ABSTRACT: There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 47 breast cancer experts and 13 patient advocates participated. The proceedings of the conference are being published in six installments in successive issues of oncology. This fifth part examines the potential role of antiestrogens and selective estrogen receptor modulators (SERMs) in breast cancer patients being treated for estrogen deficiency symptoms. [ONCOLOGY 13(5):721-735, 1999]
Proceedings of a ConferenceHeld at the Boar's Head Inn, Charlottesville,Virginia, September 21-23, 1997
V. Craig Jordan, phd: In the 1970s, interest in the development of anticancer therapies intensified. Since a link between estrogens and breast cancer was known, therapy with antiestrogens was postulated to be an appropriate intervention. This was confirmed with the antiestrogen tamoxifen (Nolvadex), which has become the standard treatment for estrogen receptor (ER) positive breast cancer.
Studies of Tamoxifen
While investigating the toxicity of tamoxifen in the 1980s, my group found that, despite the importance of estrogen for preserving bone density, antiestrogens have an estrogenic effect on bone—an effect that I describe as an estrogenic “tickle.” Consequently, these agents maintain bone density. These observations changed the strategic development of the antiestrogens and also changed their name; this drug group is now known as the selective estrogen receptor modulators (SERMs).
All of the first clinical trials used 1 year of tamoxifen therapy, which did not produce survival advantages. Now we know that 5 years of tamoxifen may be the optimal duration for producing survival advantages in women with breast cancer. However, with longer durations of therapy it was essential to evaluate the entire physiologic system. It was of particular interest to determine, initially under laboratory conditions, whether antiestrogens would do harm to bone, but the opposite was found. In fact, both tamoxifen and a related compound, raloxifene (Evista), demonstrated target site–specific effects. They acted like estrogens at certain sites in the body and like antiestrogens at other sites.
In 1989, I suggested that the estrogenic properties of tamoxifen or other antiestrogens might be exploited therapeutically. In the future, tamoxifen (or any antiestrogen) might be considered as a substitute for estrogen. Multiple goals were identified: reduce the risk of endometrial cancer, lower the risk of breast cancer, and prevent bone loss. For the first time it was possible to envision targeted antiestrogens having multifaceted effects throughout the body. The drugs would be able to switch on or off different biological actions. A clinical trial by the Wisconsin group, published in The New England Journal of Medicine, demonstrated that tamoxifen was not harmful to bone, and, in fact, had a statistically significant beneficial effect.
All of the studies conducted in the 1980s confirmed this general pattern of the biological behavior of these compounds in women. The overview analysis of breast cancer clinical trials clearly demonstrated that tamoxifen produces survival advantages in women: Breast cancer patients live longer if they take up to 5 years of tamoxifen. It is the only agent that produces a decrease of nearly 40% in contralateral breast cancer. So, it is antiestrogenic with respect to this parameter. However, it also has an estrogenic “tickle” that has some effect on lowering cholesterol and preserving bone density.
All was not favorable however, particularly with regard to the risk of endometrial cancer associated with tamoxifen treatment. We believed that there was a link between tamoxifen and human endometrial cancer growth. The experiment used a breast cancer implanted on one side of an athymic animal and an endometrial cancer on the other side. Animals were then treated with estrogen and tamoxifen to see whether tamoxifen controls the growth of both tumors. Tamoxifen completely controlled the growth of the breast cancer but caused a significant increase in the growth of the endometrial cancer. Based on this information, our group was the first to urge that the association between tamoxifen and endometrial cancer be investigated further in the clinic.
The fact that tamoxifen had been successfully used to treat endometrial cancer did not exclude the possibility of an increased incidence of endometrial tumors during prolonged tamoxifen therapy for breast cancer. A large cohort of patients taking long-term tamoxifen therapy had to be monitored to resolve this issue.
For the past decade there has been intense interest in this topic, and in 1996 the International Agency for Research on Cancer reviewed all of the relevant data. The agency’s report concluded that tamoxifen does produce rat liver tumors and is associated with an increased incidence of endometrial cancer. The drug was classified as a carcinogen. However, the agency stressed that no woman being treated with tamoxifen for breast cancer should have that treatment stopped because of the conclusions of the working group, since her risk of developing endometrial cancer was far lower than the benefits that a woman with breast cancer might derive from tamoxifen therapy.
