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Departments of Molecular Pharmacology, Biological Chemistry (V.C.J.), and Surgery (M.M.), Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611
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Abstract |
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I. Introduction |
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), both originally
described as antiestrogens and used today in a clinical trial to
prevent breast cancer in high-risk women (see Section IX).
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). The triphenylethylenes are long acting and are
stored in body fat (11, 12, 13, 14), whereas the hydroxystilbene derivatives
are short acting (9, 15, 16), primarily because of rapid-phase II
metabolism after absorption. However, Dodds and associates (17, 18)
described an extremely potent compound, diethylstilbestrol (Fig. 1),
that was widely used in gynecology and also subsequently used, at high
doses, as a treatment for advanced breast cancer in postmenopausal
women (19, 20). In the 1950s and 1960s it became clear that adrenalectomy, with glucocorticoid support, could also improve the prognosis of some postmenopausal women with advanced breast cancer (21). In fact, about one third of the women responded, i.e., about the same proportion as premenopausal women after oophorectomy. The reason for the apparently arbitrary responses, however, would not become clear until the discovery of the estrogen receptor (ER) by Jensen and Jacobson (22) and the subsequent application of this knowledge to predict the hormone responsiveness of a patient’s tumor to endocrine ablation (23). This was an extremely important finding because it prevented those patients who had an ER-negative tumor from having additional major surgery with little hope of a response. Only patients whose tumors had high levels of ER were likely to respond to endocrine ablative surgery (24). It is important, however, to stress that in the early 1970s, there was no significant clinical experience available with the class of drugs called antiestrogens, and no large clinical studies had linked the efficacy of antiestrogens with the presence or absence of the ER. Several antiestrogens had been tested in small clinical studies, but tamoxifen, the first clinically useful antiestrogen for the treatment of advanced breast cancer in postmenopausal women, was not approved by the Food and Drug Administration in the United States until 1977 (25).
Although antiestrogens are important therapeutic agents today, 40 yr
ago there was very little interest in treating breast cancer
with new hormonal drugs, and most of the research in endocrinology was
focused on an understanding of reproduction. The discovery of the
nonsteroidal antiestrogens was serendipitous and resulted from an
interest in contraception in the 1950s. The first nonsteroidal
antiestrogen to be reported in the literature, MER25 (Fig. 1), was
described by Lerner and co-workers in 1958 (26) as an agent that had no
other hormonal or antihormonal properties in any species tested. In
fact, it was a blocking drug for estrogen action with almost no
estrogenic properties. The drug failed in clinical trial because large
doses were required (MER25 has low potency), which caused serious
central nervous system side effects (27). On one hand this was
disappointing but, it must be stressed, that a pure antiestrogen such
as MER25 would ultimately have been catastrophic as an agent to prevent
breast cancer. Drug discovery switched to the triphenylethylene-based
compounds that resulted first in clomiphene and then tamoxifen (25).
Subsequently, drug discovery concentrated on compounds with a high
affinity for ER (25). Only a research focus on cancer in the 1970s
facilitated tamoxifen’s development as a breast cancer therapy for all
stages of the disease (25).
The critical property of the so called "antiestrogens," which permitted their subsequent development as long-term preventives for breast cancer, was that they are antiestrogens at some sites, like the breast, but had estrogen-like properties at other sites to maintain bone density and lower circulating cholesterol (28, 29, 30, 31, 32, 33, 34, 35). The unusual target site-specific action as an estrogen or as an antiestrogen was true for both tamoxifen and raloxifene (29, 30). Lacassagne’s prediction (7) of developing an antagonist to estrogen action to prevent breast cancer in healthy women would not have occurred if the available drugs had increased the risk of osteoporosis and coronary heart disease.
The goal of this review is to provide an up-to-date analysis of the current status of efforts to prevent breast cancer in women by the strategic use of antiestrogens. One aim of our review is to identify the principles, established in the laboratory, that have, through the clinical trial process, proven to be valid in patients with breast cancer or women at risk for breast cancer. The review will also provide the scientific basis for the ongoing trial called Study of Tamoxifen And Raloxifene (STAR). This trial is examining the worth of raloxifene, a drug approved for the prevention of osteoporosis, to prevent breast cancer in postmenopausal women with elevated risk factors. The biological basis for consideration of the antiestrogen raloxifene to be used as a breast cancer preventive is described in Section VIII. In the interests of space it is not possible to review the antiestrogen literature exhaustively, but we intend to provide sufficient background to link laboratory research with clinical results.
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II. Lacassagne’s Prevention Principle: A Target and an Estrogen Antagonist |
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The MCF-7 breast cancer cell line is ER positive (40, 41), and the cells have found ubiquitous applications in cancer research laboratories throughout the world (42). Most importantly, access to these cells has resulted in a fundamental change in the understanding of hormone action that has resulted in the discovery of the steroid receptor superfamily of receptors (43, 44). Jensen and co-workers (45, 46) first developed monoclonal antibodies to ER derived from MCF-7 cells. The antibodies were used to establish that the ER was a nuclear protein (47), and the technology of immunocytochemistry is now standard for the determination of receptor status in breast biopsies (48, 49). However, the application of monoclonal antibodies as probes to clone and sequence the ER gene (50, 51, 52) is of fundamental significance for the understanding of the ER as a nuclear transcription factor.
The ER is a nuclear protein (47, 53, 54), which, for convenience, is
subdivided into six functional domains (Fig. 2) (55, 56). The E regions make up the
steroid-binding domain that undergoes a conformation change to lock
estradiol into its hydrophobic pocket (see Section IV.A).
Changes in conformation of the ER permits the binding of coactivators
to the activating function 1 and 2 regions (AF-1 and 2) (57, 58, 59) and
facilitates the interaction of the ER with DNA through the DNA-binding
domain (C region) (60, 61). The transcription unit is selectively
located as a homodimer in the promoter region of estrogen-responsive
genes to initiate the events associated with estrogen-stimulated cell
replication. Unfortunately, it is not possible to provide much more
than the basic concepts in hormone action because our article is
focused on progress in breast cancer chemoprevention. The topic of gene
regulation is a rapidly evolving story, so we strongly recommend that
interested readers consult recently published reviews that provide
further information (62, 63, 64).
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Adjuvant studies with tamoxifen have proved to be successful in increasing survival (72, 73, 74) but, perhaps most importantly, the interaction between laboratory and clinical research endeavors has ultimately elucidated both the principal mechanism of action of tamoxifen as an antitumor agent in women and identified those women most likely to benefit from adjuvant tamoxifen treatment. During the past 12 yr there has been some confusion in the literature about whether tamoxifen was active in ER-positive breast cancer exclusively or whether ER-negative breast cancer could respond (75, 76, 77). Additionally, there was controversy as to whether tamoxifen was significantly active as an adjuvant in premenopausal women (78). The reader is referred to recent reviews on the clinical investigation and development of tamoxifen (79, 80, 81, 82, 83) for further information, but we will summarize the latest findings of the world-wide randomized clinical trials (84). It is important to appreciate that the general principles derived from the use of tamoxifen as a therapy for breast cancer can be used as a basis for consideration of tamoxifen as a estrogen antagonist for the prevention of breast cancer.
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III. Tamoxifen as an Antitumor Agent |
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This clinical trial data base (84) can now be used to answer the questions raised over the past two decades by laboratory results and hypotheses. In the 1970s three laboratory observations emerged that merited evaluation in clinical trial: 1) tamoxifen blocks estrogen binding to the ER, making patients with ER-positive disease more likely to respond than those with ER-negative disease (85), 2) tamoxifen prevents mammary cancer in rats (86, 87) so the drug could reduce the incidence of primary breast cancer, and 3) long-term treatment was better than short-term treatment to prevent rat mammary carcinogenesis; therefore, longer adjuvant therapy with tamoxifen should be superior to short-term adjuvant therapy (88, 89, 90), i.e., 5 yr of tamoxifen should be superior to 1 yr of tamoxifen. By the late 1980s, tamoxifen had been shown in the laboratory to block estrogen-stimulated breast tumor growth but to encourage the growth of human endometrial cancer implanted in the same athymic mouse (91, 92). The clinical question therefore became "are patients, who are receiving long-term adjuvant tamoxifen therapy, at risk for an increased incidence of endometrial cancer?" (92).
