1. 55 ESTROGENS AND in the chick. Tamoxifen exhibits the properties of a partial estrogen ago-
nist/antagonist in rats and women. It is this balance of biologic proper-
ANTIESTROGENS ties that is key to the current strategies for the use of tamoxifen.
V. CRAIG JORDAN, PHD,DSC MODE OF ACTION IN BREAST CANCER Tamoxifen is a competitive
inhibitor of estradiol binding to the ER. 26 Estradiol causes the prolif-
eration of ER-positive breast cancer cells in culture, and tamoxifen can
It has been known since the turn of the 20th century1 that approxi- reversibly prevent estrogen-stimulated growth.27 Similarly, tamoxifen
mately one-third of premenopausal women with advanced breast cancer will prevent estrogen-stimulated growth of ER-positive breast cancer
will respond to oophorectomy. Advances in the understanding of repro- cells transplanted into immune deficient (athymic) mice.28
ductive endocrinology and steroid biochemistry during the early decades Estrogens are believed to modulate cell growth by causing an
of the 20th century permitted the development of specific strategies to increase in stimulatory growth factors (e.g., transforming growth fac-
restrict the availability of estrogen, the hormone widely believed to be tor-alpha [TGF-α]) and a decrease in inhibitory growth factors (e.g.,
responsible for the development of breast carcinoma.2 Breast cancer in the family of transforming growth factors beta [TGF-β]).29 These
postmenopausal women responds to hypophysectomy3 and adrenalec- growth factors are thought to initiate, or prevent, progress through the
tomy,4 but, paradoxically, high-dose therapy with synthetic estrogens, cell cycle by interaction with their respective membrane receptors. The
such as diethylstilbestrol (DES)5 and trianisylchorethylene (TACE),6 regulatory mechanism functions as an autocrine loop. There are also
causes breast tumor regression7,8 (Figure 55.1). However, it was unclear paracrine (cell–cell) influences of growth factors (e.g., insulin-like
which patient would respond until the discovery of the estrogen receptor growth factor-1 [IGF-1]) that can play a role in modulating the repli-
(ER)9,10 and the development of models11,12 to describe the subcellular cation of epithelial cells.
actions of estrogen in its target tissues, including the uterus, vagina, pitu- Antiestrogens negate the stimulatory effects of estrogen by block-
itary gland, breasts, and some breast cancers.13 ing the ER, causing the cell to be held at the G1 phase of the replica-
Studies of the structure–activity relationships of estrogens have pro- tive cycle (Figure 55.3).30 Tamoxifen also causes a decrease in the cir-
vided the medical community with inexpensive, simple molecules that culating levels of IGF-1.31
have proved to have powerful biologic effects in a woman’s target tissues. A variety of alternate, non–ER-mediated biochemical interactions
The wide application of estrogens in the gynecologic community has have been described for antiestrogens that might also contribute to the
resulted in the realization that estrogens might cause a number of cancers.2 antitumor activity of tamoxifen. This topic has been reviewed.32
As early as 1936, Lacassagne predicted that a therapeutic agent CLINICAL PHARMACOLOGY Tamoxifen (Nolvadex) is available in
might be found that could block the stimulatory effects of estrogen in 10-mg tablets as the citrate salt. Treatment schedules vary depending
breast tissue. 14 The nonsteroidal antiestrogen MER 25 (Figure 55.2) on the country and its initial clinical trials evaluating the drug. Sched-
was first described by Lerner and co-workers in 1958.15 This discov- ules of 10 mg bid are recommended in the United States, although 10
ery provoked clinical testing for a variety of applications, but trials mg tid and 20 mg bid are routinely used in other countries. Doses
were stopped because of toxic side effects.16 Nevertheless, in response above 100 mg bid have been used to treat breast cancer, but retinal
to the encouraging clinical findings, the pharmaceutical industry syn- degeneration has been reported.33 In general, the high therapeutic
