REVIEW

Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease

V. Craig Jordan, Susan Gapstur, Monica Morrow

Affiliations of authors: V. C. Jordan (Robert H. Lurie Comprehensive Cancer Center), S. Gapstur (Department of Preventive Medicine), M. Morrow (Department of Surgery), Northwestern University Medical School, Chicago, IL.

Correspondence to: V. Craig Jordan, Ph.D., D.Sc., Robert H. Lurie Comprehensive Cancer Center, 710 North Fairbanks Court, Olson Pavilion 8258, Chicago, IL 60611 (e-mail: vcjordan{at}nwu.edu).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
The recognition of selective estrogen receptor modulation in the laboratory has resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. SERMs are antiestrogenic in the breast but estrogen-like in the bones and reduce circulating cholesterol levels. SERMs also have different degrees of estrogenicity in the uterus. Tamoxifen is used specifically to reduce the incidence of breast cancer in premenopausal and postmenopausal women at risk for the disease. In contrast, raloxifene is used specifically to reduce the risk of osteoporosis in postmenopausal women at high risk for osteoporosis. The study of tamoxifen and raloxifene (STAR) trial is currently comparing the ability of these SERMs to reduce breast cancer incidence in high-risk postmenopausal women. There is intense interest in understanding the molecular mechanism(s) of action of SERMs at target sites in a woman's body. An understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications as preventive agents or treatments of breast cancer and endometrial cancer, coronary heart disease, and osteoporosis.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
It is well established that estrogens and progestins play an important role in breast cell proliferation and in the promotional stage of hormone-responsive tumors. In postmenopausal women, exposure to endogenous steroid hormones, particularly estrogen, has been associated with an increase in the risk of breast cancer (1). The association between postmenopausal hormone replacement therapy (HRT) and breast cancer risk is more controversial. The results of more than 60 epidemiologic studies of this association are inconsistent, and these inconsistencies have been attributed to issues related to small sample sizes and differences in statistical methodology. To address these problems, the Collaborative Group on Hormonal Factors in Breast Cancer (2) combined original data from 51 studies and reported a 14% higher risk of breast cancer for women who had ever used compared with those who had never used HRT. Among the current or recent users of HRT for 5 or more years, the risk of breast cancer was 2.3% higher per year of use compared with nonusers (P<.05); in contrast, among women who had not used hormones for more than 5 years, there was no evidence of an association of duration of HRT use with breast cancer risk. Because HRT use must be long-term to prevent osteoporotic fracture, evidence of an association between duration of use and breast cancer risk has particular clinical importance.

Recent studies (3,4) have suggested that combined estrogen replacement therapy (ERT) and progestin may confer a higher risk of breast cancer than ERT alone. In one case–control study (3), unopposed estrogen increased breast cancer risk by 6% (P = .18) per 5 years of use. In contrast, per 5 years of use of estrogen plus progestin, the risk of breast cancer was increased by 24% (P = .005). These epidemiologic findings are supported by studies in macaque monkeys, in which combined therapy induced greater breast cell proliferation than unopposed estrogen (5).

Other indirect evidence that HRT use affects the risk of breast cancer comes from studies of mammographic breast density, an independent risk factor for breast cancer (6). Data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial (7) were used to examine the associations of breast density with use of conjugated equine estrogen (CEE), CEE plus either cyclic medroxyprogesterone acetate (MPA) for 12 days per month or daily MPA, or CEE plus micronized progesterone for 12 days per month. After 36 months, density increases were found in 2% of the women in the placebo group, in 8% of the women in the unopposed estrogen group, and in more than 18% of the women in each of the other three combined HRT groups. Most of these increases occurred in the women within 12 months of initiating HRT.

Although HRT may increase the risk of breast cancer, studies (810) have found a lower breast cancer mortality or improved survival among HRT users compared with nonusers. These findings have been attributed to an increased use of breast cancer screening in women on HRT. In an analysis of data from the Iowa Women's Health Study, Gapstur et al. (11) showed that HRT was associated with an increased risk of breast cancers of a favorable histologic subtype (papillary, tubular, mucinous, and medullary), but there was little evidence of an association between HRT use and the risk of more common invasive ductal and lobular carcinomas. The frequency of screening does not explain these results, since the tumors with a favorable histology are not precursor lesions for invasive ductal and lobular carcinomas.

The uncertainty regarding the magnitude of the breast cancer risk associated with the use of HRT, the influence of the type of hormone preparation on the level of risk, and the absence of data demonstrating an increase in breast cancer mortality all make decisions regarding the risks and benefits of HRT difficult for many women. Some of the benefits of HRT include the alleviation of menopausal symptoms and protection against bone loss and, perhaps, coronary heart disease (CHD) and Alzheimer's disease (1214). However, the risks of HRT use include endometrial cancer (for ERT alone in women with a uterus), deep vein thrombosis, and, most likely, breast cancer (12,15). Although the age-adjusted annual CHD mortality rate among U.S. women is more than twice that from breast cancer (16), concerns about breast cancer cause some women to avoid using HRT. Until recently, there were few alternatives to HRT. The availability of the selective estrogen receptor modulators (SERMs) provides new options for postmenopausal health maintenance, particularly for women at increased risk for breast cancer.


