SERMs: Protection without worry?
The fear of breast cancer—and its link to estrogen use—causes many women to decline or discontinue estrogen replacement therapy. SERMs offer many of the same benefits with fewer risks, broadening the options for protecting long-term health.
- Among ER-positive breast cancer patients treated with tamoxifen for 5 years, the annual recurrence rate is cut in half and the annual death rate is reduced by 28%.
- Tamoxifen has been shown to reduce the incidence of breast cancer by 44%, 51%, and 55% in women aged 35 to 49, 50 to 59, and 60 and older, respectively.
- Raloxifene mimics the effects of estrogen on the skeleton and lipids, but acts as a complete estrogen antagonist in the breast and uterus.
- Recent data indicate that 4 years of raloxifene therapy reduces the risk of all ER-positive breast cancers by 72% compared with placebo.
- The ideal candidate for raloxifene is a postmenopausal woman with osteopenia or osteoporosis, no increased risk of thromboembolism, and few or no vasomotor symptoms.
Although it was initially considered a female sex hormone, estrogen is now recognized as a systemic substance that affects every organ system and appears to be important for both men’s and women’s health. 1-4 At puberty, elevated circulating estrogen levels transform girls into young women and shape their feminine fig-ures. In boys, estrogen is important in the closure of the epiphyseal plates to arrest postpubertal growth and support bone health throughout life. It also may have beneficial actions on the male cardiovascular system.2
As a systemic hormone, estrogen is important in women for the health of the skeleton, the heart, the integuments, and the brain.1,3 Women who suffer the loss of estrogen through surgery, illness, or early menopause often are advised to consider estrogen therapy to protect these organs from premature failure.
Unfortunately, estrogen replacement therapy (ERT) is a double-edged sword, with significant benefits in some organs and significant risks in others. ERT protects against vasomotor symptoms, urogenital atrophy, osteoporosis, cardiovascular disease, and perhaps Alzheimer’s disease.1,3 Unfortunately, it also increases the risk of venous thromboembolic events, recurrent myocardial infarction and cardiac death5 (in diseased hearts), and cancers of the uterus and breast.4
Of the many diseases that impact the lives of American women, none is more feared than breast cancer, the most common cancer in females and the second leading cause of female cancer mortality.6 The fear of this disease causes many women to decline or discontinue ERT, a decision that can profoundly affect their long-term health.7 Hence, the controversy regarding ERT centers on weighing the risk-benefit balance, i.e., trying to select patients who are more likely to benefit from the hormone and less likely to suffer from its adverse effects.
Physicians—particularly gynecologists who devote their care exclusively to women’s health—have longed for the ideal estrogen that will impart all of the benefits without the risks. This ideal estrogen would relieve women of vasomotor and urogenital symptoms and prevent the dire consequences of osteoporosis, accelerated atherosclerosis, neurogenic deficit, and collagen loss from the skin, without increasing the risk of cancer and thromboembolic phenomena. Some experts believe this ideal may be found in the new class of compounds referred to as selective estrogen receptor modulators (SERMs). Although several SERMs with desirable estrogenic properties are available, none is ideal. Nevertheless, this new class of estrogenic substances—with multiple beneficial effects and fewer risks—represents an important pharma-cotherapeutic advance in the care of postmenopausal women.
Tamoxifen citrate (Nolvadex; AstraZeneca, Wilmington, Del) has wide clinical applications in the treatment and prevention of breast cancer. In 1980, tamoxifen was approved by the FDA for postmenopausal women with node-positive breast cancer and for premenopausal women with estrogen-receptor (ER) positive advanced breast cancer. In 1990, the FDA extended the approval of tamoxifen to include pre- and postmenopausal women with node-negative, ER-positive breast cancer.
