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NEWS & VIEWS |
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Two articles in the June 25 issue of JAMA (2003; 289:3243–3253) provide additional information on combined hormone replacement therapy (CHRT) as a breast cancer risk factor.
In a new analysis of data from the Women’s Health Initiative (WHI), a randomized, controlled trial comparing the effects of combination hormone therapy (estrogen plus progestin) with placebo, Rowan Chlebowski, MD, MPH and colleagues report that not only did women who took CHRT have a 24% greater incidence of breast cancer, but their cancers were harder to detect by mammography and were found at a more advanced stage. In addition, breast cancer risk rises within five years of starting CHRT—much sooner than previous observational epidemiologic studies had suggested.
More than 16,000 postmenopausal women ages 50 to 79 took part in the WHI trial of CHRT versus placebo, which after a mean follow-up interval of 5.2 years, was stopped ahead of schedule in 2002 when researchers found that CHRT increased the incidence of breast cancer, coronary heart disease, stroke, and pulmonary emboli.
The earlier analysis demonstrated an overall negative impact on risk of several serious chronic diseases, and clearly showed that long-term CHRT is not an effective intervention for preventing chronic disease, as had been suggested by earlier observational studies. But, the safety of short-term CHRT for treating menopausal symptoms remained in question. The new analysis adds several pieces of new information relevant to choices about short-term CHRT. First, the WHI data show an increase in false-positive mammograms, leading to unnecessary biopsies, which is evident within the first year of CHRT.
Second, breast cancer incidence appeared to be reduced during the first four years of CHRT. At that time, the incidence curves cross, and the excess risk associated with CHRT continues to increase. However, this initial drop in incidence is bad news for CHRT, the authors explain. The likely reason is that CHRT increases breast density, making mammography less sensitive. Consequently, within one year, CHRT starts increasing the false-negative mammography rate, and it takes several additional years before many of these cancers are eventually discovered, at a later stage than they would have been otherwise.
The practical implication is that even one year of CHRT prescribed for relief of menopausal symptoms may cause harms associated with increased false-positive and false-negative mammograms.
Writing in the same issue of JAMA, editorialists Peter H. Gann, MD, ScD, and Monica Morrow, MD, both of Northwestern University concluded that, "The increased risk of breast cancer and the mammographic abnormalities among women in the WHI study provide further compelling evidence against the use of combination estrogen plus progestin hormone therapy." But, some questions regarding CHRT remain to be answered. According to Gann and Morrow, "...the risks and benefits of short-term use of hormone replacement therapy for menopausal symptoms need to be clarified in rigorous investigations, and studies examining lower dosage formulations and alternative delivery methods, such as skin patches, would be useful."
In the second JAMA article, Christopher I. Li, MD, PhD, and colleagues from the University of Washington, Seattle, report on a population-based case-control study of breast cancer risk associated with several forms of hormone replacement therapy. An excess risk of breast cancer was associated with CHRT use, and its magnitude (a 50% increase with CHRT duration of 5 to 14.9 years) was similar to that reported in the WHI trial.
This study addresses two additional issues. The first question is whether the form of CHRT (sequential versus continuous) influences the association with breast cancer risk. The answer is, "no."
The second question is whether estrogen replacement therapy (ERT) also increases breast cancer incidence. Li and colleagues did not find any appreciable increase in breast cancer incidence associated with ERT, although they note the size of the study was not sufficient to detect a small effect. Interestingly, WHI is also conducting an ERT versus placebo study among women who have had a hysterectomy, and are, therefore, unaffected by the association of ERT and endometrial cancer. Chlebowski and colleagues mention that, as of May 31, 2002, the WHI data and safety monitoring board (the group that terminated the CHRT versus placebo study last year when CHRT was found to increase breast cancer incidence) found no such increase associated with estrogen replacement alone. A more definitive answer is still a couple of years away; that portion of the study is scheduled to be completed in 2005.
Meanwhile, Gann and Morrow raise an interesting question concerning ERT—"If the observational studies are again correct, estrogen-only use could have much less impact on breast cancer risk than estrogen plus progestin use. The findings related to heart disease in the estrogen-only use will be of particular interest. If estrogen-only use reduces the risk of heart disease and has little impact on breast cancer risk, a reanalysis of the risk-benefit ratio of estrogen-only use in women with an intact uterus would seem warranted."
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