thesized a wide range of compounds in the 1960s, but there were few index has permitted such wide variations in dosage. There is a low
clinical successes. One notable exception was clomiphene (Clomid) incidence of side effects, the most frequent of which is hot flashes.25
(see Figure 55.2), a mixture of cis and trans geometric isomers of a Tamoxifen is rapidly absorbed and attains steady-state serum lev-
substituted triphenylethylene (note the similarity to the structure of els within 4 to 6 weeks.34 The drug is extensively metabolized (Figure
TACE). Although clomiphene is an antifertility agent in rodents,17 the 55.4) to N-desmethyltamoxifen (major metabolite) and 4-hydroxyta-
compound was shown to induce ovulation in women.18 Clomiphene is moxifen (minor metabolite). Both metabolites have the potential 35 to
routinely used as a profertility agent in subfertile women with a func- be converted to 4-hydroxy-N-desmethyltamoxifen, which is also a
tioning hypothalamo-pituitary-ovarian axis.19 minor metabolite.36,37 Nevertheless, 4-hydroxylated triph-
Several antiestrogens20 were tested as therapeutic agents to control enylethylenes have high affinity for the ER 38 and may play a signif i-
the growth of advanced breast cancer in postmenopausal women, but cant role in the antitumor actions of tamoxifen.39
only tamoxifen (ICI 46474, Nolvadex)21,22 was developed further Tamoxifen has a long serum half-life (7 days) and N-desmethylta-
because of demonstrated efficacy and a low incidence of side effects. moxifen has a serum half-life of 14 days.40 This long serum half-life
TAMOXIFEN
GENERAL PHARMACOLOGY IN THE LABORATORY Tamoxifen is the
trans geometric isomer of a substituted triphenylethylene with well-
characterized antifertility23 and antitumor24 activity in the rat. As a
group, the triphenylethylene-type antiestrogens have an extremely inter-
esting species-specific pharmacology.25 In short-term tests in the
mouse, tamoxifen can cause increases in uterine wet weight and vaginal
cornification. In contrast, tamoxifen is classified as a pure antiestrogen
Figure 55.1. The structure of synthetic estrogens. Figure 55.2. The structure of nonsteroidal antiestrogens.

2. Figure 55.3. The mode of action of anti-
estrogens in inhibiting replication in a
breast cancer cell. Antiestrogens (AE) can
bind to the estrogen receptor (ER). This
produces an incomplete change in the ter-
tiary structure of the ER26 so that there is an
altered interaction with the estrogen
response elements (ERE) on the SNA. As a
response to the binding of AE to ER there
is a decrease in the production of trans-
forming growth factor alpha (TGF-α) but
an increase in the production of some
members of the transforming growth factor
beta (TGF-β) family. Studies in breast can-
cer patients demonstrate that tamoxifen can
down-regulate TGF-α29, but there is an
induction of TGF-β29 in the tumor. Antie-
strogens also cause a decrease in insulin-
like growth factor 1 (IGF-1) 31 that may
stimulate cell replication from adjacent
cells (paracrine) or organs (endocrine).
Cell culture studies have demonstrated that
antiestrogens cause an arrest in the G1
phase of the cell cycle.30
is probably why a withdrawal response has not been routinely docu- (29%) are the side effect most commonly reported during tamoxifen
mented when tamoxifen therapy is discontinued. therapy. Patients with ER-positive disease are more likely to benefit
Tamoxifen exhibits weak estrogen-like properties in post- from tamoxifen therapy.25 Correlation of clinical response and ER sta-
menopausal women.25,41 There is a partial decrease in luteinizing hor- tus indicates that 48% (159 of 333) of patients with ER-positive dis-
mone (LH) and follicle-stimulating hormone (FSH) levels, increases ease had partial or complete responses, whereas only 13% (17 of 129)
in sex hormone–binding globulin (SHBG) levels, decreases in of ER-negative patients had responses. A variety of combinations of
antithrombin III, some changes in vaginal cytology, and hyperplasia of other hormonal agents and combination chemotherapy have been
the endometrium (although the last is not consistently reported). examined,25 but tamoxifen is usually administered as monotherapy.