In patients with node-positive breast cancer, the 10-year-survival rate improves from 50% in control subjects to 61% in patients treated with tamoxifen for 5 years. Similar improvements in survival have been reported with tamoxifen therapy in node-negative breast cancer patients. After 5 years of tamoxifen therapy and a median follow-up of 10 years, the reduction of breast cancer recurrence and death with tamoxifen treatment compared with placebo are 47% and 26%, respectively.8
For women with ER-positive tumors (about 70% of all breast cancers), tamoxifen therapy of at least 1 year’s duration results in statistically significant recurrence and survival benefits. These results increase with the duration of treatment up to 5 years. Among ER-positive women treated with tamoxifen for 5 years—the optimal length of therapy—the annual recurrence rate is cut in half and the annual death rate is reduced by 28% (Figure 1).9 Treatment beyond 5 years does not accrue additional benefits and is associated with increased adverse events.10 Tamoxifen has little effect on animal tumors and ER-negative tumors in cell cultures and confers little or no benefit to women with ER-negative tumors.9
In ER-positive tumors, tamoxifen is believed to exert its anti-tumor effects by inhibiting the estrogen-dependent secretion of growth factors and angiogenic factors by the tumor cells, and by inducing programmed death of the tumor cells.9 An understanding of this mechanism, along with the observation that tamoxifen-treated breast cancer patients not only experience a reduction in breast cancer recurrence but also a 47% reduction in contralateral breast cancer, led to the launch of the tamoxifen chemoprevention trials in North America and Europe.
In 1992, the National Surgical Adjuvant Breast and Bowel Project (NSABP) Tamoxifen Breast Cancer Prevention Trial was launched in the United States and Canada. The results of this trial were released early because of the compelling evidence of tamoxifen’s therapeutic efficacy. The drug was found to reduce the incidence of breast cancer by 44%, 51%, and 55% in women aged 35 to 49, 50 to 59, and 60 or older, respectively. Tamoxifen also was found to reduce ductal carcinoma in situ by 50%. Although tamoxifen decreased the overall occurrence of ER-positive tumors by 69%, it did not have a significant impact on the incidence of ER-negative tumors.11
Based on these results, the FDA approved the use of tamoxifen for the primary prevention of breast cancer in high-risk women. It is important to limit the use of tamoxifen to high-risk women because of the potential for serious side effects, which include endometrial cancer, pulmonary embolism, deep vein thrombosis (DVT), and cataract formation. 9-11
The issue of whether tamoxifen inhibits the initial development of a tumor or suppresses an occult tumor remains unresolved. It is possible that both mechanisms are involved. This is not merely an academic concern. Questions remain as to whether a suppressed tumor may develop resistance to tamoxifen or even be stimulated by the drug, becoming more virulent during or after discontinuation of therapy. However, given the extensive data and longterm clinical experience and follow-up with tamoxifen, this scenario seems unlikely. In fact, the reduction in the incidence of breast cancer appears to continue for years after the therapy is discontinued.12,13
FIGURE 1Effect of tamoxifen on ER-positive breast cancer
Adapted from: Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339:1609-1618.
Raloxifene hydrochloride (Evista; Eli Lilly and Company, Indianapolis, Ind) was originally investigated for the treatment of breast cancer and was found to be similar to tamoxifen in its anti-tumor activity. Raloxifene was subsequently studied for its skeletal effects and was approved for osteoporosis prevention in postmenopausal women in December 1997, and for fracture prevention in 1999.
The agent mimics the effects of estrogen on the skeleton and lipids. However, it acts as a complete estrogen antagonist in the breast and the uterus, making it a more desirable SERM in the management of menopausal women with an intact uterus.
The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled, multicenter study involving 7,705 postmenopausal women with osteoporosis at baseline. Although bone metabolism and fractures were the primary endpoints, many other outcomes were evaluated, including uterine and endometrial effects, bleeding, breast cancer incidence, lipid levels, clotting factors, patient tolerance, and adverse events.14-18 The results of these studies support the classification of raloxifene as a SERM with several desirable estrogen-agonistic and -antagonistic effects. Even so, it is far from perfect.