    CONCEPT OF SELECTIVE ESTROGEN RECEPTOR MODULATION
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
SERMs are compounds with both estrogenic and antiestrogenic activities at different sites in the body. At present, two SERMs, tamoxifen for the prevention of breast cancer and raloxifene for the prevention of osteoporosis, are clinically available. Tamoxifen was initially developed as an antiestrogen for the treatment of breast cancer (17,18). The low incidence of side effects facilitated the expanded use of tamoxifen as a treatment for all stages of estrogen receptor (ER)-positive breast cancer in women and in men (1921).

During the mid-1980s, the strategy of testing long-term (5 years) tamoxifen therapy in ER-positive, lymph node-negative women and the proposed testing of tamoxifen as a preventive agent in high-risk women raised concerns about the effects of an antiestrogen on bone density and the risk of CHD. Tamoxifen, however, is not a pure antiestrogen; it has both antiestrogenic and weak estrogenic activities (22). The primary evidence that tamoxifen is a selective estrogen at sites such as bone but is an antiestrogen in mammary tissue and prevents carcinogenesis and tumor growth comes from laboratory studies (2325). Similar laboratory studies starting in the 1980s (23,24,26) support the SERM action of raloxifene.


    MECHANISMS OF ACTION
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
Although the precise molecular mechanism of estrogen or SERMs at the ER is unknown, estrogen action in target tissues is modulated by the following two ERs: 1) ER{alpha}, the classical ER (27); and 2) ER{beta} (28), which modifies the action of ER{alpha} and reduces the estrogen-like actions of tamoxifen (29). The resolution of the crystal structure of the entire ER by x-ray crystallography has not been possible to date, but information on the ligand-binding domains complexed with estrogens and SERMs has been published (3032). This knowledge has provided insight into the external shapes of estrogen and SERM complexes (Fig. 1Go). The ERs are nuclear transcription factors that bind estrogens, dimerize, and form a transcription complex with coactivators and other molecules that facilitate DNA unwinding. The transcription of messenger RNA via RNA polymerase occurs at estrogen-responsive genes (Fig. 2Go). SERM–ER complexes appear to modulate the signal transduction pathway to estrogen-responsive genes (through estrogen response elements [EREs]) by binding fewer or different coactivators or by binding a corepressor protein (Fig. 2Go). However, this is a simple model of estrogen and antiestrogen action and does not explain the subtleties of SERM action.



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Fig. 1. Functional domains of estrogen receptor (ER){alpha}. The important regions are the C region that is required for DNA binding and the E region that binds estrogens and selective estrogen receptor modulators (SERMs). When estrogen binds, the two activating functions (AF-1 and AF-2) can dock with coactivators that make up the transcription complex (see Fig. 2Go). The functional domains of ER{beta} are similar, but an AF-1 area is absent and there are important differences in the amino acid sequences in the ligand-binding domain. The DNA-binding domains are similar. The SERMs tamoxifen, raloxifene, and GW7604 (a tamoxifen derivative in development) (30, 31, 92, 93) silence AF-2 in ER{alpha} to produce antiestrogenic actions; however, in the case of tamoxifen, AF-1 is not fully silenced. This finding explains the increased estrogen-like activity for tamoxifen in certain cell types. The shape of the estrogen or SERM–ER complex programs the response in a particular tissue by binding coactivators or corepressors (see Fig. 2Go) on the surface. On the basis of the x-ray crystallography of estrogen and SERM complexes with the ligand-binding domain (30, 31), it is possible to generate computer models of the external surfaces of the SERM complexes. A spectrum of complexes is proposed (93). Estrogen is sealed within the ligand-binding domain by helix 12. This change in receptor conformation allows coactivator binding in the putative AF-2 site. The surface aspartic acid at 351 (D351) is known to interact differently with the antiestrogenic side chains of SERMs to produce altered biologic effects (30, 31, 39, 94). Simply stated, the tamoxifen–ER complex binds coactivators in a novel binding site distinct from AF-2 (38, 39) to produce estrogen-like action. Coactivators bind because the tamoxifen side chain that protrudes from the ER complex cannot shield the charge on D351. In contrast, raloxifene's side chain fully shields D351 (95), and the experimental compound GW7604, a SERM with a carboxylate side chain (92, 93) that strongly repels D351, disrupts the surface charge to block coactivator binding (94). Further research is required to crystallize the whole ER and to determine the modulation imposed by ER{beta} complexes and alternate pathways (see Fig. 2Go) (96) (modified and reproduced with permission from the American Association for Cancer Research).

 


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Fig. 2. The signal transduction pathways available to estrogen or a selective estrogen receptor modulator (SERM) to initiate gene transcription. Estrogen binds to either estrogen receptor (ER){alpha} or ER{beta} and subsequently binds coactivator (CoA) molecules required to form a transcription complex at an estrogen response element (ERE) located in the promoter region of an estrogen-responsive gene. The antiestrogenic action of a SERM results from the inappropriate folding (see Fig. 1Go) of an ER{alpha} or ER{beta} complex that either cannot recruit CoA molecules or instead recruits corepressor (CoR) molecules. This programmed change in conformation produces antiestrogen action at specific sites like the breast but estrogen-like effects in the uterus if an excess of CoA molecules is present. These events modulate gene transcription through EREs. SERM–ER complexes may also initiate gene transcription to produce an estrogen-like effect, by forming a protein–protein interaction at fos/jun that activates activating protein (AP)-1 sites. In addition, SERMs may produce nongenomic effects and alter tissue biochemistry without interacting with ERs.