Tamoxifen causes ovarian stimulation in premenopausal women with Prospective randomized clinical trials of tamoxifen versus either
ovulatory cycles and increases in steroidogenesis.42–45 Women are at megestrol acetate, 40 mg four times daily,47 or medroxyprogesterone
risk for pregnancy during tamoxifen therapy. Tamoxifen is not recom- acetate, 300 mg three times daily,48 indicate similar response rates, but
mended if a woman is pregnant, and patients should be counseled the author recommends tamoxifen as first-line endocrine therapy on
about the need for barrier contraception. Clinical cases of teratogene- the basis of side effects and time to progression. Aminoglutethimide
sis have not been reported with tamoxifen. (plus hydrocortisone) produces response rates similar to those seen
US EI N ADVANCED BREAST CANCER Tamoxifen is the endocrine treat- with tamoxifen, 49 and a combination is not superior to either agent
ment of choice for metastatic disease in postmenopausal patients.25 alone. However, the toxic effects are significantly greater in patients
Approximately, one-third of patients respond, and the response rate is taking aminoglutethimide. Aminoglutethimide is an effective second-
similar to that seen with DES therapy.46 However, side effects are line agent following tamoxifen,50 but the peripheral aromatase
reported to be lower with tamoxifen than with DES. The most preva- inhibitor anastrazole (Arimidex) is the agent of choice.51
lent side effects noted with DES are nausea (51%), edema (53%), vagi- Tamoxifen is effective in the treatment of advanced disease in pre-
nal bleeding (15%), and incontinence (10%). In contrast, hot flashes menopausal women. 42,44 Small randomized trials have demonstrated
Figure 55.4. The metabolities of tamoxifen.

3. that tamoxifen produces a response rate and overall survival similar to CHAPTER 55 / Estrogens and Antiestrogens 745
what is seen after oophorectomy.52,53 Regrettably, the patient popula-
tion is too small to demonstrate whether any benefit would preferen- the ER-positive patient, if given for more than 5 years,68 but these data
tially accrue from one treatment approach in comparison with the are imprecise for application to clinical practice.
other. However, tamoxifen does cause increases in circulating estra- The National Surgical Adjuvant Breast and Bowel Project
diol levels42–45 that could potentially reduce the efficacy of the anti- (NSABP) clinical trials organization has conducted a registration
estrogen. Laboratory studies have, however, demonstrated that high study of 2 years of combination chemotherapy with L-phenylalanine
levels of estradiol are required to reverse the actions of tamoxifen. mustard (melphelan, L-PAM) and fluorouracil (5-FU) and tamoxifen
Combinations of tamoxifen and luteinizing hormone–releasing hor- plus an additional year of tamoxifen alone69 to build on the successes
mone (LHRH) agonists (to reduce ovarian steroidogenesis by prevent- of their earlier trials, which demonstrated the efficacy of tamoxifen in
ing LH release from the pituitary gland) appear to be superior to either ER-positive postmenopausal patients. Overall, these investigators
agent alone. Tamoxifen is currently available in the United States to concluded that 3 years of tamoxifen conferred a significant advantage
treat ER-positive disease in premenopausal women. over 2 years of tamoxifen.
USEAS ADJUVANT THERAPY The low incidence of side effects was an A report from Italy has demonstrated that the addition of combi-
important factor when the Eastern Cooperative Oncology Group nation chemotherapy of CMF (six cycles followed by four courses of
(ECOG) established their adjuvant trial of tamoxifen in elderly epirubicin) to long-term tamoxifen (5 years) for the treatment of
patients who would be unable to cope with the rigors of chemother- ER-positive, node-positive disease does not seem to improve signifi-
apy.54 Similar adjuvant trials with tamoxifen were conducted in the cantly the clear-cut effectiveness of tamoxifen alone in preventing
United Kingdom,55–60 Canada,61 and some countries in Europe.62–63 recurrence.70 In contrast, NSABP protocol B16 shows benefit for
Mainly, a conservative course of 1 or 2 years of adjuvant tamoxifen tamoxifen-treated postmenopausal patients with the addition of an
was selected. However, this decision was based on a number of reason- Adriamycin-containing chemotherapy regimen.71
able concerns. Patients with advanced disease usually respond to tamox- TAMOXIFEN ALONE Although the 2-year adjuvant tamoxifen study
ifen for perhaps 1 or 2 years so that it was expected that ER-negative dis- conducted by the Nolvadex Adjuvant Trial Organization (NATO)
ease would be encouraged to grow prematurely during adjuvant demonstrates a survival advantage for women,57,58 subsequent clinical
therapy. If this occurred, then the physician would have already used a trials show a superior benefit for a 5-year duration of tamoxifen therapy.