The process of evaluating the impact of translational research is important to establish what works and achieves clinical progress and what does not. A clinical trial should not begin without a strong hypothesis and the incorporation of relevant scientific results. For convenience, the discussion in this section will be subdivided, but the end points of duration of tamoxifen usage, menopausal status, and ER status interact, making the size of a pharmacological effect subject to change.
A. ER status and the duration of tamoxifen
The ER status of the patient is highly predictive of a treatment
response to long-term tamoxifen therapy. The treatment effect, based on
receptor status, is summarized in Table 1. The recurrence reductions produced by
tamoxifen in ER-positive patients are all highly significant
(2P < 0.00001), and the trend between the different
durations of tamoxifen is also highly significant
(
2 = 45.5, 2P < 0.00001). By contrast,
the therapeutic effect of tamoxifen on ER-negative patients is minimal.
Additionally, the questions could be asked, "Does more ER give a
better response to tamoxifen?" and "Does an additional progesterone
receptor (PgR) assay help to improve the results with tamoxifen?" In
the trials of about 5 yr of tamoxifen treatment, the proportional
reductions of recurrence were 43 ± 5% and 60 ± 6% for
patients with below or above 100 fmol/mg cytosol ER protein. This
translated to a reduction in mortality of 23 ± 6% and 36 ±
7%, respectively. Clearly, one can conclude the ER is a powerful
predictor of tamoxifen response, a conclusion consistent with
tamoxifen’s proven mechanism of action as an estrogen antagonist in
breast cancer (82). Although PgR-positive status might be thought to be
of benefit, these data show that there was little additional value if
the tumor was already ER positive. A comparison of interactions is
shown in Table 2. A comparison of the
2,000 women who had ER-positive and PgR-negative tumors and the 7,000
women who had ER-positive and PgR-positive tumors shows there was no
apparent difference in the effect of tamoxifen on either the recurrence
rates or mortality rates. Additionally, the numbers were too few (602
women) in the Overview Analysis (84) to allow a meaningful prediction
of the benefits of tamoxifen in patients who had an ER-negative but
PgR-positive tumor.
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. The duration of
tamoxifen therapy is critical for the premenopausal patient: the effect
of 1 yr of treatment is virtually nonexistent compared with the benefit
of 5 yr of treatment. It is also important to point out that the
reduction of death rates in women under 50 yr of age and over 60 yr of
age treated with 5 yr of tamoxifen is identical, at around 33% (Table 3). By contrast, the effect of tamoxifen
duration on women over the age of 60 is less dramatic because 1 yr of
tamoxifen is much more effective in postmenopausal women. These data
are illustrated in Table 3, which shows a 2- to 3-fold increase in the
effectiveness of tamoxifen when the duration is increased from 1 to 5
yr, whereas there is a 20-fold increase in tamoxifen’s effectiveness
for premenopausal women with an increased duration of 1–5 yr (Fig. 3).
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). In fact, 1 yr of adjuvant tamoxifen
does not significantly reduce the incidence of contralateral breast
cancer compared with control because the SD is so large
(13 ± 13% reduction compared with control).
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C. Endometrial cancer
The overall increase in the incidence of endometrial cancer in the
Overview Analysis was 2- to 3-fold (84). There was no association with
dose, i.e., 20 mg and 30–40 mg daily produced relative risk
(RR) ratios of 2.7 and 2.4, respectively. However, there was a
suggestion that 1 and 2 yr of tamoxifen doubled the incidence of
endometrial cancer and 5 yr quadrupled the incidence. However, the side
effect is so rare (i.e., the numbers are too small) that the
risk ratios are not significantly different from one another for each
duration of tamoxifen. It is important, however, to state that the
absolute increase in endometrial cancer was only half as big as the
absolute decrease in contralateral breast cancer.
The Overview Analysis was able to identify 3,673 women who took 5 yr of adjuvant tamoxifen. With 26,400 woman years of follow-up before breast cancer recurrence in this group, there were seven endometrial cancer deaths. It is estimated that during the whole first decade, the cumulative risk was two deaths per 1,000 women. It is important to state that the current knowledge about the association of tamoxifen with endometrial cancer will improve these statistics. In general, the reported trials were conducted without awareness of the endometrial side effects of tamoxifen. This is no longer the situation, and early detection will improve mortality figures associated with tamoxifen.
D. Conclusions
Tamoxifen has been extensively tested in clinical trials of
adjuvant therapy for 20 yr. The Overview shows that the proportional
mortality reductions were similar for women with node-positive or
node-negative disease (84). However, the absolute reductions in
mortality were much greater in node-positive than node-negative
disease. Additionally, patients with ER-positive disease have an
increased reduction in death rate with longer duration of tamoxifen
treatment, whereas patients who are ER-negative do not benefit from
tamoxifen, regardless of the duration of therapy. The value of a long
duration of treatment is most important for the premenopausal patient
(Fig. 3). This latter finding is new, as the results for premenopausal
women could not be ascertained with certainty in earlier overviews
(74). The Oxford Overview Analysis has established the veracity of the
laboratory concepts that tamoxifen would be most effective in
ER-positive disease, longer duration would be more beneficial, and
tamoxifen would prevent primary breast cancer, in this case
contralateral disease (85, 86, 87, 88, 89, 90).
Overall, the absolute improvement in recurrence was greater during the first 5 yr after surgery, but improvement in survival increased steadily throughout the first 10 yr. This is an important finding because the patient is clearly benefiting from tamoxifen even after therapy has been discontinued. There is an accumulation of the tumoristatic/tumoricidal actions of tamoxifen for at least the first 5 yr of treatment, but the benefit continues after therapy stops. This is also true for the reduction in contralateral breast cancer; the breast seems to be protected so the value remains after therapy stops. This observation is extremely important for the application of tamoxifen as a preventive because a 5-yr course of tamoxifen would be expected to protect a woman from breast cancer for many years afterward.
Finally, the risk/benefit ratio of tamoxifen therapy can be stated to be strongly in the benefit category. The risk of endometrial cancer, a concept derived from laboratory studies (92), is of concern, but the benefits clearly outweigh the risks. In contrast, early concerns about the carcinogenic effects of tamoxifen in the rat liver (see Section VII) do not translate to the clinic as there is no evidence from the Overview Analysis of an increase in either liver or colorectal cancer in patients who take tamoxifen (84)
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IV. Selective ER Modulation |
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The ER-positive breast cancer cell line MCF-7 (for a review see Ref. 42) can be heterotransplanted into immune-deficient athymic mice but the cells will only grow into tumors with estrogen support. Paradoxically, tamoxifen, an estrogen in the mouse, does not support tumor growth (103) but stimulates mouse uterine growth with the same spectrum of tamoxifen metabolites present in both the uterus and the human tumor (28). To explain the selective actions of tamoxifen in different targets of the same host, it was suggested that the ER complex could be interpreted as a stimulatory or inhibitory signal at different sites (28). The concept was consolidated with experimental evidence from two further models. First, tamoxifen and raloxifene maintain bone density in the ovariectomized rat, but both compounds inhibit estradiol-stimulated uterine weight (29) and prevent carcinogen-induced mammary tumorigenesis (30). Second, the finding that tamoxifen would partially stimulate the growth of a human endometrial carcinoma transplanted into athymic mice (91) allowed the investigation of two human tumors bitransplanted in the same mouse to determine whether tamoxifen could inhibit estrogen-stimulated growth of two tumors in the same host equally (92). Tamoxifen demonstrated target site specificity: breast tumor growth was controlled but endometrial tumors continued to grow. Again the range of tamoxifen metabolites were consistent in all target tissues despite the contrasting biological responses, so it was concluded that the ER complexes must be interpreted differently in different target tissues.