 
There are currently several lines of investigation to elucidate the molecular mechanism of SERM through ERs. The complex is interpreted as an inhibitory signal at some sites but as a stimulatory complex at others (33,34). The SERM–ER complex has several options to produce a multiplicity of effects through gene activation (Fig. 2Go). Studies with ER{alpha} , ER{beta}, and ER{alpha}{beta} knockout mice (35) show the dominant role of the ER system in the action of estrogen and SERM. The ERs may be modulated by different levels or types of coactivator or corepressor protein in target cells (36,37). Indeed, the estrogen-like properties of tamoxifen have been shown to be enhanced through a novel coactivator-binding site on ER{alpha} (38,39) that is not available on the raloxifene–ER{alpha} complex (39) (Fig. 1Go). There is as yet, however, no precise knowledge of all the potential molecular modulators (coactivators or corepressors) that could be involved at different sites.

Since SERMs are known to have different actions at target genes through either ER{alpha}–SERM or ER{beta}–SERM complexes (40), it is possible that one complex modulates the other (29). Clearly, the relative concentrations of ER{alpha} and ER{beta} (41) at different sites could ultimately control the actions of SERMs. A complete distribution map of ER{alpha} and ER{beta} in tissues, however, is not available.

Alternatively, the SERM–ER complexes could activate genes by a novel protein–protein interaction with fos/jun at AP-1 sites (42) that is not available to estrogen–ER complexes (Fig. 2Go). Finally, it is equally possible that SERM action may be modified through nongenomic effects in specific tissues.


    TAMOXIFEN FOR PREVENTION OF BREAST CANCER
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
The laboratory findings of mixed estrogenic and antiestrogenic activities for tamoxifen (2325,34,43) have been confirmed in humans. Tamoxifen maintains bone density in postmenopausal women (44,45), lowers the level of circulating cholesterol (46), and produces an estrogen-like increase in the risk of endometrial cancer (47,48). Long-term (i.e., >=5 years) treatment with tamoxifen in ER-positive breast cancer patients reduces the risk of death by 28% and the incidence of contralateral breast cancer by 47% (20).

The largest study of tamoxifen for prevention of breast cancer was the prospective, randomized trial initiated by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in 1992 (49), which included women aged 60 years or older or women between the ages of 35 years and 59 years whose 5-year risk of breast cancer was equal to that of a 60-year-old woman. Risk was calculated by use of the Gail model (50), which uses a woman's age, race, ages at menarche and first birth, number of first-degree relatives with breast cancer, number of previous breast biopsies, and the presence of atypical hyperplasia on biopsy to predict the 4-year and lifetime risks of breast cancer development. The Gail model used in the NSABP trial was modified to predict only the risk of invasive carcinoma. Participants were randomly assigned to receive either 20 mg of tamoxifen or placebo daily for 5 years. The primary end point of the study was the occurrence of invasive breast carcinoma; the secondary end points were the incidence of bone fractures and cardiac events. A total of 13 388 women entered the study. Of the 5969 women in the placebo group, the Gail model predicted that 159 would develop invasive carcinoma, and 155 carcinomas were observed (51). After a mean follow-up of 47.7 months, in the tamoxifen-treated group, there was a 49% reduction in the incidence of invasive carcinoma as well as a 50% reduction in the incidence of noninvasive cancer. The benefit of tamoxifen was consistent across all of the subgroups examined and was independent of the level of breast cancer risk, the participant's age, or the cause of the increase in risk. Women with atypical hyperplasia and lobular carcinoma in situ experienced particular benefit, i.e., 86% and 56% reductions in cancer incidence, respectively (52). These results are summarized in Fig. 3Go.



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Fig. 3. Percentage reduction in invasive breast cancer observed in the tamoxifen prevention trial (49). High-risk (50) premenopausal and postmenopausal women were randomly assigned to receive either tamoxifen or placebo. The reduction in invasive breast cancer produced by tamoxifen in all women was 49%, which is comparable to the 47% reduction in contralateral breast cancer noted in the overview analysis (20). The results illustrate the effectiveness of tamoxifen in reducing invasive breast cancer in different high-risk groups. Only women with one first-degree relative with breast cancer are shown in the family history risk. The 95% confidence intervals (error bars) are shown. LCIS = diagnosis of lobular carcinoma in situ.

 
Tamoxifen reduced the incidence of ER-positive tumors by 69% but had no effect on ER-negative tumors. It is likely that some of the reduction in cancer incidence in the tamoxifen-treated group was due to the treatment of clinically occult disease. However, benefit was observed for each year of follow-up in the study, with the 33% risk reduction observed in year 1 increasing to 69% in year 5. Mathematical modeling suggests that these results are best explained by a combination of both treatment and prevention (53). The observation from the overview analysis (20) that the reduction in contralateral breast cancer incidence persists 5 or more years after tamoxifen is stopped further supports the idea that tamoxifen not only treats but also prevents breast cancer. Long-term follow-up data on breast cancer incidence beyond 5 years as well as breast cancer recurrence and mortality in women who have used tamoxifen for prevention are needed to definitely answer this question.