valuable palliative drug and would only have combination chemother- A small randomized clinical trial comparing 3 years of tamoxifen with
apy to slow the relentless growth of recurrent disease. A related argu- no treatment has demonstrated a survival advantage for ER-positive
ment involved the changing strategy for the application of combina- patients receiving tamoxifen.72 Similarly, a Scottish trial that has com-
tion chemotherapy. Recurrent treatment cycles (2 years) were found to pared 5 years of tamoxifen with no treatment has demonstrated a sur-
be of no long-term benefit for the patient. The strategy was formulated vival advantage for patients taking tamoxifen.73 The Scottish trial is par-
that an aggressive course of short-term treatment (6 months), with the ticularly interesting because it addresses the question of whether to
most active cytotoxic drugs, could have the best chance to kill tumor administer tamoxifen early or to save the drug until recurrence. Most
cells before the premature development of drug resistance. Using the patients in the control arm received tamoxifen at recurrence. Since an
same argument, there was an intuitive reluctance to use long-term overall survival advantage is observed for patients receiving adjuvant
tamoxifen therapy because this would lead to premature drug resis- tamoxifen, this demonstrates that early resistance to tamoxifen does not
tance. Longer might not be better. Finally, there was a sincere concern occur. The Scottish study included a mixture of node-positive and node-
about the side effects of adjuvant therapy and the ethical issue of treat- negative patients, but the greatest effect was observed in the node-posi-
ing patients in whom disease might not recur. Although this argument tive cohort. The problem with being able to demonstrate a significant
primarily focused on chemotherapy and node-negative patients, it is advantage for the node-negative group is the statistical power necessary
fair to say that very few patients in the mid-1970s had received to show an effect because of the low frequency of recurrence.
extended therapy with tamoxifen so that long-term side effects were The NSABP has focused attention on the use of adjuvant tamox-
mainly unknown. The majority of tamoxifen-treated patients, up to ifen to delay the recurrence of ER-positive node-negative disease. 74
that point, had received only about 2 years of treatment for advanced Tamoxifen increases the disease-free survival, and the antiestrogen is
disease before drug resistance occurred. Potential side effects— active in premenopausal women. The NSABP protocol B14 used an
thrombosis, osteoporosis, or other phenomena—were only of sec- initial treatment period of 5 years of tamoxifen, but the patients were
ondary importance. The use of tamoxifen in the disease-free patient randomized to continue tamoxifen for another 5 years or stop. At pre-
would change that perspective. sent, no overall survival advantage has been noted for longer treatment
The overall success of 1, 2, or 5 years of adjuvant tamoxifen ther- of node-negative patients.75 It is recommended that 5 years of tamox-
apy has recently been evaluated in a meta-analysis of randomized clin- ifen is optimal for the ER-positive node-negative patient. It is also
ical trials.64 Two conclusions can be drawn. Tamoxifen confers a sur- important to stress that the effects of tamoxifen as an antitumor agent
vival advantage to postmenopausal women with ER-positive disease, continue after stopping the drug.64
whereas combination chemotherapy confers a survival advantage to In summary, multiple clinical trials have demonstrated the effec-
premenopausal women. Laboratory studies demonstrated the value of tiveness and safety of long-term (5 years) tamoxifen therapy for treat-
long-term tamoxifen therapy,65 and in the Oxford overview analysis, 5 ing breast cancer.
