Raloxifene and the Prevention of Breast Cancer

Abstract & Commentary

Synopsis: The Multiple Outcomes of Raloxifene Evaluation is a large, multicenter trial of the antiestrogen, raloxifene, in postmenopausal women with osteoporosis. Breast cancer incidence was reduced by 76% in the groups receiving raloxifene.

Source: Cummings SR, et al. JAMA 1999;281:2189-2197.

Raloxifene hydrochloride is a selective estrogen receptor modulator (SERM) that has anti-estrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipids, and coagulation proteins. Cummings and colleagues report the results of a large clinical trial of this agent in postmenopausal, osteoporotic women with the outcome of interest being the development of breast cancer.

The Multiple Outcomes of Raloxifene Evaluation (MORE) study included a total of 7705 postmenopausal women, younger than 81 years (mean age, 66.5 years) with osteoporosis, defined by the presence of vertebral fractures or femoral neck or spine T-score of at least 2.5 S.D.s below the mean for young healthy women. Women with a history of breast cancer or who were taking estrogen were excluded. Enrolled volunteers received two pills per day. They would receive either raloxifene 60 mg twice a day, raloxifene 60 mg once a day and placebo once per day, or placebo twice a day. Of the 5129 women who received raloxifene, 13 cases of breast cancer occurred over the three years of the study. In contrast, there were 27 cases among the 2576 women assigned to placebo (relative risk, 0.24; 95% confidence interval, 0.13-0.44). Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90%, but had no apparent effect upon the development of estrogen receptor-negative, invasive breast cancers.

In this study, raloxifene was generally well tolerated. The primary untoward effect was hot flashes, but compliance remained high, and the rate of patients withdrawing from study was comparable among the three groups.

There was no increased endometrial cancer in the raloxifene-treated women, although there was a slightly increased endometrial tissue thickness by transvaginal ultrasonography (performed on a subset of volunteers, n = 1781). However, there was an increase in the risk for thromboembolic disease. By 40 months of follow-up, there was a higher rate of deep venous thrombosis (38 cases, 0.7%) and pulmonary embolus (17 cases, 0.3%) in the raloxifene-treated individuals when compared to the placebo control group (5 cases of venous thrombosis, 0.2% and 3 cases, 0.1% of pulmonary embolus).

Thus, among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during the three years of treatment and the toxicity was considered manageable.

Comment by Dan L. Longo, MD, FACP

The prototype anti-estrogen, tamoxifen, was shown in the Breast Cancer Prevention Trial (BCPT) to be effective in the primary prevention of breast cancer in high-risk individuals (older, with family history, etc.).1 In a group of patients with a risk of about 1.66% or greater in five years, based on their individual profile of prognostic factors, the risk of developing breast cancer was reduced by about 50% by tamoxifen. Although earlier, smaller studies had failed to show any benefit for tamoxifen in primary prevention, there is confidence in the BCPT findings because of the scope and size of the study and the robust findings.2,3 Enthusiasm for the development of alternative anti-estrogens was based upon some of the toxicity of long-term tamoxifen treatment, including deep vein thrombosis and endometrial cancer. Raloxifene offers the theoretical advantage of having anti-estrogenic functions at the endometrium (and breast) while functioning as an estrogen agonist at bone.4

This clinical trial, conducted at 180 centers in 25 countries (but mainly in the United States and Europe) effectively evaluated a large number of patients by using a fairly simple clinical trial design. Individuals were not at unusually high risk for breast cancer, except for their age. They were not selected for family history or by other risk factors. In fact, breast cancer has been reported to be less common in women with osteoporosis, perhaps related to their more complete or long-standing estrogen-deficient status. Yet, once again, a robust reduction in the development of new cancers was observed. As expected, no enhanced endometrial cancer was observed. There was an increase in deep venous thrombosis and pulmonary embolus. Although data were not shown in this regard, the individuals enrolled on this trial (all with significant osteoporosis) did have decreased vertebral fracture (but not fracture at other sites). Thus, raloxifene may prove to be more useful than tamoxifen in the primary prevention of breast cancer. It appears that its efficacy is at least comparable, and it may be better tolerated (with less endothelial proliferation) than tamoxifen. Comparisons in other aspects of health are also needed. Will raloxifene have the same (or better) salutory effects on serum lipids and cardiovascular end points? None of the anti-estrogens have been evaluated for their effect on cognitive function, yet hormone replacement therapy has been shown to promote cognitive function and reduce the incidence of Alzheimer’s disease. Will the anti-estrogens and SERMs promote cognitive decline? Longer term and more comprehensive studies are needed to determine if this reduction in breast cancer incidence will be diminished with time as the estrogen-receptor-bearing tumors become resistant to the hormonal intervention and to evaluate the influence of the intervention on all-cause morbidity and mortality. (Dr. Longo is Scientific Director, National Institute on Aging, Baltimore, MD.)

References

1. Fisher B, et al. J Natl Cancer Inst 1998;90:1371-1388.

2. Veronesi U, et al. Lancet 1998;352:93-97.

3. Powles T, et al. Lancet 1998;352:98-101.

4. Delmas PD, et al. N Engl J Med 1997;337:1641-1647.

14. In developing a primary breast cancer prevention strategy, raloxifene offers a theoretical advantage over tamoxifen based upon:

a. its proven superiority in preventing estrogen-receptor breast cancer.

b. its reduced stimulatory effect on the uterine endometrium and, therefore, a reduced potential to induce endometrial cancer

c. its proven superiority in preventing bone loss in patients with breast cancer.

d. its better tolerability and greater patient compliance profile.