During the past decade an intense effort has been made to discover the reason for the target site-specific effects of antiestrogens. Not only will this knowledge permit a rational application of tamoxifen and raloxifene in patients, but also the discovery of new mechanisms for drug selectively will open the door for new innovations in drug discovery. For the sake of completeness, we will briefly consider some of the current hypotheses that could explain the molecular mechanisms of antiestrogen action in different tissue sites.
A. Antiestrogenic activity at the ER
The crystallization of the ligand-binding domain of the ER with
estradiol and raloxifene has provided an important insight into the
conformational changes that occur in the receptor (104) liganded with
an estrogen or an antiestrogen, respectively. Estradiol causes helix 12
to seal the ligand inside the hydrophobic pocket of the ligand-binding
domain (Fig. 5A). This causes receptor
activation through the binding of coactivators on the surface of helix
12 (see Section IV.B). By contrast, the binding of
raloxifene prevents helix 12 from sealing the hydrophobic pocket (Fig. 5B), and gene transcription cannot occur because coactivators cannot
bind. Unfortunately, the final shape of the ER and anti-ER
complexes do not tell us how the tertiary changes in protein
structure occur. However, the crystal structure provides proof of the
critical importance of AA351 (aspartate) for raloxifene action. The
alkylaminoethoxy side chain is the essential structural feature of
nonsteroidal antiestrogens (for a review see Ref. 105). The distance
between the nitrogen and the oxygen must be optimal (106), the
conformations available to the side chain must not be restricted (107),
and the basicity of the nitrogen must be correct (108). Removal of the
side chain results in loss of all activity or an increase in estrogenic
properties (109). The side chain was originally predicted (110, 111) to
bind to an "antiestrogenic region" in the ligand-binding domain of
the ER to neutralize the estrogenic properties of the receptor. Simply
stated, the antiestrogen was perceived to act like a stick to prevent
the jaws of the ER from closing around the ligand. Looked at another
way, an estrogenic complex would only be created by the protein
enveloping the ligand. For the nonsteroidal antiestrogens, the
"antiestrogenic region" is now known to be AA351 on helix 3. The
discovery of an ER mutant in a tamoxifen-stimulated MCF-7 breast tumor
(112) and the finding that it can increase the estrogenic properties of
4-hydroxytamoxifen (113, 114), the active metabolite of tamoxifen
(115), and convert raloxifene from an antiestrogen to an estrogen (116, 117) is valuable biological proof that AA 351 is important for the
antiestrogenic activity of these specific compounds. This interaction,
at the critical contact point of helix 3 and helix 12, prevents helix
12 from sealing the ligand into the binding pocket (Fig. 5B).
Interestingly, a recent report of the crystal structure of
4-hydroxytamoxifen and the ligand-binding domain of ER (118) shows a
complex interaction of the side chain with several amino acids
including AA 351. The distance between AA 351 and the nitrogen of
4-hydroxytamoxifen is further than the comparable interaction in
raloxifene. This difference between the crystal structure of the
raloxifene ER complex (104) and the 4-hydroxytamoxifen ER complex
(118) may explain the promiscuous nature of the 4-hydroxytamoxifen ER
complex. However, it must be stressed the AA 351 has no role for the
antiestrogenic action of the pure antiestrogen ICI 182,780 (117) and
other amino acids may be found to be involved in the antiestrogenic
mechanisms of novel compounds in the future.
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) of the ER that control interaction with
transcription factors and binding to DNA. Subtle changes in the whole
protein shape could be responsible for changes in the intrinsic
efficacy of the receptor complex at different target sites.
B. Coactivators for ER
A host of coactivator and corepressor proteins has been implicated
in the construction of a transcription complex in target cells (63, 64, 119, 120, 121, 122, 123). The finding that an antiestrogen ER complex could become
increasingly estrogenic in different cell contexts (124, 125) raised
the possibility that the differential distribution of coactivators or
corepressors could be responsible for changes in estrogenicity between
the breast and, for example, bones (126, 127). The activating function
(AF-2) region in the ligand-binding domain (Fig. 2) is known to be
repressed by tamoxifen and raloxifene, but the AF-1 region is
unaffected by tamoxifen binding (125). Clearly, the shape of a
particular complex of ligand and ER will be different for different
drugs (125). Thus coactivators could modulate estrogenicity
differentially in different target sites. The candidate proteins could
therefore amplify the anti-ER complex into an estrogenic complex.
Alternatively, the anti-ER complex might recruit completely new
proteins at a specific target site to induce or to suppress gene
transcription.
C. Alternate response elements on DNA
Anti-ER complexes can bind to an estrogen response element but
cannot recruit coactivators to initiate transcription of
estrogen-responsive genes (114). However, it is possible that the
anti-ER complex can bind to alternate sites in the promoter region to
initiate transcription. Alu DNA repeats were originally thought to be
functionally inert, but these elements may be able to activate gene
transcription with antiestrogens through an ER-related mechanism (128, 129). Additionally, a specific region of the transforming growth
factor-ß promoter is believed to be activated by raloxifene (130). A
raloxifene response element has been identified (131), but the authors
are now convinced that a simple protein DNA interaction does not occur
(132).
D. An alternate ER-ERß
The discovery of a second ER, named ERß (133), has introduced a
new dimension into the possible mechanisms of tamoxifen or raloxifene
action. Although ERß has similar functional homology in the
DNA-binding domain, there is only 55% homology between ERß and ER
in the ligand-binding domain. Clearly, one possibility to explain the
target site specificity and altered estrogenicity of antiestrogens is a
differential distribution of ER and -ß to different tissues (134).
The mechanism of action of the differential pharmacology between ER
and -ß may also involve different methods of gene activation. A novel
signal transduction pathway has been identified as a protein-protein
interaction between ERß anti-ER complexes and AP-1 (fos and jun)
(135) that is capable of activating a reporter gene. Estradiol,
however, does not activate the reporter. Therefore, the pathway would
be of pharmacological rather than physiological significance.
Interestingly, an ER tamoxifen complex will activate AP-1 reporter
systems in the context of an endometrial cancer cell (136). This has
led to speculation that the target site specificity of antiestrogens
could be both receptor and context selective.
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V. Biological Basis for Tamoxifen as a Breast Cancer Preventive |
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A. Animal models
Tamoxifen prevents rat mammary carcinogenesis induced by
dimethylbenzanthracene, N-nitrosomethylurea, and
ionizing radiation (86, 87, 88, 89, 30, 137), and long-term treatment prevents
spontaneous carcinogenesis in C3H/OUJ mice infected with mouse mammary
tumor virus (138). The latter result is of interest because tamoxifen
is classified as an estrogen in the uterus and vagina of the mouse (93, 100). This, again, illustrates the target site specificity of tamoxifen
in the mouse model, as mammary cancer is prevented almost completely.
Although the athymic mouse model heterotransplanted with breast cancer
cell lines has been extremely instructive for the use of therapeutic
tamoxifen (103), and valuable as a model for understanding drug
resistance (112), there are few parallels to chemoprevention. The MCF-7
cell line is derived from a pleural effusion, and the cells are,
therefore, metastatic breast cancer (40). As such, the cell line does
not replicate carcinogenesis in the breast or mimic primary breast
cancer cells that have not developed the metastatic phenotype.
B. Bones
Tamoxifen maintains bone density in the ovariectomized rat (29, 31), and these observations have been translated to clinical trials.