years of tamoxifen is superior to 2 years of tamoxifen for ER-positive TOXICOLOGIC CONSIDERATIONS IN POSTMENOPAUSAL WOMEN Sev-
pre- or postmenopausal women. 64 One year of tamoxifen is of little eral concerns have been expressed about the biologic consequences of
or no benefit, and the drug is virtually ineffective as an adjuvant in long-term tamoxifen treatment for women with breast cancer. One
ER-negative disease. concern about adjuvant tamoxifen in premenopausal women is the rise
Clinical experience with long-term (5 years) tamoxifen therapy in circulating estrogen levels.76 This does not appear to affect the effi-
has been garnered from nationwide clinical trials, with and without cacy of the drug as an antitumor agent. However, premenopausal
chemotherapy, in pre- and postmenopausal patients with node-positive women must be counseled about the need to use barrier contraception,
and node-negative disease. as they are at risk for pregnancy. In the main, the toxicologic concerns
CHEMOTHERAPY PLUS TAMOXIFEN The ECOG has evaluated the dura- (Table 55.1) are minor, compared with the ability of tamoxifen to con-
tion of tamoxifen therapy in postmenopausal patients, all of whom trol the recurrence of a fatal disease.64
received combination chemotherapy (cyclophosphamide plus methotrex- OPHTHALMIC EFFECTS Triphenylethylenes are known to cause
ate plus fluorouracil, CMF). An early analysis66 has demonstrated an cataracts in rats during long-term therap y. Clomiphene is particularly
increase in disease-free survival with 5 years versus 1 year of tamoxifen. active, and ocular effects have been noted with tamoxifen.25
The 5-year arm has now gone through a second randomization to eval- An evaluation77 of patients receiving tamoxifen, 10 mg/d, for up to
uate the value of indefinite tamoxifen therapy. A similar study in pre- 2 years noted no ocular changes. Nevertheless, high-dose tamoxifen
menopausal women has been reported.67 Tamoxifen appears to benefit therapy has been associated with retinal changes (keratopathy and

4. 746 SECTION 15 / Principles of Endocrine Therapy therapy or raloxifene.105 Patients with a known history of thromboem-
bolic disorders should be carefully evaluated before a decision is made
multiple paramacular refractile lesions in the nerve fiber and inner to use long-term tamoxifen therapy.
plexiform layers),33 and it may be possible that accumulated toxicity Uterine Stimulation. Tamoxifen is known to produce some
will occur with decades of tamoxifen therapy. There is no evidence that estrogen-like effects in postmenopausal women.25 Recent research
severe ocular changes occur. There is, however, evidence that tamox- demonstrates increases in endometrial thickness, hyperplasia, and
ifen is associated with a modest increased incidence of cataracts and fibroids following several years of tamoxifen therapy.106 Endometrial
cataract operations.78,79 Regular eye examinations are not recom- thickening is associated with the stromal component of the uterus
mended, although patients should be questioned about changes in rather than the epithelial component.107 Transvaginal ultrasonography
visual acuity. Patients with pre-existing macular degeneration should is an unreliable tool for the evaluation of patients taking tamoxifen.108
be carefully evaluated when starting tamoxifen therapy.80 One particular focus of research has been the effect of tamoxifen on
ANTIESTROGENIC EFFECTS Osteoporosis. Estrogen is important endometrial carcinoma. Tamoxifen does have some efficacy in the
to maintain bone in premenopausal women. After menopause, hor- treatment of endometrial carcinoma.109 Nevertheless, the findings that
mone replacement therapy is often recommended to prevent the devel- ER-progesterone receptor (PgR)-positive human endometrial carci-
opment of osteoporosis. Clearly, the long-term administration of an noma can have enhanced growth in athymic mice with tamoxifen110 and
antiestrogen has the potential to precipitate premature osteoporosis. other antiestrogens raised concerns about the safety of long-term tamox-
