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

JAMA. 2010 Oct 20;304(15):1684-92. doi: 10.1001/jama.2010.1500.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology*
  • Drug Combinations
  • Estrogens, Conjugated (USP) / adverse effects*
  • Estrogens, Conjugated (USP) / therapeutic use
  • Female
  • Follow-Up Studies
  • Hormone Replacement Therapy / adverse effects*
  • Humans
  • Incidence
  • Lymphatic Metastasis
  • Medroxyprogesterone Acetate / adverse effects*
  • Medroxyprogesterone Acetate / therapeutic use
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Postmenopause*
  • Prognosis
  • United States / epidemiology

Substances

  • Drug Combinations
  • Estrogens, Conjugated (USP)
  • Prempro
  • Medroxyprogesterone Acetate

Associated data

  • ClinicalTrials.gov/NCT00000611

Grant support