Sporadic reports (32, 139) and placebo-controlled randomized trials
(33, 140) demonstrate that tamoxifen can increase bone density in the
lumbar spine, forearm, and neck of the femur by 1–2%. Although the
increases are modest compared with the results obtained with estrogen
use or bisphosphonates (
5% increase in bone density), tamoxifen
produced a significant decrease in hip and wrist fractures as a
secondary end point in the breast cancer prevention trial (141). There
is, however, a report that tamoxifen can reduce bone density in
premenopausal women by 1–2% (142), but the decrease appears to be
without clinical significance as there is no increase in the fracture
rate. The reason for this may be the fact that a small decrease in bone
density in a premenopausal woman is still well above the range of bone
densities observed for women in their late 60s and 70s at risk for
fractures.
C. Lipids
Tamoxifen reduces circulating cholesterol (34, 35). Low-density
lipoprotein cholesterol is reduced by about 15%, but high-density
lipoprotein cholesterol is maintained. It is hypothesized that this
magnitude of fall in circulating cholesterol is a good surrogate marker
for protection from coronary heart disease and atherosclerosis. In this
regard there is evidence that woman who have been treated with 5 yr of
adjuvant tamoxifen for breast cancer have a reduced incidence of fatal
myocardial infarction (143, 144). Additionally, longer treatment (5 yr)
appears to be superior to shorter treatment (2 yr) in reducing the
number of hospital admissions for any cardiac condition (145).
Conversely, a large study in the United States of five or more years of
tamoxifen for the adjuvant treatment of breast cancer found no
statistically strong evidence for the protection of women from coronary
heart disease (146). Nevertheless, the incidence of coronary heart
disease doubled once tamoxifen treatment was stopped, and, most
importantly, there was no evidence for a detrimental effect of
tamoxifen, i.e., tamoxifen did not increase the rate of
coronary heart disease in pre- or postmenopausal women. The reasons for
the disparate results probably reflect the populations studied. Breast
cancer clinical trials usually require a good general health status
before enrollment. Obviously, women at high risk for a second disease,
coronary heart disease, would not be enrolled into a trial evaluating
the efficacy of an antiestrogenic therapy in, for example,
node-negative breast cancer where the prognosis, for the majority of
women, would be expected to be good. Only a prospective randomized
trial in a high-risk population would provide accurate data to support
a claim for cardio-protection. At this point in time, there is no
evidence that tamoxifen is detrimental based on current clinical
evaluations, but there is no prospective clinical evidence that
tamoxifen will reduce the risk of coronary heart disease.
D. Uterus
It is well known that tamoxifen produces a partial agonist action
in the rat uterus (93), but the histology is different than the
epithelial hyperplasia noted with estradiol (147). Until the late
1980s, there was very little information about the actions of tamoxifen
in the normal human uterus. However, it is now clear that a variety of
endometrial changes occur in unselected populations of women (148). The
most significant finding is an increase in the stromal component rather
than endometrial hyperplasia (149, 150). Despite the fact that
tamoxifen has been used to treat endometrial cancer, the laboratory
data suggesting that tamoxifen has the potential to encourage the
growth of preexisting disease harbored in the uterus (91, 92) provoked
an intense investigation of the rates of detection of endometrial
cancer in women using adjuvant tamoxifen treatment for breast cancer.
These data have been reviewed (151), and it is clear from the recent
results of the tamoxifen prevention trial (141) that tamoxifen does not
cause an excess of endometrial cancer in premenopausal women but does
increase risk by 3- to 4-fold in postmenopausal women. This is
consistent with the fact that women harbor 4–5 times the level of
endometrial cancer than is detected clinically (152). In other words,
the increase in the detection of endometrial cancer from 1 per 1,000
women per year to 3 per 1,000 women per year is consistent with the
known rate of occult disease. Most importantly, the stage and grade of
endometrial cancer observed in women taking tamoxifen is the same
as those in the general population (141, 153).
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VI. Risk Factors for Breast Cancer |
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Most women with a family history of breast cancer do not have the genetically transmitted form of the disease, and therefore their increase in risk is much less than that seen in women who have inherited a predisposition gene. The cumulative probability that a 30-yr-old woman with a mother and sister with breast cancer will develop breast cancer by the age of 70 is reported to be between 7% and 18% (163, 164). While this risk increases as the number of relatives with breast cancer increases, the probability of cancer development if both a mother and sister have bilateral breast cancer has been reported to be only 25% (162, 164). The cumulative risk of breast cancer development in women with a family history of breast cancer rarely exceeds 30%, making it critically important to distinguish those women with hereditary breast cancer from those with a family history of the disease. Factors that should increase the clinician’s index of suspicion that a woman is at risk for genetically transmitted breast cancer include multiple relatives (maternal or paternal) with the disease, a family history of ovarian cancer in association with breast cancer, and a family history of bilateral and/or early onset of breast cancer. Although not all women with these factors will have genetically transmitted breast cancer, a referral for genetic counseling will allow the construction of a detailed pedigree to estimate both breast cancer risk and the competing causes of death due to an increased risk of the development of other types of cancer.
Breast cancer is clearly related to endogenous hormones, and numerous studies have linked breast cancer risk to the age of menarche, menopause, and first pregnancy. Although the absolute age-specific incidence of breast cancer is higher in postmenopausal than premenopausal women (165), the absolute rate of rise of the curve is greatest up to the time of menopause, and then slows to one-sixth of that seen in the premenopausal period. Further support for the promotional role of estrogen in breast cancer development comes from the observations that early menarche (166), late menopause (167), nulliparity, and late age at first birth (168) all increase the risk of breast cancer development. An increased number of ovulatory cycles is suggested to be the common mechanism of increased risk.
Other hormonal risk factors have been suggested but are not as well established. Abortion, whether spontaneous or induced, has been reported by some authors to increase risk (169, 170), while other studies have found no relationship between abortion and breast cancer risk (171, 172). Studies of the effect of lactation on breast cancer risk have also been inconclusive (173, 174), but recent studies have suggested that a long duration of lactation reduces breast cancer risk in premenopausal women (175). Physical activity in adolescence is reported to decrease risk, perhaps due to a higher rate of anovulatory cycles (176, 177), but an increased level of physical activity later in life has not been shown to reduce breast cancer risk (178). Postmenopausal obesity has also been shown to increase risk (179), perhaps due to increased peripheral estrogen production, but this relationship between weight and risk is not observed in premenopausal women. In fact, some studies have reported an inverse relationship between weight and risk at a younger age (180).
The effects of exogenous hormones in the form of oral contraceptives
and hormone replacement therapy on breast cancer risk have been studied
extensively, but few firm conclusions may be drawn. Overall, there is
no convincing evidence of an increase in breast cancer risk in women
who have ever used oral contraceptives (181). However, some studies
have suggested that the long-term use of oral contraceptives in young
women before first birth may increase breast cancer risk (182, 183).
Two recent meta-analyses of the effect of estrogen replacement therapy
demonstrate small but statistically significant increases in risk for
users (184, 185). However, Steinberg et al. (184) noted no
increase in risk until after at least 5 yr of estrogen use, after which
a proportional increase in risk for each year of estrogen use was
observed, while Sillero-Arenas et al. (185) did not observe
a significant association between duration of hormone replacement
therapy and breast cancer risk. In summary, although hormonal risk
factors are clearly implicated in the pathogenesis of breast cancer,
most of them are associated with a RR of 3 or less of breast cancer
development (Table 4), and the presence
of a single hormonal risk factor is insufficient to classify a woman as
high risk.
|
. Nonproliferative
disease is associated with no increase in breast cancer risk, while
proliferative disease increases risk by a factor of 1.5–2.0, and
atypical hyperplasia by a factor of 4–5. Approximately 70% of
palpable breast masses contain nonproliferative disease (186), and only
3.6% are atypical hyperplasia. The incidence of atypia is somewhat
higher in biopsies performed for mammographic lesions, ranging from
7–10% (187, 188). However, the risk of breast cancer development 15
yr after a diagnosis of atypical hyperplasia is only 8% in the absence
of a family history of breast cancer. Proliferative breast disease is
also noted more frequently in women with a significant family history
of breast cancer than in controls, further supporting its role as a
risk factor (189).
|
A number of environmental factors have also been linked to breast cancer risk. Exposure to ionizing radiation, whether secondary to nuclear explosion or medical procedures, has been clearly demonstrated to increase breast cancer risk (191, 192, 193). The level of risk varies with the age of exposure, with a minimal increase in risk observed for exposure in women older than 40 yr. A larger amount of attention has been directed toward the role of diet in the etiology of breast cancer. This link has been suggested by the large international variation in breast cancer incidence rates and the observation that national per capita fat consumption correlates with breast cancer incidence and mortality (194). However, prospective studies of diet and breast cancer risk have failed to identify a relationship between dietary fat intake and breast cancer incidence for up to 10 yr of follow-up (195). The lack of a relationship between dietary fat intake and cancer risk within the context of a Western diet is confirmed by a pooled analysis of seven cohort studies involving a total of 337,816 women, which demonstrated no difference in risk for women with the lowest and highest quintile of fat intake (196). However, all of these studies have addressed fat intake during adult life, and they do not exclude the possibility that fat intake during childhood and adolescence may influence subsequent breast cancer risk.
