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Results echo patient concerns

After menopause, women take hormone replacement therapy generally to improve their health in some way. They may hope to alleviate the symptoms experienced during menopause, to reduce bone loss that can lead to osteoporosis and to protect themselves from heart disease. Along with many benefits, however, hormone replacement therapy has always posed increased risks of certain types of cancers. This new study published in JAMA once again raises this issue.

When hormone therapy was first used, women were given estrogen alone. But then studies linked estrogen to a marked increase in uterine (endometrial) cancers. Soon the hormone progestin was added to estrogen to lessen this risk. Most women now take combined estrogen/progestin therapy.

Weighing the risks
This latest study confirms the reality that there is a certain amount of increased risk of cancer with some of these agents. More importantly, this risk increases with the duration of use. In addition, this and other studies suggest that the decrease in uterine cancer risk with combination therapy may be offset by an increase of the breast cancer risk. It’s a reminder of the many things that need to be taken into account when deciding whether to take hormone replacement therapy after menopause.

Exactly what this risk is is hard to determine from the study as presented. When examining one chart provided in this study, the risk of breast cancer from taking HRT could be as low as a 5 percent increase, or as high as a two and a half times the normal risk. This study shows there is an increased risk, but exactly how much we can’t tell. Similarly, even though the risk of breast cancer appears to be somewhat higher for combination therapy than for estrogen alone, it is difficult to be sure of the magnitude of the difference.

Small sample size
That’s in part because these were not huge numbers being reported, despite the initial review of many thousands of women. In the end, there were just 300 or 400 cases in each group being examined. So I don’t think you can conclude anything beyond the fact that there seems to be an increased risk.

It’s also important to note that the women in this study were all in a breast cancer detection program and were regularly screened with mammograms. This differs from the general population, where screening rates may not be as high. It could have resulted in more breast cancers being detected among the participants.

Fueling cell growth
One thing should be stressed. Taking HRT does not "cause" breast cancer. What does happen is that cancer cells already present are stimulated by HRT and grow at a faster rate. This causes the cancer in women taking HRT to show up sooner than if they had not taken HRT. In fact, this may explain the observation that most of the breast cancers detected occurred relatively soon after HRT was used.

Pros and cons
This study highlights the need for a woman to consider her unique, individual health characteristics when deciding on HRT. This decision must balance a woman’s risk of cardiovascular disease or osteoporosis with her risk of breast cancer. Interestingly enough, women at risk of osteoporosis may have a lower than normal risk of breast cancer. That’s because these women may not produce as much estrogen, which, in turn, has a relatively protective effect against breast cancer. Thus, a woman who is at high risk for osteoporosis, but at relatively low risk for breast cancer, is likely to derive significant benefit from HRT.

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On the other hand, a woman who has no particular risk factors for osteoporosis or heart disease, but an elevated risk for breast cancer, may be better off not using HRT.

Evaluate breast cancer risk
Women at high risk of breast cancer may decide against HRT. These women have a first-degree relative (mother, sister) with breast cancer or they may have had breast cancer themselves. Other risk factors include beginning menstruation at a young age, a late first pregnancy and a late menopause. These last factors all have to do with how much estrogen the breast tissue has been exposed to over a lifetime.

It all comes down to how cells respond to estrogen. Yes, estrogen stimulates breast and uterine cancer cells to grow, but it also helps brain cells work better, bones stay strong and helps prevent heart disease. We now know that the estrogen receptors for these different types of cells—that is, the doorways where estrogen enters the cells—are not all the same.

Designer estrogens
We hope someday soon to have drugs that can act like estrogen for bones, the cardiovascular system and the brain, but don’t have that effect on breast or uterine cells. One drug under investigation at Yale right now is raloxifene, which is used to treat osteoporosis. In a partnership with the Hospital of Saint Raphael, we are participating in a national trial examining whether this drug can actually help protect against breast cancer. The hope is that these drugs will make hormone replacement therapy obsolete.

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Dr. Michael Reiss is director of the Yale Cancer Center’s Breast Cancer Research Program and a medical oncologist affiliated with Yale-New Haven Hospital.