Animal studies show that tamoxifen has estrogenic effects in ifen therapy. Indeed, animals bitransplanted with an MCF-7 breast tumor
bone.81,82 Clinical studies show that 2 years of adjuvant tamoxifen and endometrial carcinoma had target-site-specific effects with tamox-
therapy does not decrease bone density,83–86 and there is evidence to ifen. Estradiol-stimulated growth of the breast tumor is controlled by
suggest that tamoxifen is beneficial and maintains bone in the lumbar tamoxifen, whereas the endometrial tumor grows more rapidly.111
spine and the neck of the femur.87–89 Tamoxifen shows a nonsignif i- The clinical situation is more complex. Only about one-third of
cant decrease in fractures in the NSABP prevention study; however, it endometrial tumors are hormone responsive, although it is widely
must be stressed that this was not a primary end point, and that the believed that estrogen stimulation is responsible for the promotion of
study population was not at risk for osteoporosis.79 all early disease. 2 Endometrial carcinoma has been reported to occur
Atherosclerosis. Estrogen lowers low-density lipoprotein (LDL) in patients receiving adjuvant tamoxifen therapy,112 but this is unre-
cholesterol levels and raises high-density lipoprotein (HDL) choles- markable, as breast and endometrial carcinoma are known to be asso-
terol levels. It is possible that this change in blood lipids is responsible ciated. The Stockholm113 and NSABP114 adjuvant trials of tamoxifen
for the decrease in myocardial infarction observed in premenopausal noted an increase in endometrial carcinoma, compared with the rates
women, when compared with men. Following menopause, women are in a control arm. However, a review of the literature uncovered only a
at the same risk for coronary heart disease as men. It can be argued that few hundred endometrial carcinomata worldwide that were associated
the long-term administration of an antiestrogen could produce a popu- with tamoxifen therapy in the past decade.115 Most cases are stage 1
lation at risk for premature coronary heart disease. However, the estro- (82%), grade I or II disease (80%), which is consistent with the
gen-like effects of tamoxifen25 lower the circulating levels of choles- Surveillance, Epidemiology, and End Results (SEER) report of 74%
terol in female patients.90–97 and 79%, respectively, for stage I and grade I or II endometrial carci-
An analysis of the Scottish clinical trial of 5 years of adjuvant noma. There is a modest increase in endometrial carcinoma associated
tamoxifen showed a significant decrease in fatal myocardial infarc - with tamoxifen that is estimated to be 3 to 4 per 1,000 woman-years,
tion.98 However, an NSABP study in a small series of women not at but only in postmenopausal women. A recent study has noted that the
risk for coronary heart showed only a nonsignificant decrease in coro- women who might develop endometrial cancer while taking tamoxifen
nary heart disease.99 have known risk factors for the disease and have taken estrogen
ESTROGENIC EFFECTS The fact that tamoxifen has an appropriate replacement therapy.116 Premenopausal women are not at risk for an
level of estrogenic activity may be a two-edged sword. The adminis- increase in endometrial cancer.79 There is no strong association with
tration of estrogen to women is known to increase the risk for throm- duration of therapy, and tamoxifen is not associated with high-grade,
bosis and endometrial carcinoma. poor-prognosis disease.115,117 All cases of persistent vaginal bleeding
Thromboembolic Disorders. There are several anecdotal reports should be followed up with a gynecologic examination and an
associating the administration of tamoxifen for advanced breast cancer endometrial biopsy. It is clear, though, that patients should not be
with subsequent thromboembolic episodes.100–102 Similarly, an associa- denied the advantages of tamoxifen to control the recurrence of breast
tion between adjuvant tamoxifen therapy given with chemotherapy and cancer because of the potential complication of endometrial carci-
thrombosis has been reported.66 A study reported from Sweden showed noma, which has a good prognosis.