Stronger evidence exists to support an association between alcohol and
breast cancer. A meta-analysis of 12 case control studies demonstrated
a RR of 1.4 for each 24 g of alcohol consumed daily (197).
Defining a relationship between age of alcohol consumption and breast
cancer risk is more difficult, with conflicting data on the importance
of drinking early in life (198, 199). A summary of the magnitude of
increase in risk associated with the factors discussed is provided in
Table 4.
A. Interactions among risk factors
A major problem in the clinical identification of the "high risk
woman" is the lack of knowledge of the interactions among the various
factors known to alter breast cancer risk, since the majority of
studies have focused on defining individual risk factors. Most women
have a combination of factors that both increase and decrease risk,
complicating the assessment of an individual’s level of risk. In
addition, it is unclear whether the risk conferred by multiple risk
factors is additive, multiplicative, or varies with the risk factor
under study.
The interactions between a family history of breast cancer and other risk factors have been examined, often with conflicting results. Dupont and Page (186) observed that the combination of atypical hyperplasia and a family history of a first-degree relative with breast cancer increased the RR of breast cancer to 11 times that of an index population, compared with a RR of 4.4 for atypia alone. However, Rosen et al. (200) found that the presence of a family history of breast carcinoma did not alter the level of risk after a diagnosis of LCIS, a lesion often considered part of a continuum with atypical hyperplasia. An analysis of data from the Nurses Health Study (201) found that in women with a mother or sister with breast cancer, known risk factors of age at menarche or menopause, parity, age at first birth, alcohol use, and the presence of benign breast disease did not further alter risk. In contrast, Anderson and Badzioch (202) and Brinton et al. (203) have reported that hormonal factors further modulate risk in women with a family history of breast cancer, although the effect varies with the factor under study.
Studies of the interaction between estrogen replacement therapy and other known breast cancer risk factors also have variable results, depending on the risk factor under study. In a meta-analysis of 16 published studies, Steinberg et al. (184) found that the effect of estrogen replacement did not differ among parous and nulliparous women and those with or without benign breast disease. However, an enhanced risk was observed in women with a family history of breast cancer. The analysis of the interaction among risk factors is further complicated by the fact that some factors may be important for the risk of premenopausal, but not postmenopausal, cancer and vice versa, and these effects may not be constant over time.
A model to predict the risk of breast cancer development in women at a
given age over a defined time interval was developed by Gail et
al. (204) using data from 4,496 matched pairs of cases and
controls in the Breast Cancer Diagnosis and Demonstration Project. The
model incorporates the risk factors of age at menarche, age at first
live birth, number of first-degree relatives with breast cancer, and
number of previous breast biopsies, and has been shown to predict risk
accurately in two validation studies of women undergoing annual
mammographic screening (205, 206). However, the model overpredicts
breast cancer risk by 33% among women age 60 and younger who do not
undergo annual screening. There are several other limitations of the
model. Because only first-degree relatives are considered, it is not an
appropriate model for women with extensive family histories of breast
cancer, where risk may be underestimated. In women with risk due to
LCIS or atypical hyperplasia, the model underestimates risk, since the
highest RR for breast biopsy is 2.0. Similarly, for the woman with
nonproliferative disease, the model may overestimate risk. In spite of
these limitations, the model is a clinically important tool for
identifying a woman’s level of risk over a clinically relevant time
period, after correction for competing causes of mortality. The Risk
Disk, which is available from the National Cancer Institute, uses the
Gail model to provide a numeric estimate of a woman’s 5 yr and
lifetime risk of developing breast cancer compared with an "average
risk" woman of the same age. Examples are given in Figs. 6 and 7.
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|
|
VII. Prevention of Breast Cancer with Tamoxifen |
|---|
5,000) has been published (210), but again
this is a small component of a 20,000-volunteer trail that has now been
stopped.
A. Royal Marsden Pilot Study
Powles and co-workers (211) recruited high-risk women aged 30–70
to a placebo-controlled trial using 20 mg of tamoxifen daily for up to
8 yr. Women were eligible if their risk of breast cancer was increased
due to family history. Each participant had at least one first-degree
relative with breast cancer under age 50, or a first-degree relative
affected at any age plus an additional affected first- or second-degree
relative, or a first-degree relative with bilateral breast cancer.
Women with a history of benign breast biopsy and an affected
first-degree relative of any age were also eligible. Women with a
history of venous thrombosis, any previous malignancy, or an estimated
life expectancy of fewer than 10 yr were excluded (209, 212). A total
of 2,494 women consented to participate in the study, and 23 were
excluded from final analysis due to the presence of preexisting ductal
carcinoma in situ (DCIS) or invasive breast carcinoma (209)
The trial was originally undertaken to evaluate the problems of
accrual, acute symptomatic toxicity, compliance, and safety as a basis
for subsequent large national, multicenter trials designed to test
whether tamoxifen can prevent breast cancer (211). However, the trial
has also been analyzed for breast cancer incidence (209). The stated
goal of this pilot study was to act as a vangard for a 20,000 strong
volunteer trial throughout the United Kingdom and Australia. The
national study is ongoing, but the recruitment goal has been cut to
12,000.
Acute symptomatic toxicity was low for participants on tamoxifen or placebo in the pilot study, and compliance remained correspondingly high: 77% of women on tamoxifen and 82% of women on placebo remained on medication at 5 yr (212). There was a significant increase in hot flashes (34% vs. 20%), mostly in premenopausal women (P < 0.005); vaginal discharge (16% vs. 4%; P < 0.005); and menstrual irregularities (14% vs. 9%; P < 0.005), respectively. At the most recent follow-up, 320 women had discontinued tamoxifen and 176 had discontinued placebo before the study’s completion (P < 0.005) (209).
Until their report in 1994, the Marsden group (212) observed no thromboembolic episodes; a detailed analysis of other coagulation parameters in a sequential subset of women also found no significant changes in Protein S, Protein C, or cross-linked fibrinogen degradation products. At 70 months, no significant difference in the incidence of deep vein thrombosis or pulmonary embolism was observed between groups. A significant fall in total plasma cholesterol occurred within 3 months and was sustained over 5 yr of treatment (142, 213, 214). The decrease affected low-density lipoproteins with no change in apolipoproteins A and B or high-density lipoprotein cholesterol.
In contrast, tamoxifen exerted antiestrogenic or estrogenic effects on bone density, depending on menopausal status. In premenopausal women, early findings demonstrated a small but significant (P < 0.05) loss of bone in both the lumbar spine and hip at 3 yr (142). It will be most important to evaluate the results at 5 and 8 yr of therapy, as current indications suggest bone stabilization rather than continued loss. In contrast, postmenopausal women had increased bone mineral density in the spine (P < 0.005) and hip (P < 0.001) compared with untreated women (142).
