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In the January issue of the [i]Journal of the National Cancer Institute[/i], Valerie Beral and co-workers report an update on the association between use of hormone therapy (HT) and breast cancer risk in the Million Women Study cohort [1]. After extended follow-up, more postmenopausal women (1,129,025 vs. 828,923) and more incident breast cancers (15,759 vs. 7140) were included in the new analysis than in the previous report from 2003 [2]. As before, a greater risk for current users of estrogen + progestogen (E+P) therapy than for estrogen-only therapy was found: relative risk (RR) 1.96, 95% confidence interval (CI) 1.90–2.02, average duration of use 6.8 years; RR 1.38, 95% CI 1.32–1.44, average duration of use 8.0 years, respectively. The updated data still point to an excessive risk in users of tibolone (RR 1.38, 95% CI 1.25–1.52, average duration of use 7.0 years). There was a rapid decline in risk after cessation of therapy: for 2 up to 14 years after discontinuation of use, the risk was similar to that in never-users (RR 0.99, 95% CI 0.93–1.05).


The main focus in this new analysis was on the influence of timing on breast cancer risk for the different treatment regimens. Relative risks were found to be higher if therapy was started before or soon after menopause than in the case of a longer gap ([i]p[/i] < 0.001). Among current users of estrogen-only therapy, there was little or no increase in risk if use began 5 years or more after menopause (RR 1.05, 95% CI 0.89–1.24), whereas risk was increased if use began before or within 5 years after menopause (RR 1.43, 95% CI 1.35–1.51). A similar pattern was seen for users of E+P (RR 1.53, 95% CI 1.38–1.70 vs. RR 2.04, 95% CI 1.95–2.14). Figures for tibolone showed a similar tendency but did not reach statistical significance. A total of 6267 women diagnosed with breast cancer had started treatment with either estrogen-only therapy or E+P therapy and only 515 of those did so more than 5 years after menopause. The average time between menopause and start of HT in this subgroup was 10.3 years for estrogen-only therapy and 9.3 years for E+P therapy. 


The authors conclude that there was substantial heterogeneity in breast cancer  risk among current users of HT. Risks were greater for E+P than for estrogen-only use and if treatment started at around the time of menopause than later.


  • Bo von Schoultz
    Professor Emeritus, Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden


  1. Beral V, Reeves G, Bull D, et al. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 2011;103:296-305.
  2. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27.
  3. Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Womens Health Initiative clinical trial and observational study. Am J Epidemiol 2008;167:1407-15.
  4. Fournier A, Mesrine S, Boutron-Ruault MC, et al. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risk? J Clin Oncol 2009;27:5138-43.
  5. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95(Suppl 1):S1-66.
  6. Horwitz KB, Sartorius CA. Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: a hypothesis. J Clin Endocrinol Metab 2008;93:3295-8.
  7. Milanese TR, Hartmann LC, Sellers TA, et al. Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst 2006;98:1600-7.
  8. Opatrny L, DellAniello S, Assoulines S, et al. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG 2008;115:169-75.
  9. Shapiro S. The Million Woman Study: potential biases do not allow uncritical acceptance of the data. Climacteric 2004;7:3-7.
  10. Nelson HD, Fu R, Griffin JC, et al. Systemic review: comparative effectiveness of medications to reduce risk of breast cancer. Ann Intern Med 2009;151:703-15.
  11. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708.
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