no significant increases in thromboembolic disorders during long-term Liver Carcinogenesis. Tamoxifen produces DNA adducts in the
tamoxifen monotherapy.103 Nevertheless, decreases in antithrombin III rat liver,118 and lifetime treatment with > 3 g/kg causes carcinogenesis
levels have been noted in postmenopausal patients treated with tamox- in the liver.119,120 The relevance of these laboratory findings for the
ifen for advanced104 or node-positive breast cancer,41 although most treatment of human disease has been discussed;121 however, an
patients have values well within the normal range. Decreases in increase in human hepatocellular carcinoma has not been noted since
antithrombin III levels rarely reach the level of clinical concern (.30% tamoxifen was introduced into the market in 1978,122 and no increase
decrease). An analysis of NSABP clinical trials79 shows a significant in liver tumors is noted in the overview analysis.64
increase in thromboembolic disorders in postmenopausal women. This TAMOXIFEN IN THE PREVENTION OF BREAST CANCER Tamoxifen
increase is comparable with increases noted with hormone replacement will prevent carcinogenesis in rodent models of mammary can-
cer.123,124 These laboratory data, in conjunction with the efficacy of
tamoxifen in preventing74,113 the appearance of second primary breast
Table 55.1. Potential Concerns About the Use of Long-term Tamoxifen
cancers, increased enthusiasm for the use of tamoxifen as a preventive
Therapy in Postmenopausal Patients in women at risk for breast cancer.125–127 The carcinogenic insult that
initiates breast cancer probably occurs during the reproductive years.
Ophthalmic Tamoxifen cannot be used as a true preventive because the timing of
Antiestrogenic effects the event is unknown and the unrestricted use of tamoxifen in young
Osteoporosis women of reproductive age (15–30 years) would be unwise. Three
Atherosclerosis clinical trials were initiated to address the value of tamoxifen in reduc-
Estrogenic effects ing the incidence of breast cancer: the NSABP P-1 trial, the UK Royal
Thromboembolic disorders Marsden/International Breast Cancer Intervention Study (IBIS) and
Uterine stimulation the Italian Study. The NSABP originally planned to recruit 16,000
Liver carcinogenesis
high-risk pre- and postmenopausal women using the Gail model but

5. closed recruitment with about 13,500 women because their calculated CHAPTER 55 / Estrogens and Antiestrogens 747
risk was higher than anticipated so that the question could be answered
effectively with fewer participants.79 By contrast, the Royal Marsden but has a high affinity for the ER.134 Toremifene is less potent than
Study was a pilot study of approximately 2,500 high-risk women85,128 tamoxifen, and consequently, clinical studies are using a higher dose
(though lower risk than the NSABP study) as a prelude to a 16,000 than during tamoxifen therapy. Phase III studies indicate that 60 mg of
volunteer IBIS study, and the Italian study planned to recruit 20,000 toremifene given as a single daily dose is effective for the treatment of
normal-risk young women. Only the NSABP data79 are based on a ER-positive advanced breast cancer.135 Currently, clinical trials are eval-
completed prospective clinical trial. The IBIS study is currently uating high-dose (100–240 mg/d) toremifene therapy. Interestingly, no
recruiting 8,000 volunteers, but as would be expected, the Marsden liver cancer has been described during laboratory tests,136 but this is a
study did not show an advantage for tamoxifen.129 Similarly, the Ital- unique property of rats that selectively metabolize tamoxifen through a
ian study abandoned recruitment of volunteers after 5,000 women rat-specific metabolic pathway. The pathway is blocked by toremifene.
