Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 5
Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 5
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 bonean
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
sitespecific 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 agencys 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 womans 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
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
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 antibreast cancer effects of tamoxifen.
A representative from Eli Lilly reported that the companys
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.