Two additional studies (54,55) have examined the use of tamoxifen for breast cancer prevention, and neither has shown an overall benefit. However, differences in eligibility criteria, sample size, and study design between these studies and the NSABP trial raise questions about their ability to definitively address the role of tamoxifen in prevention. The Italian prevention trial (54) recruited 5408 women who had undergone a hysterectomy for a benign disease. No increase in breast cancer risk was required for enrollment in the trial. After a median follow-up of 46 months, only 41 cancers had occurred, and no differences were noted between the tamoxifen and placebo groups. With further follow-up, a 70% reduction in breast cancer incidence with tamoxifen has been noted in the subset of women using ERT (56). The Royal Marsden Hospital trial (55) reported on 2471 women at increased risk of breast cancer development, primarily on the basis of family history of breast cancer, who were randomly assigned to receive either tamoxifen or placebo and who were followed for a median of 70 months. Seventy cancers occurred, and no differences between the treatment groups were noted. The three studies (49,54,55) are compared in Table 1Go. The NSABP trial (49), with its precise numerical definition of risk, has significantly greater statistical power than the other two studies and was the only one of the three that was designed to be a definitive prevention trial in high-risk women. The results are consistent with the tamoxifen effects observed in the overview analysis (20) and in a treatment trial of intraductal carcinoma (57).


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Table 1. Comparison of tamoxifen prevention studies*
 
In the NSABP study, the SERM action of tamoxifen was demonstrated by a 19% reduction in the incidence of fractures (relative risk [RR] = 0.81; 95% confidence interval [CI] = 0.63 to 1.05). A 45% reduction in fractures of the hip (RR = 0.55; 95% CI = 0.25 to 1.15) was observed, and benefit was also seen for Colles' fractures (RR = 0.61; 95% CI = 0.29 to 1.23) and vertebral fractures (RR = 0.74; 95% CI = 0.41 to 1.32). When only women aged 50 years and older were considered, a greater benefit was noted (RR = 0.79; 95% CI = 0.60 to 1.05). Some (58,59), but not all (60), studies of tamoxifen use for the adjuvant treatment of breast cancer show a reduced incidence of fatal myocardial infarction (58) or hospitalizations for any cardiac conditions (59) in populations not selected for cardiovascular risk. However, no differences in any ischemic heart disease end points were noted in the prevention trial (61).


    RISK–BENEFIT ASSESSMENT FOR TAMOXIFEN USE
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
Although tamoxifen has clear benefit in reducing breast cancer incidence, it also has side effects, some of which are potentially life-threatening. When one is evaluating the risks and benefits of tamoxifen for prevention, it is useful to separate women into premenopausal and postmenopausal groups. In premenopausal women, the toxic effects of tamoxifen are symptoms that may affect quality of life but that are not life-threatening. There is no increase in the incidence of venous thrombosis or endometrial carcinoma in premenopausal women. Health-related quality of life was evaluated in detail in 11 064 women recruited in the first 2 years of the prevention trial (62). An increase in hot flashes (RR = 1.19), night sweats (RR =1.22), and vaginal discharge (RR = 1.60) was observed in the tamoxifen group (62). It is noteworthy, however, that 68.6% of the placebo group experienced hot flashes during the study, compared with 81.6% of the tamoxifen group, and only 7.5% of women taking tamoxifen had extremely severe hot flashes. In addition, no evidence of depression or affective disorder, as measured by the Center for Epidemiological Studies Depression Scale or the Medical Outcomes Study 36-Item Short Form Health Status Survey, was seen in women of any age taking tamoxifen. Tamoxifen was not associated with weight gain (62).

In postmenopausal women, tamoxifen was noted to increase the risk of endometrial carcinoma, any venous thrombotic events, and cataract formation. Tamoxifen increased the risk of stroke (RR = 1.75; 95% CI = 0.98 to 3.20), deep vein thrombosis (RR = 1.71; 95% CI = 0.85 to 3.58), and pulmonary emboli (RR = 3.19; 95% CI = 1.12 to 11.15), although only the risk of pulmonary emboli reached statistical significance (49). The incidence of pulmonary emboli was increased from 0.31 per 1000 women per year to one per 1000 women per year. The incidence of endometrial carcinoma was increased fourfold, but no deaths due to endometrial carcinoma occurred in the tamoxifen arm. Endometrial cancer occurred in 3.05 per 1000 women per year taking tamoxifen. Bernstein et al. (63) examined the effect of the known risk factors for endometrial carcinoma, obesity and previous estrogen use, in women taking tamoxifen; they found no increase in endometrial cancer with tamoxifen use in the absence of these factors. Tamoxifen was also noted to increase the risk of cataract surgery from three per 1000 to 4.72 per 1000 per year (49).

Models to assess the risks and benefits of tamoxifen in women at varying ages and levels of breast cancer risk have been developed (64). In general, older women require a higher level of breast cancer risk to clearly benefit from tamoxifen, particularly if they have a uterus. For white women under the age of 50 years with a uterus, a net benefit for tamoxifen was seen with a 5-year risk of breast cancer development of 1.5%. For those aged 50–59 years, this increases to a 4.0%–5.9% risk for a moderate probability of benefit (0.60 to 0.89) or a 6.0% or greater risk for a high probability of benefit (0.90 to 1.00).


