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A recent paper by Crandall and colleagues, based on data from the Women’s Health Initiative (WHI) clinical trial, reported that ‘new-onset breast tenderness during conjugated equine estrogens plus medroxyprogesterone therapy was associated with increased breast cancer risk’ [1]. The authors assert that new-onset breast tenderness (NOBT) is a useful predictor of breast cancer and caution that ‘an increase in breast tenderness, easily detected by physicians or patients, identifies a population at particular risk for breast cancer. These findings should be considered by women who experience NOBT while receiving combined hormone therapy and by their prescribing physicians to inform decisions regarding continued combined hormone therapy’ [1]. 


Breast tenderness was assessed by a self-administered menopause symptom questionnaire that asked about the degree of bother in the past 4 weeks, using a 4-point scale (none, mild, moderate, severe). Of the 16,608 women in the trial of conjugated equine estrogens (CEE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg daily, 14,538 women reported no breast tenderness at study entry. Of these, 6555 were assigned to placebo and 6868 were assigned to active treatment. After 12 months on their assigned treatment, 770 women given placebo and 2477 women given CEE plus MPA reported any breast tenderness (mild, moderate, or severe) on repeat administration of the same questionnaire. Thus, the rate of breast tenderness within the prior 4 weeks was 11.8% in women given placebo and 36.1% in women given CEE plus MPA after 12 months of treatment, a roughly three-fold difference. Over the 5.6-year average follow-up interval, the annualized rates of breast cancer in women with NOBT were 4.4 and 6.0 per 1000 in women given placebo and active treatment, respectively [1].


In parallel with the three-fold difference in NOBT at 12 months, a basic Cox regression model testing NOBT as a predictor of breast cancer found a hazard ratio of 1.37 with a 95% confidence interval of 1.05–1.77. However, after the addition of treatment assignment to the model, the hazard ratio was reduced to 1.29 and the 95% confidence interval was no longer significant (0.99–1.70). The sensitivity of NOBT for predicting breast cancer risk was 41% and the specificity was 64%. The positive predictive value was 2.7% [1].


  • Robert D. Langer
    Principal Scientist and Medical Director, Jackson Hole Center for Preventive Medicine; Adjunct Scholar in Epidemiology, University of Pennsylvania Center for Clinical Epidemiology & Biostatistics; Professor of Family and Preventive Medicine, University of California San Diego (retired)


  1. Crandall CJ, Aragaki AK, Chlebowski RT, et al. New onset breast tenderness after initiation of estrogen plus progestin therapy and breast cancer risk. Arch Intern Med 2009;169:1684-91. Published October 12.
  2. Harvey J, Scheurer C, Kawakami FT, et al. Hormone replacement therapy and breast density changes. Climacteric 2005;8:185-92.
  3. Deeks A, Zoungas S, Teede H. Risk perception in women: a focus on menopause. Menopause 2008;15:304-9.
  4. Mosca L, Jones WK, King KB, et al. Awareness, perception, and knowledge of heart disease risk and prevention among women in the United States. American Heart Association Womens Heart Disease and Stroke Campaign Task Force. Arch Fam Med 2000;9:506-15.
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  7. Chang ST, Chen CL, Chu CM, et al. Ankle-disease is a useful test for clinical practice in outpatients with suspected coronary artery disease. Circ J 2006;70:68690.
  8. Boyd NF, Martin LJ, Li Q, et al. Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2006;15:961-6.
  9. Stefanick ML, Anderson GL, Margolis KL, et al.; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.
  10. Rockhill B, Spiegelman D, Byrne C, et al. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 2001;93:358-66.
  11. Elmore JG, Barton MB, Moceri VM, et al. Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998;338:1089-96.
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