Breast Cancer Chemoprevention: Tamoxifen versus Raloxifene
The Current State-of-the-Art
I have been asked to briefly present the current state-of-the-art in breast cancer chemoprevention with the two SERMS, tamoxifen (Nolvadex) versus raloxifene (Evista). The state of chemoprevention until recently has been such that despite a clear indication and FDA approval for use of tamoxifen to prevent breast cancer, relatively few eligible women actually are at present on tamoxifen as a preventive strategy, in part because physicians in a position to prescribe tamoxifen for chemoprevention are frequently non-oncologists and so have relatively little familiarity with the drug, and more importantly also because of concerns about thromboembolism and toxic effects.
The STAR Trial Findings in Brief
The best evidence comes from the prospective, double-blind randomized trial STAR (Study of Tamoxifen and Raloxifene) Trial, the largest breast cancer prevention trial ever conducted, which compared tamoxifen, 20 mg/d, vs raloxifene, 60 mg/d, over 5 years, reporting results after a median follow-up of 4 years. In short, both drugs reduced the risk of developing invasive breast cancer by about 50 percent, and hence both were equally effective at preventing invasive breast cancer in women at high risk for the disease, and mortality in the two groups was similar, but thromboembolic events occurred significantly less often in the raloxifene vs tamoxifen group (the raloxifene group experiencing fewer pulmonary embolisms and deep vein thromboses), and raloxifene had a more favorable adverse risk profile. It is important to remember here that these results are restricted to estrogen receptor-positive but NOT estrogen receptor-negative breast cancer, and only in postmenopausal women.
So raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer; the significance, if any, of a nonstatistically significant higher risk of noninvasive breast cancer is not clear. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. Thus both treatments were not associated with differences in death from any cause, other invasive cancers, cardiovascular risk (no differences in incidence of ischemic heart disease for myocardial infarction, severe angina, and acute ischemic syndrome), or osteoporotic fractures. Raloxifene was also associated with slightly fewer thromboembolic events, cataracts, and cataract surgeries. Although women receiving raloxifene had significantly less uterine hyperplasia, there was not a statistically significant difference between groups in the incidence of endometrial cancer; that is, women on raloxifene had 36 percent fewer uterine cancers, but again remember the difference was not statistically significant; and 29 percent fewer blood clots than the women who were assigned to take tamoxifen. As many women know, uterine cancers, especially endometrial cancers, are a rare but serious side effect of tamoxifen. Both tamoxifen and raloxifene are known to increase a woman's risk of blood clots. Thus, the quality of life and the adverse-effect burden of raloxifene and tamoxifen are comparable.
My Interpretation of the Data
But my own sense of these findings is that although raloxifene, if not superior to tamoxifen, is indeed more acceptable and tolerable, and the trend, even though not statistically significant, of lower incidence of endometrial cancer and thromboembolic events (blood clots, pulmonary embolisms and deep vein thromboses), and cataracts, is still an important differentiating factor in raloxifene's (Evista) favor; in addition, teasing out certain other underreported differences, it's also my sense that women who wish to avoid leg cramps or vaginal bleeding/discharge might also prefer raloxifene.
Their benefits include prevention of breast cancer in postmenopausal women at increased risk and, in the case of raloxifene, reduction of fractures related to osteoporosis. As to anti-osteoporotic benefit, one study suggested that In postmenopausal women with low bone density, improvements in BMD and markers of bone turnover were substantially greater during treatment with alendronate compared to raloxifene (Philip Sambrook at the University of Sydney). However, as to the most critical aspect of osteoporosis protection, reduction of hip fracture (mortality from hip fracture is higher than that from breast cancer), the efficacy of both drugs on hip fractures (-20 to -60%), however, appears to be comparable, and despite inconsistencies across trials, WHO researchers Serge Ferrari and René Rizzoli reviewing the evidence to date earlier this year argued convincingly that there is no decisive data suggesting one agents superiority over the other, so raloxifene (Evista) remains an excellent choice for anti-osteoporotic protection.
Summary, and A Look Forward
All told, therefore for estrogen receptor-positive postmenopausal women at high risk of breast cancer, including those with significant family history and / or with known BRCA mutation, raloxifene Evista) at this time remains the foremost prospect for the chemoprevention of breast cancer, and for this category of high-risk women, raloxifene display a favorable risk-to-benefit ratio. Three things to remember:
1. prevention is not solely chemoprevention, so this should be part of a comprehensive breast cancer risk reduction program that includes exercise, dietary and weight control and caloric restriction modalities, as well as emerging CAM (complementary and alternative medicine) interventions (high-dose Vitamin D3 for example among others);
2. there is some future prospect, I would speculate, of tamoxifen resurging in interest and benefit over raloxifene if the efficacy of LD-TAM (low-dose tamoxifen at 5mg / daily) is confirmed in the chemoprevention setting, as that reduces or removes the major adverse events associated with tamoxifen; and
3. several other new SERMS currently in clinical trial, as well as other classes of agents like the Retinoids, are being explored and showing considerable promise for breast cancer chemoprevention, so it is unlikely that any one electing to begin chemoprevention with raloxifene (Evista) would remain on this agent indefinitely, switching over to better agents as they appear and are proven in safety and efficacy.