    CLINICAL USES OF RALOXIFENE
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
Although raloxifene (originally named keoxifene) was developed initially for breast cancer treatment (24,65), its use was abandoned in the late 1980s because clinical trials showed no activity in tamoxifen-resistant patients (66). A recent study (67) of 300 mg of raloxifene given daily (five times the recommended dose for the prevention of osteoporosis) showed that the drug had modest activity in 21 postmenopausal, ER-positive patients with metastatic breast cancer. Raloxifene has not been tested as an adjuvant therapy and is not recommended as an alternative to tamoxifen for the treatment of breast cancer outside a clinical trial. Raloxifene has only 2% bioavailability; unlike tamoxifen, which accumulates (22), raloxifene is rapidly excreted (68).

The current clinical use of raloxifene is the direct result of the concept that SERMs could be developed for the prevention of osteoporosis or atherosclerosis but reduce the risk of breast cancer as a beneficial side effect (18,23). This hypothesis (18) was tested successfully in clinical trials of raloxifene for the treatment and prevention of osteoporosis (6971).

In a prospective, randomized trial of 7705 postmenopausal women with osteoporosis, raloxifene at a dose of 60 or 120 mg given daily reduced the risk of vertebral fractures by 30%–50%, at a mean follow-up of 36 months (70). This reduction occurred despite the fact that raloxifene does not reduce bone turnover and does not increase bone density as much as a CEE (72). Raloxifene also increased bone density in the femoral neck, but no difference in the rate of nonvertebral fractures was noted. In this study, raloxifene reduced the incidence of invasive breast cancer by 76% (RR = 0.24; 95% CI = 0.13 to 0.44) (71). As in the tamoxifen trial, the reduction was seen only in ER-positive tumors. Unfortunately, the reduction in the incidence of breast cancer cannot be compared directly with the findings from the NSABP P-1 trial, since the patients were substantially older and their breast cancer risk status was unknown in the raloxifene osteoporosis trial. In the placebo arm of the raloxifene osteoporosis trial, however, the incidence of invasive breast cancer was only 3.6 per 1000 women, compared with 6.76 per 1000 in the NSABP P-1 trial.

Raloxifene increased the incidence of hot flashes from 6.4% in the placebo group to 9.7% in the group receiving 60 mg of raloxifene (P<.001) (70). Results from several other trials (73,74) confirm this finding. A small increase in the occurrence of leg cramps (3.7% for the placebo group; 7.0% for the group receiving raloxifene at a dose of 60 mg; P<.001) was also noted (70). Limited information is available on the effect of raloxifene on mood and cognition. A sample of 143 participants in a placebo-controlled study on raloxifene and osteoporosis was evaluated with the Memory Assessment Clinics Battery, the Walter Reed Performance Assessment Battery, and the Geriatric Depression Scale after 12 months of treatment. Raloxifene had no effect on mood or cognition (75). An assessment of quality of life in 398 asymptomatic, postmenopausal women randomly assigned to receive raloxifene (60 or 120 mg), CEE (0.625 mg), or placebo for 12 months showed no difference in overall quality of life between the groups. In particular, in the raloxifene group, there was no decrease in memory or concentration or no increase in depression (74).

Raloxifene increased the incidence of venous thromboembolism (RR = 3.1; 95% CI = 1.5 to 6.2) (70), and the magnitude of the increase was similar to that observed with both tamoxifen and ERT in postmenopausal women (49,76). However, raloxifene does not appear to increase the risk of endometrial carcinoma (70,7779), and endometrial thickness is not increased after treatment with raloxifene for 1–3 years (7779). After 12 months of therapy, in a randomized study of raloxifene, CEE, or placebo, 1.7%, 39.8%, and 2.1% of women, respectively, had proliferative changes on endometrial biopsy (P<.001) (79). Raloxifene was not associated with vaginal bleeding in these studies. This result represents an advantage over HRT, where the requirement for a progestin in women with a uterus results in cyclical bleeding and may cause breast tenderness, edema, and other symptoms associated with menstruation.

Like HRT, raloxifene lowers circulating cholesterol levels (80) and homocysteine levels (81). In the laboratory, raloxifene and HRT increase coronary blood flow in sheep (82), and some (83), but not all (84), studies demonstrate that raloxifene reduces aortic atherosclerosis in laboratory animals. These findings have resulted in raloxifene being the first SERM to be examined prospectively for the prevention of CHD in high-risk women (Table 2Go).


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Table 2. Continuing evaluation of selective estrogen receptor modulator (SERM) action in randomized clinical trials
 

    CLINICAL CONSIDERATIONS
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
Many questions regarding the clinical applications of SERMs remain to be answered. Ongoing clinical trials (Table 2Go) will provide information on the long-term safety of raloxifene, the relative merits of tamoxifen and raloxifene in women at increased risk for breast cancer, and the cardiovascular benefits of raloxifene. In the absence of these data, there are a number of indications for the use of SERMs. Physicians should discuss tamoxifen use with premenopausal women with a 5-year, Gail model risk of breast cancer of 1.7% or more (64). The absence of major toxic effects in premenopausal women results in a favorable risk/benefit ratio above this risk level, although many women may not opt to take tamoxifen because of the relatively small absolute reduction in breast cancer risk. Some form of barrier contraception should be used, since tamoxifen stimulates ovulation (22). Tamoxifen should not be initiated until childbearing is complete, since its efficacy as a preventive agent when given intermittently is uncertain.