Finally, the Marsden group has made an extensive study of gynecological complications associated with tamoxifen treatment in healthy women. Since ovarian and uterine assessment by transvaginal ultrasound became available some time after the trial’s start, many subjects did not have a baseline evaluation. Ovarian screening demonstrated a significantly increased risk (P < 0.005) of detecting benign ovarian cysts in premenopausal women who had received tamoxifen for more than 3 months compared with controls. There were no changes in ovarian appearance in postmenopausal women (212). A careful examination of the uterus with transvaginal ultrasonography using color Doppler imaging in women taking tamoxifen showed that the organ was usually larger; moreover, women with sonographic abnormalities had significantly thicker endometria (215). Of particular interest in this regard was the recent observation (150) that 20 mg of tamoxifen daily caused a time-dependent proliferation of the endometrium in premenopausal and early postmenopausal women. This effect appeared to be mediated by the stromal component, since no cases of cancer or even epithelial hyperplasia were observed among the tamoxifen-treated group in this Italian study with 33 women (150).
Although the Marsden pilot study has provided invaluable information about the biological effects of tamoxifen in healthy women, the trial was not designed to answer the question of whether tamoxifen prevents breast cancer. In spite of this, an analysis of breast cancer incidence was reported at a median follow-up of 70 months, when 42% of the participants had completed therapy or withdrawn (209). During the study, 336 women receiving tamoxifen and 305 on placebo received hormone-replacement therapy. No difference in the incidence of breast cancer was observed between the groups. There were 34 carcinomas in the tamoxifen group and 36 in the placebo group—a RR of 0.98. Of the 70 cancers, only 8 were ductal carcinoma in situ. An analysis of the subset of women on hormone-replacement therapy did not demonstrate an interaction with tamoxifen treatment. At present there is no satisfactory answer to the question of why the Marsden Pilot study shows no decrease in breast cancer incidence in the tamoxifen arm. The authors suggest (209) that perhaps they have a high population of BRCA-1 and -2 carriers that are hormone unresponsive but this is unproven. The fact that women on the Marsden trial were allowed to take hormone replacement therapy, but the women on the NSABP P-1 trial were not is unlikely to be responsible for the Marsden result. We believe that the study, by chance, is underpowered to show a difference. If this is true, then it appears that a precise instrument to evaluate risk may be a key factor in the success of the NSABP study as well as the large volunteer population with adequate events to answer the question posed.
B. NSABP/NCI Study
This prospective clinical trial opened in the United States and
Canada in May of 1992 with an accrual goal of 16,000 women to be
recruited at 100 North American sites. The specific aim was to test the
worth of tamoxifen as a preventive for breast cancer. It closed after
accruing 13,388 in 1997 because of the exceptionally high-risk status
of the participants. This means that the events would be adequate to
establish statistical significance. The study design is illustrated in
Fig. 8. Those eligible for entry included
any woman over the age of 60, or women between the ages of 35 and 59
whose 5-yr risk of developing breast cancer, as predicted by the Gail
model (204), was equal to that of a 60-yr-old woman. Additionally, any
woman over age 35 with a diagnosis of LCIS treated by biopsy alone was
eligible for entry to the study. In the absence of LCIS, the risk
factors necessary to enter the study varied with age, such that a
35-yr-old woman must have had a RR of 5.07, whereas the required RR for
a 45-yr-old woman was 1.79. Routine endometrial biopsies to evaluate
the incidence of endometrial carcinoma in both arms of the study were
also performed.
|
The first results of the NSABP study were reported in September 1998, after a mean follow-up of 47.7 months (141). There were a total of 363 invasive and noninvasive breast cancers in the participants: 124 in the tamoxifen group and 239 in the placebo group. A 49% reduction in the risk of invasive breast cancer was seen in the tamoxifen group, and a 50% reduction in the risk of noninvasive breast cancer was observed. A subset analysis of women at risk due to a diagnosis of LCIS demonstrated a 56% reduction in this group. The most dramatic reduction was seen in women at risk due to atypical hyperplasia, where risk was reduced by 86%.
The benefits of tamoxifen were observed in all age groups, with a RR of
breast cancer ranging from 0.45 in women aged 60 and older to 0.49 for
those in the 50–59 yr age group, and 0.56 for women aged 49 and
younger (Fig. 9). A benefit for tamoxifen
was also observed for women with all levels of breast cancer risk
within the study, indicating that the benefits of tamoxifen are not
confined to a particular lower-risk or higher-risk subset. Benefits
were observed in women at risk on the basis of family history and those
whose risk was due to other factors.
|
). Tamoxifen reduced the
rate of invasive cancers of all sizes, but the greatest difference
between the groups was in the incidence of tumors 2.0 cm or less in
size. Tamoxifen also reduced the incidence of both node-positive and
node-negative breast cancer. The beneficial effects of tamoxifen were
observed for each year of follow-up in the study. After year 1, the
risk was reduced by 33%, and in year 5, by 69%.
|
) (141). However, the overall
difference approached, but did not reach, statistical significance.
This reduction was greatest in women who were 50 and older at study
entry. No difference in the risk of myocardial infarction, angina,
coronary artery bypass grafting, or angioplasty was noted between
groups (141).
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More women in the tamoxifen group developed deep vein thrombosis than in the placebo group (141). Again, this excess risk was confined to women aged 50 and older. The RR of deep vein thrombosis in the older age group was 1.71 (95% confidence interval 0.85 to 3.58). An increase in pulmonary emboli was also seen in the older women taking tamoxifen, with a RR of approximately 3. Three deaths from pulmonary emboli occurred in the tamoxifen arm, but all were in women with significant comorbidities. An increased incidence of stroke (RR 1.75) was also seen in the tamoxifen group, but this did not reach statistical significance
An assessment of the incidence of cataract formation was made using patient self-report. A small increase in cataracts was noted in the tamoxifen group—a rate of 24.8 women per 1,000 compared with 21.7 per 1,000 in the placebo group. There was also an increased risk of cataract surgery in the women on tamoxifen. These differences were marginally statistically significant and were observed in the older patients in the study. These findings emphasize the need to assess the patient’s overall health status before making a decision to use tamoxifen for reduction of breast cancer risk.
An assessment of quality of life showed no difference in depression scores between groups. Hot flashes were noted in 81% of the women on tamoxifen compared with 69% of the placebo group, and the tamoxifen-associated hot flashes appeared to be of no greater severity than those in the placebo group. Moderately bothersome or severe vaginal discharge was reported by 29% of the women in the tamoxifen group and 13% in the placebo group. No differences in the occurrence of irregular menses, nausea, fluid retention, skin changes, or weight gain or loss were reported.
C. Italian study
The third tamoxifen prevention study, performed in Italy, began in
October 1992, and randomized 5,408 women aged 35 to 70 to 20 mg of
tamoxifen daily for 5 yr (210). Originally, 20,000 volunteers without
risk factors were to be recruited, but the study was stopped
prematurely because of poor recruitment and compliance. Women were
required to have had a hysterectomy for a nonneoplastic condition to
obviate concerns about an increased risk of endometrial carcinoma.
There was no requirement that participants be at risk for breast cancer
development, and, in fact, those who underwent premenopausal
oophorectomy with hysterectomy (47%) actually had a reduced risk of
breast cancer development. Women with endometriosis, cardiac disease,
and deep venous thrombosis were excluded from the study. Although 5,408
women (mean age 51 yr old) were randomized into this study, 1,422
withdrew and only 149 completed 5 yr of treatment. A valid breast
cancer prevention study would only be possible if more than 10,000
normal-risk women had completed 5 yr of tamoxifen vs. 10,000
on placebo.
The incidence of breast cancer did not differ between groups, with 19 cases in the tamoxifen group and 22 in the placebo group. Tumor characteristics, including size, grade, lymph node status, and receptor status, also did not differ between groups.
The incidence of thrombophlebitis was increased in the tamoxifen group. Fifty-six women experienced a total of 64 events: 38 women in the tamoxifen group and 18 women in the placebo group (P = 0.0053). However, 42 of these cases were superficial phlebitis. No differences in the incidence of cerebrovascular ischemic events were observed.
