Estrogen and Breast Cancer
Estrogen and Breast Cancer
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH , Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: New data from the Women's Health Initiative Study estrogen-only arm demonstrates that estrogen treatment not only was associated with a lower incidence of breast cancer diagnosis, but also fewer breast cancer deaths.
Source: Anderson GL, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012; Mar 6 [Epub ahead of print].
Subjects in the Women's Health Initiative (WHI) trial estrogen-only study randomized to receive conjugated estrogens had a lower incidence of invasive breast cancer than did those who received placebo. The aim of the present study was to assess the influence of estrogen use on longer-term breast cancer incidence and mortality by evaluating extended follow-up of this cohort. Between 1993 and 1998, 10,739 postmenopausal women aged 50–79 years who had undergone hysterectomy and had normal breast health screening with clinical exam and mammography from 40 U.S. clinical centers were randomly allocated to receive either oral conjugated equine estrogen (0.625 mg/day; n = 5310) or matched placebo (n = 5429). The study drug was terminated early in February 2004, because of an adverse effect of treatment on stroke, but follow-up continued until the planned termination of March 2005 with original results reported from these data. After this, consent was sought for extended surveillance from 9786 living participants in active follow-up, and 7645 (78%) agreed. Data from this extended follow-up cohort available through August 14, 2009, was evaluated to assess the long-term effects of estrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. The authors used Cox regression models to estimate hazard ratios (HR) in the intention-to-treat population.
They found that after a median follow-up of 11.8 years, the use of estrogen for a median of 5.9 years was associated with a significantly lower incidence of invasive breast cancer (151 cases, 0.27% per year) compared with placebo (199 cases, 0.35% per year; HR 0.77, 95% confidence interval [CI] 0.62 to 0.95; P = 0.02) with no significant difference in risk reduction in those women diagnosed during the intervention phase (21% decrease) and post-intervention (25% decrease). In subgroup analyses, they noted that the breast cancer risk reduction with estrogen use was limited to women without a personal history of benign breast disease (P = 0.01) or a family history of breast cancer (P = 0.02). Significantly, in the estrogen group, fewer women died from breast cancer (six deaths, 0.009% per year, compared with controls 16 deaths, 0.024% per year; HR 0.37, 95% CI 0.13 to 0.91; P = 0.03) or from any cause after a breast cancer diagnosis (30 deaths, 0.046% per year, compared with 50 deaths, 0.076% per year; HR 0.62, 95% CI 0.39 to 0.97; P = 0.04).
The authors concluded that these results provide reassurance that breast cancer diagnosis and mortality are not increased for women with hysterectomy who use estrogen-only menopausal therapy, but were cautious to note that these data do not support use of estrogen for breast cancer risk reduction.
Commentary
The great thing about the weather in Oregon in the spring is change. If you don't like it now, just wait 20 minutes and the rain, snow, and hail will change to brilliant sunshine and balmy temperatures. Although it often switches back, the days become progressively longer, brighter, and warmer. So goes the Women's Health Initiative Study, the large NICHD-funded evaluation of hormonal therapy in postmenopausal women. The initial news from the combined Prempro® arm was devastating, and the shock affected the confidence of clinicians and women such that use of postmenopausal HRT declined precipitously and many symptomatic women found it difficult to obtain treatment. The combined treatment with conjugated estrogen and medroxyprogesterone acetate (MPA) increased the risk of breast cancer, and increased the risk of cardiovascular complications like coronary heart disease, venous thrombosis, and stroke.1 Over the years, much more has been learned. First, the results of the estrogen-only WHI studies differed from the combined therapy arm with respect to several clinically important outcomes; there was no overall impact on coronary heart disease with estrogen-only treatment and there was the trend toward a reduction in risk of invasive breast cancer in the estrogen-only arm.2 The decreased risk of invasive breast cancer persisted in a 2011 analysis of results from this study,3 and the present publication now provides more evidence showing that breast cancer mortality is also reduced. Taken together with similar favorable results evaluating cardiovascular effects with estrogen-only therapy, and in younger users of combined HRT, it seems that spring may be returning to hormonal therapy.
Given the fact that a steady diet of negative reporting has led many women and clinicians to view estrogen as a cancer-causing poison, the Anderson report is bound to cause confusion or, worse yet, to be ignored entirely. However, there is substantial basic research that suggests the true role of estrogen is a trophic hormone that positively affects growth of many tissues, including some cancers. More like a fertilizer than a toxin. You put fertilizer in the garden to support the growth of vegetables, accepting that it will improve the growth of weeds too. Natural estradiol should be viewed as a healthy organic fertilizer that helps the brain, bones, and many other tissues. While the data do not support that estrogens cause cancer, they will support the growth of these unwanted cells too; routine mammography is the way to identify these "weeds." The use of a progestogen complicates the picture in the breast. Using core needle biopsies, Murkes and colleagues found greater breast cell proliferation in postmenopausal women using oral conjugated estrogens and MPA than in those treated with transdermal estradiol and oral micronized progesterone.4 Since increasing numbers of women are reaching menopause with an intact uterus, we need to re-energize research to develop and market local progestogen delivery systems (like the LNG IUS) for postmenopausal use. Until then, off-label use of the LNG IUS should be considered.
References
- Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA2002;288:321-233.
- Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712.
- LaCroix AZ, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA 2011;305:1305-1314.
- Murkes D, et al. Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women. Fertil Steril 2011;95:1188-1191.
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