In postmenopausal women, an assessment of the risk of breast cancer, osteoporosis, cardiovascular disease, and menopausal symptoms is needed before a health maintenance strategy is selected. For those whose major concern is symptom management, HRT remains the treatment of choice. HRT is also an appropriate long-term strategy for many women. Models have been developed to predict the benefits of HRT for women with various breast cancer and cardiovascular risks (8587). These models can provide reassurance to women concerned about an increased breast cancer risk associated with HRT. For the woman at average to slightly increased risk of breast cancer development who is unwilling to accept the small increase in breast cancer risk seen with long-term HRT, raloxifene is an excellent alternative. There is good evidence (71,7779) of breast and endometrial safety, even if breast cancer prevention effects remain uncertain. However, caution should be used in prescribing raloxifene for breast cancer patients after 5 years of tamoxifen therapy. Tamoxifen-stimulated breast cancer is well recognized (88) and provides the rationale for stopping tamoxifen therapy at 5 years. Raloxifene has been shown to promote the growth of tamoxifen-stimulated tumors in the laboratory, raising concern about its use in this clinical circumstance (89).

Tamoxifen should be reserved for women for whom breast cancer is the major risk and concern. The model (64) developed to assess risk levels needed to achieve a net benefit from tamoxifen is a useful starting point in evaluating a woman's suitability for tamoxifen, but consideration should also be given to an individual's risk factors for endometrial carcinoma and thromboembolic disease. In the postmenopausal woman taking tamoxifen, screening with transvaginal ultrasound and endometrial biopsy is not indicated. Recent prospective studies (90,91) have demonstrated high false-positive rates for both procedures, resulting in additional invasive testing. Because of the low incidence of and mortality from the disease, it is estimated that annual screening of tamoxifen-treated women would reduce mortality by only 0.03% (90). The majority of endometrial carcinomas present with bleeding. Women should be advised to seek medical attention promptly if spotting and bleeding occur. Tamoxifen and raloxifene should be avoided in women with a history of thromboembolic disorders. At present, there are no data to indicate that screening for coagulation abnormalities in asymptomatic women is beneficial or cost-effective.


    CONCLUSION
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 
Tamoxifen and raloxifene are the first clinically available agents in the new drug group known as SERMs. It will be at least 10 years before their overall impact on postmenopausal health can be evaluated. However, these compounds have provided proof of principle of the SERM concept, which will allow further improvements (Fig. 4Go) in the development of multifunctional medicines in this drug class.



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Fig. 4. Potential profile for an ideal selective estrogen receptor modulator (SERM). Estrogen is associated with decreases in osteoporosis, and there are unconfirmed beneficial effects with estrogen in preventing Alzheimer's disease and coronary heart disease. The principal positive action of estrogen is to alleviate menopausal symptoms and mood changes. The negative actions of estrogen are an increased risk of breast or endometrial cancer. An ideal SERM would enhance the benefits of estrogen but would prevent breast and endometrial cancers. In the latter case, progestin therapy would be unnecessary, and periodic menstrual bleeding would be avoided. Raloxifene possesses this property. To date, tamoxifen has been shown to decrease breast cancer risk, and raloxifene has been shown to reduce the risk of fractures. Neither tamoxifen nor raloxifene fulfills the criteria for an ideal SERM, but continuing clinical evaluation (see Table 2Go) will establish the long-term safety of the SERM concept.

 


    NOTES
 
Supported by grant DAMD 17–96–2-6013 from the Army Support Command Breast Cancer Research Program; by Public Health Service SPORE grant CA89018–01 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by the Lynn Sage Breast Cancer Research Foundation at Northwestern Memorial Hospital; and by the Avon Products Foundation.

We thank Dr. James W. Zapf (Signal Pharmaceuticals, San Diego, CA) for providing the computer lowest energy calculations for the selective estrogen receptor modulator–estrogen receptor complexes in Fig. 1Go.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Concept of Selective Estrogen...
 Mechanisms of Action
 Tamoxifen for Prevention of...
 Risk-Benefit Assessment for...
 Clinical Uses of Raloxifene
 Clinical Considerations
 Conclusion
 References
 

1 Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292–9.[Abstract/Free Full Text]

2 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–59.[Medline]

3 Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328–32.[Abstract/Free Full Text]

4 Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk. JAMA 2000;283:485–91.[Abstract/Free Full Text]

5 Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B. Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol 1996;174(1 Pt 1): 93–100.[Medline]

6 Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ. Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev 1998;7:1133–44.[Abstract]

7 Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O, et al. Effects of estrogen and estrogen–progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Ann Intern Med 1999;130(4 Pt 1):262–9.