were enrolled. Approximately 25% dropped out, and the remainder of Toremifene is cross-resistant with tamoxifen but can be used as an alter-
the low-risk women did not show an advantage for tamoxifen.130 native to treat advanced breast cancer.135
Overall, the NSABP results of a 50% decrease in invasive breast PURE ANTIESTROGENS The compound ICI 182,780 exhibits no
cancer and ductal carcinoma in situ (DCIS)79 is consistent with the estrogen-like effects in laboratory tests, but it is effective in controlling
known 47% decrease in contralateral breast cancer with 5 years of estrogen-stimulated growth.137 Preliminary clinical studies demon-
adjuvant tamoxifen.64 The biology of tamoxifen was predictable in the strate that daily injections of 5 mg of ICI 182,780 can reduce the Ki 67
NSABP study. Blood clots and a four-fold increase in endometrial labeling index of breast cancer in situ and reduce PgR levels.138 Stud-
cancer occurred in postmenopausal women, whereas tamoxifen did ies in primates have demonstrated almost complete antiuterotrophic
not cause an increase in these serious side effects in premenopausal actions.139 ICI 182,780 (Faslodex) is effective following tamoxifen
women. Bone fractures were decreased but not significantly, and there failure in the clinic.140,141
was a modest increase in the reporting of cataracts in tamoxifen- The pure antiestrogens may offer clinical advantages over tamox-
treated women. Tamoxifen is the first medicine to be approved by the ifen by decreasing tumor cell invasion, tumor flare (which is especially
U.S. Food and Drug Administration (FDA) for the reduction of breast problematic in patients with bone metastases), and the stimulation of
cancer risk in high-risk women. occult endometrial carcinoma. Overall, this class of drugs could have
a role as a first-line therapy for advanced breast cancer and as a sec-
NEW AGENTS ond-line therapy in patients in whom primary tamoxifen treatment
The success of tamoxifen in the treatment of all stages of breast fails. Long-term application as adjuvant therapy in node-negative dis-
cancer has focused attention on the possibility of developing addi- ease appears unlikely because of the high probability of developing
tional drugs with different pharmacologic properties. Several novel early atherosclerosis and osteoporosis.
compounds are being evaluated in the laboratory and the clinic,131 but RALOXIFENE Raloxifene (Evista) is an antitumor agent in animals142
only three compounds, toremifene, ICI 182780, and raloxifene (Figure but is not available for the treatment of breast cancer. The drug has not
55.5), merit comment at present. been tested successfully for any stage of the disease. Raloxifene main-
TOREMIFENE Toremifene (Farnesdon), is a structural derivative of tains bone density in rats81,143 and postmenopausal women144 and is
tamoxifen with similar antiestrogenic and estrogenic properties available for the treatment and prevention of osteoporosis.145 Raloxifene
demonstrated in laboratory animals. The drug is active against car- reduces serum cholesterol105 and is being tested for the reduction of risk
cinogen-induced rat mammary tumors and exhibits the properties of a for coronary heart disease in high-risk women. Raloxifene was pre-
tumoristatic agent. 132,133 Interestingly, toremifene has been reported dicted to reduce the risk of breast cancer, as a beneficial side effect of
to have activity against a hormone-independent mouse uterine sar- the prevention of osteoporosis.146 Preliminary evaluation of randomized
coma. However, no antitumor action can be demonstrated in hormone- trials of the use of raloxifene for the prevention of osteoporosis shows
independent breast tumors. breast safety with a significant reduction in the incidence of breast can-
The metabolism of toremifene has been described in both animals cer.147 Raloxifene is currently being tested against tamoxifen for the
and patients. In general, toremifene is highly protein bound, which could reduction of breast cancer in 22,000 high-risk postmenopausal women.
explain the long serum half-life. The principal metabolite of toremifene Raloxifene should not be used in premenopausal women.
is N-desmethyltoremifene. 4-hydroxytoremifene is a minor metabolite The side effects of raloxifene are consistent with other antiestro-
gens. Hot flashes, leg cramps, and blood clots are most commonly
noted. However, menopausal symptoms are less frequent in women in
their late 60s and 70s, and the incidence of blood clots is the same as
noted with hormone replacement therapy. Raloxifene appears to have
uterine safety in early evaluations,144,147 but since this side effect is
rare (1 per 1,000), uterine safety can only be assured through the
results of current long-term prevention trials.
CONCLUSION
The past 20 years have seen the development of antiestrogens as an
important new class of drugs.146 Drugs of this class are now referred to
as selective estrogen receptor modulators (SERMs) or designer estro-
gens.148,149 Tamoxifen has found ubiquitous applications as the front-
line endocrine therapy in the treatment of all stages of breast cancer.
Several novel antiestrogens with different pharmacologic properties are
being tested,131 not only as breast cancer therapies, but also for the pre-
vention and treatment of osteoporosis.150 A large clinical study of
tamoxifen and raloxifene (STAR) is evaluating the potential of ralox-
ifene to reduce the risk of breast cancer in high-risk women.
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