Effects on bone. In the MORE trial, both placebo- and raloxifene-treated postmenopausal women received 500 mg of supplemental calcium and 400 to 600 IU of cholecalciferol (vitamin D) daily. In these postmenopausal women with osteoporosis, a daily dose of 60 mg raloxifene increased bone mineral density (BMD) in the spine by 2.6% and in the femoral neck by 2.1% compared with placebo. The assessment of biochemical bone markers indicated that raloxifene increases BMD by decreasing bone turnover. Indeed, markers of bone resorption and formation—urinary type I collagen Ctelopeptide and serum osteocalcin—were significantly decreased with raloxifene within 3 months of therapy, similar to estrogen.14,19
Raloxifene also reduced vertebral fractures in postmenopausal women with osteoporosis. Vertebral fractures occurred in 10.1% of women randomized to placebo versus 6.6% of women receiving 60 mg raloxifene daily. Although raloxifene decreased the risk of new vertebral fractures regardless of whether a spinal fracture was present at baseline, the absolute percentage decrease in the fracture rate was higher in women who did not have a fracture at baseline.14 This finding underscores the importance of diagnosing and treating osteoporosis before the development of a fracture.
One interesting observation, which is true for raloxifene and other antiresorptive agents, particularly calcitonin, is that the magnitude of the reduction in vertebral fractures is greater than would have been predicted by the modest improvement in BMD observed during therapy. This suggests that antiresorptive agents may influence bone quality, perhaps through its architectural structure, in ways that cannot be ascertained by the assessment of BMD alone. Bone quality refers to skeletal factors that strongly impact the structural properties of bone, independent of the quantity of bone, assessed by BMD. Specific factors that contribute to the structural competence of bone include its microarchitecture, degree of bone mineralization, state of the organic matrix, and rate of bone turnover. The effects of antiresorptive agents on these factors may explain why such modest improvements in BMD—i.e., 2% to 6%—result in reductions in fracture risks in the range of 30% to 50%.
Figure 2 shows the mean changes in BMD and the corresponding reduction in vertebral fractures for the therapeutic agents currently approved for the prevention and treatment of osteoporosis. Despite significant differences in BMD increases, the reductions in vertebral fracture rates are quite comparable. In the MORE trial, there was no difference in the incidence of nontraumatic fractures at sites other than the spine, possibly because of the small number of nonvertebral fractures that occurred during the study period, which yielded insufficient power to detect a difference. A subset of patients in the MORE study is being followed for a longer time to further evaluate the incidence of nonvertebral fractures.
Effects on cardiovascular health. Raloxifene’s effects on total and low-density lipoprotein (LDL) cholesterol are similar to those of estrogen, with decreases of 11% and 6%, respectively. Unlike estrogen, which increases the circulating levels of both high-density lipoprotein (HDL) cholesterol and triglycerides, raloxifene causes an insignificant increase in HDL and a slight decrease in triglyceride levels. Serum levels of lipoprotein(a) are reduced much more with ERT (16.3%) than raloxifene therapy (4.1%), whereas fibrinogen levels are reduced more with raloxifene (12.2%) than ERT (2.8%).15
The effects of raloxifene on 2 additional independent risk factors for cardiovascular disease were recently reported. Elevated levels of C-reactive protein, a circulating marker of inflammation, are associated with a significantly greater risk of myocardial infarction. Also, elevated levels of homocysteine predict a greater risk of coronary artery disease. While ERT significantly increases circulating levels of C-reactive protein (by as much as 84%), raloxifene lacks a significant effect. Like estrogen, raloxifene significantly lowers homocysteine levels by 6% to 8%.16
The changes in serum levels of the several markers of cardiovascular health are summarized for both ERT and raloxifene in Table 1. Overall, raloxifene therapy is associated with favorable changes in the serum levels of several of these markers, suggesting that the SERM may substantially reduce the risk of heart disease in postmenopausal women. However, conclusive proof would require a clinical trial with cardiovascular events as the definitive endpoints. Such an investigation is currently being carried out in the Raloxifene Use for the Heart (RUTH) trial. The results should indicate whether these favorable biochemical effects are indeed associated with a reduction in the incidence of cardiovascular disease.