8 Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769–75.[Abstract/Free Full Text]

9 Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996;7:449–57.[Medline]

10 Bergkvist L, Adami HO, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen– progestogen replacement therapy. Am J Epidemiol 1989;130:221–8.[Abstract]

11 Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study. JAMA 1999;281:2091–7.[Abstract/Free Full Text]

12 Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med 1994;330:1062–71.[Free Full Text]

13 The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1996;276:1389–96.[Abstract]

14 Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 1996;156:2213–7.[Abstract]

15 Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998;90:814–23.[Abstract/Free Full Text]

16 National Center for Health Statistics. Health, United States. Hyattsville (MD): Public Health Service; 2000.

17 Jordan VC. The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole. Breast Cancer Res Treat 1988;11:197–209.[Medline]

18 Lerner LJ, Jordan VC. Development of antiestrogens and their use in breast cancer: eighth Cain Memorial Award Lecture. Cancer Res 1990;50:4177–89.[Abstract]

19 Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998;339:1609–18.[Free Full Text]

20 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–67.[Medline]

21 Jordan VC. Tamoxifen: a personal retrospective. Lancet Oncol 2000;1:43–9.[Medline]

22 Furr BJ, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984;25:127–205.[Medline]

23 Jordan VC, Phelps E, Lindgren JU. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 1987;10:31–5.[Medline]

24 Gottardis MM, Jordan VC. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 1987;47:4020–4.[Abstract]

25 Turner RT, Wakley GK, Hannon KS, Bell NH. Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats. J Bone Miner Res 1987;2:449–56.[Medline]

26 Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, et al. Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 1994;93:63–9.[Medline]

27 Jensen EV, Greene GL, Closs LE, DeSombre ER, Nadji M. Receptors reconsidered: a 20-year perspective. Recent Prog Horm Res 1982;38:1–40.[Medline]

28 Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996;93:5925–30.[Abstract/Free Full Text]

29 Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 1999;140:5566–78.[Abstract/Free Full Text]

30 Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;95:927–37.[Medline]

31 Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753–8.[Medline]

32 Pike AC, Brzozowski AM, Hubbard RE, Bonn T, Thorsell AG, Engstrom O, et al. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 1999;18:4608–18.[Abstract/Free Full Text]

33 Jordan VC, Robinson SP. Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc 1987;46:1870–4.[Medline]

34 Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 1988;48:812–5.[Abstract]

35 Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? [published erratum appears in Endocr Rev 1999;20:459]. Endocr Rev 1999;20:358–417.[Abstract/Free Full Text]

36 Gee AC, Carlson KE, Martini PG, Katzenellenbogen BS, Katzenellenbogen JA. Coactivator peptides have a differential stabilizing effect on the binding of estrogens and antiestrogens with the estrogen receptor. Mol Endocrinol 1999;13:1912–23.[Abstract/Free Full Text]

37 Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol 1996;10:1167–77.[Abstract]

38 Norris JD, Paige LA, Christensen DJ, Chang CY, Huacani MR, Fan D, et al. Peptide antagonists of the human estrogen receptor. Science 1999;285:744–6.[Abstract/Free Full Text]

39 MacGregor Schafer J, Liu H, Bentrem DJ, Zapf JW, Jordan VC. Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Res 2000;60:5097–105.[Abstract/Free Full Text]

40 Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 1998;54:105–12.[Abstract/Free Full Text]

41 Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, et al. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997;82:4258–65.[Abstract/Free Full Text]

42 Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, McInerney E, et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 1999;13:1672–85.[Abstract/Free Full Text]

43 Harper MJ, Walpole AL. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 1967;13:101–19.[Medline]

44 Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992;326:852–6.[Abstract]

45 Kristensen B, Ejlertsen B, Dalgaard P, Larsen L, Holmegaard SN, Transbol I, et al. Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study. J Clin Oncol 1994;12:992–7.[Abstract]

46 Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 1991;115:860–4.[Medline]

47 Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;1:117–20.[Medline]

48 Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527–37.[Abstract]

49 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.[Abstract/Free Full Text]

50 Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879–86.[Abstract]

51 Costantino JP, Gail MH, Pee D, Anderson S, Redmond CK, Benichou J, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 1999;91:1541–8.[Abstract/Free Full Text]

52 Wickerham DL, Costantino J, Fisher B, Kavanah M, Wolmark N. Average annual rates of invasive and noninvasive breast cancer by history of LCIS and atypical hyperplasia for participants in the BCPT [abstract]. Proc ASCO 1999;18:87a.

53 Radmacher MD, Simon R. Estimation of tamoxifen's efficacy for preventing the formation and growth of breast tumors. J Natl Cancer Inst 2000;92:48–53.[Abstract/Free Full Text]

54 Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998;352:93–7.[Medline]

55 Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998;352:98–101.[Medline]

56 Veronesi U. The Lynn Sage Memorial Lecture: new developments in breast cancer management. J Am Coll Surg 2001;192:761–7.[Medline]

57 Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993–2000.[Medline]

58 McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. BMJ 1991;303:435–7.[Medline]

59 Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993;85:1398–406.[Abstract]

60 Costantino JP, Kuller LH, Ives DG, Fisher B, Dignam J. Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 1997;89:776–82.[Abstract/Free Full Text]

61 Reis SE, Costantino JP, Wickerham DL, Tan-Chiu E, Wang J, Kavanah M. Cardiovascular effects of tamoxifen in women with and without heart disease: National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators. J Natl Cancer Inst 2001;93:16–21.[Abstract/Free Full Text]

62 Day R, Ganz PA, Costantino JP, Cronin WM, Wickerham DL, Fisher B. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659–69.[Abstract/Free Full Text]

63 Bernstein L, Deapen D, Cerhan JR, Schwartz SM, Liff J, McGann-Maloney E, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999;91:1654–62.[Abstract/Free Full Text]

