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).
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ABSTRACT |
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INTRODUCTION |
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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 casecontrol 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.
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CONCEPT OF SELECTIVE ESTROGEN RECEPTOR MODULATION |
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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.
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MECHANISMS OF ACTION |
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Since SERMs are known to have different actions at target genes through either ERSERM or ER
SERM complexes (40), it is possible that one complex modulates the other (29). Clearly, the relative concentrations of ER
and ER
(41) at different sites could ultimately control the actions of SERMs. A complete distribution map of ER
and ER
in tissues, however, is not available.
Alternatively, the SERMER complexes could activate genes by a novel proteinprotein interaction with fos/jun at AP-1 sites (42) that is not available to estrogenER complexes (Fig. 2). Finally, it is equally possible that SERM action may be modified through nongenomic effects in specific tissues.
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TAMOXIFEN FOR PREVENTION OF BREAST CANCER |
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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. 3.
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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 1. 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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RISKBENEFIT ASSESSMENT FOR TAMOXIFEN USE |
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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 5059 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).
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CLINICAL USES OF RALOXIFENE |
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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 13 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 2).
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CLINICAL CONSIDERATIONS |
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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.
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CONCLUSION |
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NOTES |
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We thank Dr. James W. Zapf (Signal Pharmaceuticals, San Diego, CA) for providing the computer lowest energy calculations for the selective estrogen receptor modulatorestrogen receptor complexes in Fig. 1.
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Manuscript received April 25, 2001; revised August 9, 2001; accepted August 16, 2001.
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