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Two papers from the Women’s Health Initiative (WHI), an updated assessment of the risk of breast cancer in relation to the use of unopposed estrogen therapy (ET) [1] and a review of breast cancer risk in relation to the use of hormone replacement therapy (HRT) [2], have recently been published. 


The WHI randomized, ‘double-blind’ trial of ET versus placebo [3], conducted among hysterectomized women aged 50–79 years, was terminated after an average of 6.8 years of follow-up because of an increased risk of stroke (not considered here). ‘Unblinding’ of the study medication occurred among less than 2% of the women and, overall, 53.8% discontinued their assigned treatments. In an ‘intention-to-treat’ (ITT) analysis, the hazard ratio (HR) for invasive breast cancer was 0.77 (95% confidence interval (CI) 0.59–1.01). In a second analysis [4], after 7.1 years of ‘blinded’ follow-up, the ITT HR was 0.67 (95% CI 0.47–0.97; [i]p[/i] = 0.03). In a third ‘as treated’ analysis [5], based on 7.1 years of ‘blinded’ follow-up plus an additional 3.6 years of ‘unblinded’ follow-up (total 10.7 years), the HR was 0.68 (95% CI 0.49–0.95); the risk reduction remained evident when the data were stratified by decade of age. The authors concluded that ‘the decreased risk of breast cancer persisted’. In the most recent publication [1], the median duration of follow-up was 11.8 years, and for invasive breast cancer the ITT HR for the use of ET for a median duration of 5.9 years was 0.77 (95% CI 0.62–0.95; [i]p[/i] = 0.02); in an ‘as treated’ analysis, it was 0.68 (95% CI 0.49–0.95; [i]p[/i] =0.02). For fatal breast cancer, the ITT HR was 0.37 (95% CI 0.13–0.91; [i]p[/i] = 0.03).


In the recent review of the risk of breast cancer in relation to the use of HRT [2], the authors stated that ‘recent results from large prospective cohort studies and the [WHI] randomized placebo-controlled trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestogen (E+P) influence breast cancer’. Whereas ‘the preponderance of the observational studies’ suggested that both ET and E+P increase the risk of breast cancer, in the WHI trials ‘E+P statistically significantly increased the risk of breast cancer’, but the use of unopposed ET ‘statistically significantly decreased the risk’. ‘Differential mammography usage patterns may explain differences between observational and randomized trial results’, since ‘in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups’.


  • Samuel Shapiro
    Department of Public Health and Family Medicine, University of Cape Town, South Africa


  1. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Womens Health Initiative randomized placebo-controlled trial. Lancet Oncol 2012 March 6. Epub ahead of print.
  2. Chlebowski RT, Anderson GL. Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst 2012;104:517-27.
  3. Anderson GL, Limacher M, Assaf AR, et al.; The Womens Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.
  4. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammographic screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.
  5. LaCroix AZ, Chlebowski RT, Stefanick ML, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-14.
  6. Shapiro S, Farmer RDT, Mueck AO, Seaman H, Stevenson JC. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. 2. The Womens Health Initiative: estrogen plus progestogen. J Fam Plann Reprod Health Care 2011;37:165-72.
  7. Shapiro S, Farmer RDT, Seaman H, Stevenson JC, Mueck AO. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. 1. The Collaborative Reanalysis. J Fam Plann Reprod Health Care 2011;37:103-9.
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