64 Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer [published erratum appears in J Natl Cancer Inst 2000;92:275]. J Natl Cancer Inst 1999;91:1829–46.[Abstract/Free Full Text]

65 Clemens JA, Bennett DR, Black LJ, Jones CD. Effects of a new antiestrogen, keoxifene (LY156758), on growth of carcinogen-induced mammary tumors and on LH and prolactin levels. Life Sci 1983;32:2869–75.[Medline]

66 Buzdar AU, Marcus C, Holmes F, Hug V, Hortobagyi G. Phase II evaluation of Ly156758 in metastatic breast cancer. Oncology 1988;45: 344–5.[Medline]

67 Gradishar W, Glusman J, Lu Y, Vogel C, Cohen FJ, Sledge GW Jr. Effects of high dose raloxifene in selected patients with advanced breast carcinoma. Cancer 2000;88:2047–53.[Medline]

68 Snyder KR, Sparano N, Malinowski JM. Raloxifene hydrochloride. Am J Health Syst Pharm 2000;57:1669–75; quiz 1676–8.[Medline]

69 Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641–7.[Abstract/Free Full Text]

70 Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637–45.[Abstract/Free Full Text]

71 Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999;281:2189–97.[Abstract/Free Full Text]

72 Prestwood KM, Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG. A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab 2000;85:2197–202.[Abstract/Free Full Text]

73 Cohen FJ, Lu Y. Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials. Maturitas 2000;34:65–73.[Medline]

74 Strickler R, Stovall DW, Merritt D, Shen W, Wong M, Silfen SL. Raloxifene and estrogen effects on quality of life in healthy postmenopausal women: a placebo-controlled randomized trial. Obstet Gynecol 2000;96:359–65.[Abstract/Free Full Text]

75 Nickelsen T, Lufkin EG, Riggs BL, Cox DA, Crook TH. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology 1999;24:115–28.[Medline]

76 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.[Abstract/Free Full Text]

77 Cohen FJ, Watts S, Shah A, Akers R, Plouffe L Jr. Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60. Obstet Gynecol 2000;95:104–10.[Abstract/Free Full Text]

78 Fugere P, Scheele WH, Shah A, Strack TR, Glant MD, Jolly E. Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women. Am J Obstet Gynecol 2000;182:568–74.[Medline]

79 Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol 2000;95:95–103.[Abstract/Free Full Text]

80 Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445–51.[Abstract/Free Full Text]

81 Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 2000;85:214–8.[Abstract/Free Full Text]

82 Zoma WD, Baker RS, Clark KE. Coronary and uterine vascular responses to raloxifene in the sheep. Am J Obstet Gynecol 2000;182:521–8.[Medline]

83 Bjarnason NH, Haarbo J, Byrjalsen I, Kauffman RF, Knadler MP, Christiansen C. Raloxifene reduces atherosclerosis: studies of optimized raloxifene doses in ovariectomized, cholesterol-fed rabbits. Clin Endocrinol (Oxf) 2000;52:225–33.[Medline]

84 Clarkson TB, Anthony MS, Jerome CP. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 1998;83:721–6.[Abstract/Free Full Text]

85 Col NF, Pauker SG, Goldberg RJ, Eckman MH, Orr RK, Ross EM, et al. Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women. Arch Intern Med 1999;159:1458–66.[Abstract/Free Full Text]

86 Sellers TA, Mink PJ, Cerhan JR, Zheng W, Anderson KE, Kushi LH, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 1997;127:973–80.[Abstract/Free Full Text]

87 Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37.[Medline]

88 Howell A, Dodwell DJ, Anderson H, Redford J. Response after withdrawal of tamoxifen and progestogens in advanced breast cancer. Ann Oncol 1992;3:611–7.[Abstract]

89 O'Regan RM, Gajdos C, Dardes R, de Los Reyes A, Bentrem DJ, Jordan VC. Effect of raloxifene after tamoxifen on breast and endometrial cancer growth [abstract]. Proc ASCO 2001;20:25a.

90 Barakat RR, Gilewski TA, Almadrones L, Saigo PE, Venkatraman E, Hudis C, et al. Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 2000;18:3459–63.[Abstract/Free Full Text]

91 Love CD, Muir BB, Scrimgeour JB, Leonard RC, Dillon P, Dixon JM. Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 1999;17:2050–4.[Abstract/Free Full Text]

92 Willson TM, Henke BR, Momtahen TM, Charifson PS, Batchelor KW, Lubahn DB, et al. 3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats. J Med Chem 1994;37:1550–2.[Medline]

93 Wijayaratne AL, Nagel SC, Paige LA, Christensen DJ, Norris JD, Fowlkes DM, et al. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology 1999;140:5828–40.[Abstract/Free Full Text]

94 Bentrem DJ, Dardes RC, Liu H, MacGregor-Schafer JI, Zapf JW, Jordan VC. Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen. Endocrinology 2001;142:838–46.[Abstract/Free Full Text]

95 Liu H, Lee ES, De Los Reyes A, Zapf JW, Jordan VC. Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor alpha complex. Cancer Res 2001;61:3632–9.[Abstract/Free Full Text]

96 Jordan VC. Selective estrogen receptor modulation: a personal perspective. Cancer Res 2001;61:5683–7.[Free Full Text]

Manuscript received April 25, 2001; revised August 9, 2001; accepted August 16, 2001.


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