Nevertheless, the observation did change the potential use of tamoxifen in the general population. Because of its ability to induce endometrial cancer, tamoxifen was no longer considered a candidate for the prevention of osteoporosis in postmenopausal women without breast cancer. In 1989, our group dropped its plans to test tamoxifen as a preventive agent in high-risk women. We felt that this focus was too narrow, and restated our new strategy as follows: “Important clues were being garnered about the effects of tamoxifen on bones and lipids. So, it was possible that derivatives could be targeted with applications to retard osteoporosis and atherosclerosis. In addition the ubiquitous application of novel compounds to prevent diseases associated with the progressive changes of menopause may, as a side effect, prevent breast cancer.”
What was required was an agent that would switch on or off the estrogen effect at different sites in a woman’s body. The drug should not induce hot flashes; should act as an estrogen in
the brain; should prevent myocardial infarction and breast cancer; should maintain bone density and prevent osteoporosis; and should reduce the risk of endometrial cancer. Raloxifene has many of these desirable properties.
Studies of Raloxifene
Raloxifene has gone through a variety of developmental stages. Initially proposed as a treatment for breast cancer, its development for this use was not pursued, primarily because tamoxifen was so well-established, and major advantages of raloxifene were difficult to identify. However, scientists at Eli Lilly later found that raloxifene was almost exclusively an antiestrogen in the uterus. Raloxifene exhibited much lower uterotropic properties compared to tamoxifen.
While our group was studying the effects of raloxifene on bone in 1987, we also found that the drug was able to prevent breast cancer in animal tumor models.[6,7] This was a critical experiment to develop a new preventive agent. Scientists at Eli Lilly and elsewhere confirmed our 1987 studies, showing that raloxifene maintains bone density and reduces cholesterol in rats. Most importantly, raloxifene was shown to have less estrogenic activity than tamoxifen; in fact, the estrogenic effect of tamoxifen on the uterus can be inhibited in rats by raloxifene.
Studies in humans performed by John Termine and colleagues at Eli Lilly showed that raloxifene produces an increase in bone density, as compared with a decrease in bone density with the control arm. These data thus demonstrated the translation of findings from the laboratory to the clinic.
With regard to the endometrium, we concluded from studies using transvaginal ultrasonography that endometrial thickness in subjects taking raloxifene is indistinguishable from that in subjects taking placebo. That is an encouraging, different effect from that of tamoxifen in that organ. Raloxifene is now available clinically as an FDA-approved drug for the prevention of osteoporosis.
Interim results from a phase II study of raloxifene in patients with advanced breast cancer who were ER positive, provided by Dr. Bill Gradishar at Northwestern and scientists at Eli Lilly, indicated that raloxifene is clearly not an estrogen in the breast. In this study, 18 evaluable patients who had received no previous endocrine therapy were treated with raloxifene. Three showed partial responses for a median of 18 months, and five had prolonged stable disease for 10 months, for an overall response rate of 44%. This is what would be expected for an antiestrogen in breast cancer
Preliminary data obtained from more than 10,000 women who have participated in raloxifene trials in recent years show a 55% reduction in the cumulative incidence of breast cancer and a decrease in endometrial cancer among the groups receiving active treatment. I should emphasize that these early finding must be followed up for the next 3 or 4 years to get a good indication of whether the prevention of breast cancer is a particularly useful effect of this drug.
Thus, we hope that raloxifene, the first of the SERMs (or targeted antiestrogens), will be accepted as a reasonable alternative to hormone replacement therapy (HRT). The primary hope is to prevent osteoporosis by preventing bone loss. Like tamoxifen, raloxifene decreases cholesterol. Since tamoxifen reduces fatal myocardial infarction, in a small Scottish study, clinical studies are being developed to determine whether raloxifene has a similar effect. The goal is to have a preventive maintenance therapy that would be ideal for reducing osteoporosis, coronary heart disease, breast cancer, and endometrial cancer.
In response to questions, Dr. Jordan indicated that insufficient data exist to establish whether raloxifene acts differently on ER-alpha than on ER-beta. It is unclear whether antiestrogens worked only in the presence of estrogen. Dr. Jordan also expressed some concerns about the use of progestins to block the effect of tamoxifen on the uterus, based on animal studies suggesting that progestins may interrupt the anti–breast cancer effects of tamoxifen.
A representative from Eli Lilly reported that the company’s adverse event monitoring system has not uncovered any adverse effects of raloxifene on central nervous system function. An active program is prospectively studying this issue in more detail.
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