Postmenopausal Hormone Therapy and Breast Cancer—The French E3N Cohort Study
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: French cohort study finds an increased risk of breast cancer associated with synthetic progestins.
Source: Fournier A, et al. Unequal risks for breast cancer associated with different hormone replacement therapies: results form E3N cohort study. Breast Cancer Res Treat. February 27, 2007;Epub.
E3N is a French prospective cohort study initiated in 1990.1 The participants are members of an insurance plan that covers mostly teachers. The results are obtained by self-administered questionnaires, and this report represents 12 years of follow-up of 80,377 postmenopausal women available for analysis (88.7% completed the last questionnaire in 2002). A remarkable 70% of the women had used hormone therapy for an average of 7 years. The relative risks for invasive breast cancer were as follows:
| (table adapted by L. Speroff) | ||||
| Oral Estrogen | Transdermal Estrogen | |||
| Cases | Relative Risk | Cases | Relative Risk | |
| Estrogen alone | 13 | 1.32 (0.76-2.29 | 56 | 1.28 (0.98-1.69) |
| E plus | ||||
| Progesterone | 121 | 1.08 (0.89-1.31) | ||
| Dydrogesterone | 7 | 0.77 (0.36-1.62) | 90 | 1.18 (0.95-1.48) |
| Medrogestone | 9 | 2.74 (1.42-5.29) | 28 | 2.03 (1.39-2.97) |
| Chlormadinone | 8 | 2.02 (1.00-4.06) | 35 | 1.48 (1.05-2.09) |
| Promegestone | 13 | 1.62 (0.94-2.82) | - | |
| Nomegestrol | 46 | .11 (1.56-2.86) | 91 | 1.60 (1.28-2.01 |
| Medroxyprog | 29 | 1.48 (1.02-2.16) | - | |
The authors concluded that it would be preferable to use progesterone or dydrogesterone because estrogen used with these two progestins was not associated with an increase in the relative risk of invasive breast cancer. For any given progestin, the route of administration of estrogen (oral or transdermal) had no effect on relative risk. The authors then grouped all other progestins together, and grouped oral and transdermal estrogen alone together. They reported a statistically significant increase in relative risk with estrogen alone, RR = 1.29 (1.02-1.65) and with other progestins, RR = 1.69 (1.50-1.91). The increased relative risks seemed to rapidly dissipate after discontinuation of treatment; however, this analysis was limited by small numbers.
Commentary
Hormone users are known to differ in their personal characteristics when compared with non-users. However, in this instance, the entire cohort, users and nonusers, was very homogenous (mostly teachers and all in the same insurance company), and the authors argue that for that reason it is unlikely that the results are affected by confounders. Nevertheless, in their earlier report, data were provided revealing that the hormone users did differ considerably compared with the nonusers (earlier menarche, earlier menopause, less nulliparity, more children born before age 30, more benign breast disease, less obesity, and more education).2 This leaves readers uncertain regarding the impact of confounding differences. One problem that was not assessed is the prevalence of mammography. Hormone users have a greater prevalence of mammography, and an important criticism of the study is the lack of assessment for mammography frequency.
The authors of this study argue that their results indicate that the "natural" progestins are safer than "synthetic" progestins. But to accurately differentiate among various agents one would have to be certain that the doses administered represented bioequivalent doses in terms of target tissue impact, something that would be difficult to do. Let's focus on the rapidity at which cases of breast cancer were identified. In the current report, the use of estrogen combined with "other progestins" had an increased relative risk even with less than 2 years of exposure, RR = 1.376 (1.07-1.72). In their previous report, an increased relative risk was even apparent with less than one year of exposure of estrogen combined with synthetic progestins.2
In both of the French reports from this study, the results could be due to earlier detection of pre-existing tumors, an effect accelerated by specific progestins with greater potency. At this point in time we don't know whether there is a small increase in the risk of breast cancer with postmenopausal hormone therapy or whether the epidemiologic data reflect an impact on preexisting tumors. These French data are consistent with an effect on preexisting tumors, and that, contrary to the prevailing belief, estrogen-progestin exposure causes greater differentiation and earlier detection of preexisting tumors, resulting in better outcomes.
References
- Fournier A, et al. Unequal risks for breast cancer associated with different hormone replacement therapies: results form E3N cohort study. Breast Cancer Res Treat. February 27, 2007;Epub.
- Fournier A, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448-454.
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