D. Conclusions
Based on a single trial with a positive result and two with
negative results, it may seem, at first glance, that the role of
tamoxifen in breast cancer prevention remains unresolved. However,
critical differences exist between these three studies (see
characteristics in Table 6).
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The Royal Marsden study was initially described as a pilot study to examine toxicity and compliance (211, 212, 214), which would serve as a feasibility assessment for a larger trial to determine whether tamoxifen prevents breast cancer. In spite of being designed as a pilot study, the trial is now said to have a 90% power to detect a 50% reduction in breast cancer incidence, yet shows no effect (209). The authors suggest that the positive results of the NSABP trial at 3.5 yr of follow-up are most likely due to the treatment of clinically occult carcinoma, rather than the prevention of new breast cancers. However, of the 363 total cancers in the NSABP study (141), 99 (28%) were DCIS, compared with 11% of the 70 cancers in the Royal Marsden study. The higher percentage of DCIS in the NSABP trial indicates that the detection of subclinical cancers occurred, and that any treated occult cancer was not truly amenable to detection by currently available means. Whether occult carcinoma was treated or true prevention occurred, a significantly greater number of women were spared surgery, irradiation, and chemotherapy. The data from the Overview Analysis (84) do not support the contention that these cancers will become clinically evident when tamoxifen is stopped, since the reduction in contralateral breast cancer persists through 10 yr even though tamoxifen treatment was stopped at 5 yr.
Overall, the results of the NSABP trial (141), with its large study
population, clearly support the benefit of tamoxifen for breast cancer
prevention in high-risk women. These findings are consistent with
laboratory observations and with the contralateral breast cancer risk
reduction seen with tamoxifen therapy (Fig. 4).
Tamoxifen was approved in 1998 for the reduction of risk in pre- and postmenopausal women with a high risk of breast cancer. The results of the NSABP prevention trial have established tamoxifen as the current standard of care and also opened the door for the evaluation of other agents, which might have an improved safety or efficacy profile in clinical trial. Tamoxifen causes rat liver carcinogenesis (216, 217), and there is an association with an increased incidence of endometrial cancer (151, 153). Although it is believed that metabolic activation of tamoxifen to a DNA adduct (218, 219) is unique to the rat liver (220, 221, 222, 223, 224, 225, 226), an agent that did not produce liver tumors in rats and was less estrogenic in the rodent uterus might have value for application as a breast cancer preventive. Raloxifene is being tested in the STAR trial (Section IX) against tamoxifen primarily because there is no evidence of rat liver carcinogenesis and there is less estrogen-like actions in the rodent uterus. It is possible that these laboratory qualities could translate into fewer endometrial cancers in women during raloxifene therapy, but this can only be established in large prospective clinical trials.
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VIII. Biological Basis for Raloxifene as a Breast Cancer Preventive |
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). However, raloxifene
and an analog LY 117018 (90, 230, 231, 232) are short acting compounds
because of poor bioavailability due to rapid phase II metabolism.
Indeed, a concern in the early clinical trials for the treatment of
breast cancer was an inability to monitor blood levels. Although
numerous assays are available to monitor tamoxifen and its metabolites
(105), the structure of raloxifene does not permit the use of similar
chemical methods of detection. Tamoxifen is easily converted from a
triphenylethylene to a phenanthrene by UV light so that fluorescence
detection has been used for two decades to measure drug levels as small
as 1 ng/ml serum. The analytical technique currently used to
monitor raloxifene has not been published. Nevertheless, raloxifene has
limited clinical experience for the treatment of breast cancer. The
initial study conducted at the MD Anderson Hospital in Houston showed
no responses in heavily pretreated patients with stage IV disease
(233). A second small study of 18 ER-positive patients with previously
untreated metastatic disease showed modest response rates of 30%, with
a dose of 300 mg daily (234). The key issue, which has not yet been
addressed, is cross-resistance between raloxifene and tamoxifen. The
use of raloxifene for the prevention of osteoporosis after 5 yr of
adjuvant tamoxifen cannot be assumed to be safe for the patient with
breast cancer until this issue is resolved. A clinical trial comparing
adjuvant treatment with tamoxifen for 5 yr to treatment with tamoxifen
followed by raloxifene is needed to determine whether
raloxifene-stimulated tumor growth is a clinical reality. The rationale for the use of raloxifene as a breast cancer preventive is based solely on an hypothesis formulated when SERM was first recognized (25, 29).
We have obtained valuable clinical information about this group of drugs that can be applied in other disease states. Research does not travel in straight lines, and observations in one field of science often become major discoveries in another. Important clues have been garnered about the effects of tamoxifen on bone and lipids, so it is possible that derivatives could find targeted applications to retard osteoporosis or atherosclerosis. The ubiquitous application of novel compounds to prevent diseases associated with the progressive changes after menopause may, as a side effect, significantly retard the development of breast cancer. The target population would be postmenopausal women in general, thereby avoiding the requirement to select a high-risk group to prevent breast cancer (25).
This new strategy to prevent breast cancer was described in 1990 (25). The evidence for the application of raloxifene in this new paradigm will be presented.
A. Antitumor actions
Raloxifene inhibits the growth of dimethylbenzanthracene-induced
rat mammary carcinomata (235) but, dose for dose, tamoxifen is more
effective. More importantly for the proposed evaluation as a
preventative, raloxifene reduces the incidence of
N-nitrosomethylurea-induced tumors (30, 236) if given after
the carcinogen but before the appearance of palpable tumors (Fig. 12). However, as would be anticipated
with a drug that has a short biological half-life, raloxifene is not
superior to tamoxifen at equivalent doses (30). There is no doubt that
raloxifene and its analogs are effective and potent inhibitors of the
growth of breast cancer cells in culture (237, 238), but the
complication of first-pass metabolism in vivo reduces
potency. For this reason, doses above 60 mg raloxifene daily have been
tested in clinical trial to prevent osteoporosis. As stated previously,
raloxifene has only modest antitumor activity for the treatment of
advanced disease (234). Only high-dose therapy (up to 300 mg daily) has
been tested.
|
. It should be pointed out that the
data from the raloxifene study really represent three groups: one
placebo control and two doses of raloxifene, 60 and 120 mg daily. Since
the raloxifene data are pooled and represented in the abstracts as a
percent of control, the events that can be calculated are artificially
high. A more accurate representation of total events would be 30
(control), 15 (60 mg raloxifene daily), and 15 (120 mg raloxifene
daily) for all reported invasive and noninvasive cancers at 3 yr.
Clearly, these are small numbers compared with the NSABP study.
However, the result with raloxifene is strong preliminary data as a
basis for the STAR trial, which compares tamoxifen, the standard of
care, with the test drug raloxifene in women with a high-risk for
breast cancer (see Section IX).
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) (28, 242, 243, 244, 245, 246, 247, 248). Urinary pyridinoline and serum osteocalcin are
elevated after ovariectomy, but the elevations are reduced by
raloxifene, thus indicating that raloxifene inhibits bone loss by
reducing bone resorption (243). In general, raloxifene does not
maintain bone density in the ovariectomized rat to the level observed
in an intact animal (242), but efficacy appears equivalent to estrogen
treatment although without increases in uterine weight (242). Preliminary studies in 251 normal postmenopausal women randomized to placebo, raloxifene (200 mg daily), raloxifene (600 mg daily), or Premarin (Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA; 0.625 mg daily) show decreases in serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline, and urinary calcium excretion with raloxifene that was no different than estrogen (249). However, the doses of raloxifene are far higher than the 60 mg/day currently recommended for the prevention of osteoporosis. Evaluation of raloxifene, 60 mg/day, on bone remodeling in early postmenopausal woman, using calcium tracer kinetic methods, found that although remodeling suppression was greater for estrogen, the remodeling balance was the same for the two agents (250). The authors concluded that raloxifene acted on bone as an estrogen agonist. Indeed, these results are consistent with the finding that raloxifene increases bone density by 2.4 ± 0.4% in the lumber spine and 2.4 ± 0.4% for the total hip (251). Although the percent increases in bone density are not as high as would be anticipated with estrogen or bisphosphonates, it is now clear that raloxifene produces a 40% decrease in spine fractures. There are, however, no reports of a significant decrease in hip fractures with raloxifene. This contrasts with the 50% decrease noted with tamoxifen in the prevention study (141) and adds further support for the need to compare and contrast the clinical endocrinology of tamoxifen and raloxifene in the STAR trial (see Section IX).
