therapy use at time of initial evaluation. A 3 month “wash out” was required before study entry. The time from menopause variable defined as the interval from the onset of menopause until first menopausal hormone therapy use or first study medication use (combined hormone therapy or placebo).

Figure 4

Deaths after breast cancer in the WHI clinical trial. Kaplan Meier cumulative hazard curves for: A) deaths directly attributed to breast cancer by study group and time since randomization and B) deaths from all causes following a breast cancer diagnosis, by study group and time in the trial. Hazard ratios (HRs), 95% confidence intervals (CI) and P values are from Cox regression models, stratified by age (5 year intervals) and randomization assignment in the WHI Dietary Modification trial. Quintiles for duration of study intervention (elapsed time from randomization, until the intervention stopped on July 8, 2002) are indicated by the progressive shaded regions. For example, 80%, 60%, 40% and 20% of participants were in the intervention for at least 4.6 years, 5.2 years, 5.8 years and 6.7 years, respectively. All women stopped the intervention by 8.6 years.