Menopause Live - IMS Updates

Date of release: 19 October, 2009

New findings about hormone therapy and breast cancer risk

Mortality due to breast cancer in American women is similar to that due to coronary heart disease in the age group 45–59 years old. Because of this, it is of utmost importance to establish the potential impact of hormone therapy (HT) around the time of menopause on breast cancer. Recent analyses of the Women’s Health Initiative (WHI) data suggest that women who initiate HT soon after the menopause have a higher breast cancer risk than those treated some years later. A recently published paper reports on the investigation of this possible relationship in a prospective cohort study in French women, the E3N cohort [1]. The authors studied 53,310 women from a pool of 98,995 women, using self-administered questionnaires sent biennially between 1990 and 2005. All these women were born between 1921 and 1950 and were already postmenopausal. The information on lifetime use of HT, which was recorded in the 1992 questionnaire, included start date, brand names and duration of HT use. ‘Recent use’ was defined as current use or use in the last 12 months. The time elapsed from menopause to treatment initiation was referred as the ‘gap time’.


A total of 1726 breast cancers were diagnosed during 433,647 woman-years of follow-up. The ever-use group had a significantly higher breast cancer risk when compared with never-users, but this was evident only in women with recent use of HT. Past use did not increase the risk (hazard ratios (HR) 1.09 and 1.04 for a gap time ≤ 3 years and for > 3 years of use, respectively). Recent users with a gap time ≤ 3 years had a HR of 1.61 (95% confidence interval (CI) 1.43–1.81); in those with a gap time > 3 years, the HR was 1.36 (95% CI 1.13–1.63). For treatment duration, there was no increase in the risk with short duration (< 2 years) and with a gap time > 3 years. When the gap time was ≤ 3 years, the HR was 1.54 (95% CI 1.28–1.86) except with the combination of estradiol and pure progesterone. In this case, the HRs were 0.87 and 0.90 for a treatment < 2 years and a gap time ≤ 3 years and > 3 years, respectively. However, the breast cancer risk increased after 5 years of estradiol + progesterone. If other progestogens were used for more than 2 years, the HR was in the order of 2, whatever the gap time, but dydrogesterone had an intermediate risk. In conclusion, the authors stressed that, in contrast to coronary disease, there is no ‘window of opportunity’ in regard to breast cancer risk. It appears that there is a tendency for a higher hazard ratio when treatment starts very soon after menopause. The risk is even higher with progesterone when treatment continues for more than 5 years.


This complex analysis shows us that the puzzle of HT risk/benefit in menopause management is far from being resolved. I guess that we can take home three principal lessons from this article. First, the increased risk of breast cancer with estrogen + progestogen treatment faded very quickly after its cessation. The observation that past users have no increase in risk is in line with another recent publication showing about 14% reduction in the incidence of estrogen receptor positive tumors 1–2 years following the WHI-associated sharp reduction in the use of HT [2]. Second, the risks added by different progestogens are not equal. Natural progesterone looks better than synthetic progestogens such as medroxyprogesterone acetate. This assumption needs further confirmation [3]. And third, here it seems that, contrary to what is generally accepted in regard to the risk of coronary heart disease, the sooner the treatment starts, the worse is the risk. It is already known [4] that the older a woman is at the time of menopause, the greater is the risk of breast cancer, especially when this cancer appears in the 50–59-year age group. Perhaps a long gap time without HT (> 3 years) counteracts carcinogenesis for a while and decreases the risk for breast cancer [5].


Roberto I. Tozzini
Honorary Professor and Past Professor and Chairman in Gynecology, National University of Rosario, Argentina


  1. Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks? J Clin Oncol 2009 Sep 14. Epub ahead of print.

  2. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007;356:1670-4.

  3. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103-11.

  4. Beral V; Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-59.

  5. Horwitz KB, Sartorius CA. Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancer: a hypothesis. J Clin Endocrinol Metab 2008;93:3295-8.