The Hormone Conundrum
An abrupt end to a major menopause study leaves women as confused as ever
The most intriguing question raised but not answered in the trial is whether estrogen increases breast cancer risk as much as combined HRT. WHI officials say there appeared to be no increase in breast cancer in the seven years of the trial. But some investigators aren't so sure. Stanford's Stefanick believes the different characteristics of the women in the two studies--weight and age, for example--might be obscuring the results. For example, several separate studies have shown that hormones increase breast cancer risk more for thin women as compared with overweight women, presumably because heavier women make more natural estrogen in their fat cells. So the effect of added estrogen in pill form may be less noticeable in terms of increasing breast cancer risk. Says Rossouw: "We're hypothesizing now; this is not known. But it's also possible that the body's own estrogen is a more powerful cancer producer than estrogen pills." He speculates further: "The result may be a `tamoxifenlike effect.' That's how tamoxifen works to retard breast cancer--it binds to the receptors and blocks the body's own estrogen." Investigators will analyze the results in a variety of ways to consider the weight of participants. "It's also possible," Rossouw adds, "that we haven't gone long enough to find the breast cancers."
Then why stop now? Elizabeth Barrett-Connor, a member of the safety monitoring board, believes the answer lies, in part, with the wrath expressed by physicians and drug manufacturers when the earlier HRT study was stopped. "For WHI 1," says Barrett-Connor, professor and chair of the Department of Family and Preventive Medicine, at the University of California-San Diego School of Medicine, "participants were told, a paper was done, physicians were blind-sided, but you could answer the questions." In an attempt to avoid physicians' angry reaction, everyone has been told the study is stopping, but there is no paper and no way to answer the many questions raised. "I expect many of the main purveyors of hormones will like this better," Barrett-Connor adds, "because they have more opportunity to discuss and debate unhampered by the real numbers."
Even when the real numbers are released in April, they'll be preliminary. New interpretations of the earlier HRT trial, published since the July 2002 cancellation, have changed investigators' view about HRT's impact on breast and colon cancer. There was, for instance, a 24 percent increase in breast cancer in women taking combination HRT, compared with those on the placebo. Nearly twice as many women on HRT had abnormal mammograms; increased breast density caused by HRT may explain that difference. What's newly discovered is that the cancers in women on HRT were larger, more advanced, and more likely to involve lymph nodes, leading to speculation that HRT use might result in a less favorable breast cancer prognosis.
Similarly, scientists are revising their interpretations of colon cancer results. One clear benefit seems to be a 44 percent reduction in colorectal cancers, the second leading cause of cancer death in the United States. However, Rowan Chlebowski, a WHI investigator from the Harbor-UCLA Research and Education Institute, recently found that the cancers in the hormone group were more serious: Many involved the lymph nodes--a sign that the cancer had already spread. "Though the numbers are small, these represent terminal cancer," says Chlebowski. While fewer cancers were diagnosed in the HRT group, slightly more women died of them than in the placebo group. In fact, both types of cancers were strikingly similar in HRT users, Chlebowski adds. "The data are consistent with a delay in diagnosis of two of the three most common cancers in postmenopausal women--colon and breast cancer." The final analysis of the results from both trials may not be available for several years.
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