C. Lipids
Raloxifene produces a significant decrease in low-density
lipoprotein cholesterol, but high-density lipoprotein cholesterol
remains the same (249, 251, 252). Additionally, triglycerides do not
rise during raloxifene treatment. Laboratory data from the rabbit (253)
strongly support the value of raloxifene to prevent atherosclerosis.
However, data from primates fed high-cholesterol diets do not show a
benefit for raloxifene (254). These results have proved to be
controversial (255), as both hormone replacement therapy and tamoxifen
show positive results in the primate model. To address the issue
directly, a prospective randomized clinical trial is in place to
address the question of whether raloxifene has merit for the reduction
of risk for coronary heart disease in postmenopausal women with
elevated risk factors. The study, referred to as Raloxifene Use for The
Heart (RUTH), will randomize 10,000 high-risk women to placebo or
raloxifene (60 mg daily) treatment for 5 yr. Results should be
available by 2005.
D. Uterus
Raloxifene and its analogs have low estrogen-like actions in the
rat uterus (227, 229, 230, 231). Indeed, the raloxifene analog LY117018 is
able to block (at high doses) the estrogen-like effect of tamoxifen on
the rat uterus (231). However, raloxifene and its analogs cannot be
classified as pure antiestrogens in these tests. There is not a
complete lack of uterotropic properties (256, 257), and
estrogen-regulated genes, such as the PgR, are partially activated
(232). Also, mechanistically raloxifene cannot be described as a pure
antiestrogen (117).
Raloxifene is receiving a rigorous evaluation in the human uterus. This is important because the drug is used to prevent osteoporosis. A current evaluation in women screened to ensure the absence of preexisting endometrial abnormalities shows that raloxifene, unlike estrogen, does not increase endometrial thickness (258). Although there is not enough information to prove that raloxifene reduces the incidence of endometrial cancer in treated women, there is no evidence to suggest that raloxifene increases the risk for endometrial cancer. Raloxifene does have less estrogenicity in the uterus than tamoxifen, and it only increases the growth of human endometrial carcinomas under laboratory conditions by about 50% of that noted with tamoxifen (259). This, coupled with the preliminary data with raloxifene as a potential preventive for breast cancer in elderly woman (239, 240, 241), is sufficient to propose testing against the current standard of care, tamoxifen.
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IX. Study of Tamoxifen And Raloxifene (STAR) |
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The STAR trial’s primary aim is to determine whether long-term raloxifene therapy is effective in preventing the occurrence of invasive breast cancer in postmenopausal women who are identified as being at high risk for the disease. The comparison is to be made to the established drug, tamoxifen. Its secondary aim is to establish the net effect of raloxifene therapy, by a comparison of cardiovascular data, fracture data, and general toxicities with tamoxifen. It is clear that the activation or suppression of various target sites around a woman’s body is similar for tamoxifen and raloxifene, but an evaluation of the overall comparative benefits of the agents will be an important new clinical data base for raloxifene in postmenopausal women.
Premenopausal women at risk for breast cancer are, currently, not eligible for the STAR trial. Although there is extensive information about the efficacy of tamoxifen in premenopausal breast cancer patients (84) and women at risk for breast cancer (141), clinical experience with raloxifene is confined to monitoring the action of the drug in postmenopausal women. Raloxifene is classified as an antiestrogen with less estrogen-like actions than tamoxifen (229, 230, 231). However, tamoxifen has been shown to produce a small decrease in bone density in premenopausal women (142), and there is concern that raloxifene might produce greater decreases in bone density. The National Cancer Institute is currently conducting a randomized study of raloxifene (60 mg daily and 300 mg daily) in high-risk premenopausal women to address the issue of raloxifene and bone density. Additionally, short-term raloxifene treatment (5 days or 28 days) causes elevations in circulating estradiol but does not prevent ovulation (260), consistent with the known elevation of steroid hormones produced by tamoxifen in premenopausal breast cancer patients (261). The changes in endocrine function produced by raloxifene will also be assessed as a prelude to the recruitment of premenopausal high-risk women to the STAR trial.
The results from the STAR are anticipated by 2006. Clearly it will be invaluable to establish the overall benefits of the drugs with regard to breast cancer incidence, coronary heart disease, and osteoporosis. The comparisons of endometrial cancer will be most instructive because the standard of care, i.e., self-reporting, will be employed in the STAR trial rather than routine screening with annual biopsies.
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X. The Future of Prevention |
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The major clinical question for the current application of tamoxifen as a chemopreventive is when should the 5-yr course be taken and how long will the effects last to protect a woman at elevated risk for breast cancer? The simple answer to the first part of the question is that a woman who is found to fit the elevated risk criteria for breast cancer will receive benefit through a 55% risk reduction whenever she takes tamoxifen. However, since there are no rules that can define when a woman will develop breast cancer if she is found to be at risk, then earlier rather than later would seem to be the appropriate strategy. The answer to the duration of benefit part of the question is less clear, but there are clues that indicate that 5 yr of tamoxifen therapy results in protection, i.e., risk reduction, for at least 5 yr after the drug is stopped, based on the data about contralateral breast cancer from the Overview Analysis (84). At this time, further follow-up is not available. Clearly, it will be important to discover the mechanism for the long-term beneficial effects of tamoxifen as a chemopreventive, as this could be exploited further. Similar questions about the optimal duration of raloxifene therapy for prevention will need to be addressed in the future. In the case of raloxifene, this is not as important an issue because long-term therapy for the prevention of osteoporosis is necessary.
Finally, there is the issue of whether 5 yr of tamoxifen will be sufficient for prolonged protection from breast cancer, or whether longer durations of initial treatment will provide longer periods of protection. For example, after 10 or 15 yr of treatment can a woman get 20 yr of risk reduction? However, there is a reluctance to consider this type of clinical experiment at present because of a concern about the development of tamoxifen-stimulated primary breast cancer. The concern comes from the literature about breast cancer treatment. Although 10 yr of adjuvant tamoxifen appears to be less effective than 5 yr for the treatment of breast cancer (264), this is not useful evidence to support the restricted application of tamoxifen as a chemopreventive. Drug resistance by metastatic breast cancer cells can probably develop much more rapidly than can occur during the process of carcinogenesis for primary breast cancer. As a result, it may be important to evaluate longer durations of tamoxifen as a chemopreventive agent in clinical trial. Be that as it may, the challenge for the present is first to establish the efficacy of raloxifene compared with tamoxifen in the STAR trial, and then to determine the optimal application of SERMs as a new drug group for the benefit of women’s health.
Finally, a new generation of agents that are specifically designed to
modulate ER and -ß selectively will become available for clinical
testing within the next decade. A number of postmenopausal diseases
will be targeted, such as osteoporosis and coronary heart disease, but
the beneficial side effects should include a reduction in uterine and
breast cancer in the general population. The present reduction of
breast cancer in high-risk women by 50% is an important first step
that has resulted from the rational application of translational
research. The challenge for the future is to apply developing
laboratory knowledge about the mechanisms of carcinogenesis to prevent
breast cancer completely.
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Dedication and Acknowledgment |
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Footnotes |
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1 Supported by the generosity of the Lynn Sage Breast Cancer Research
Foundation of Northwestern Memorial Hospital. 
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Abstract
I. Introduction
