Among postmenopausal women at increased risk for major coronary events with an average estimated 5-year risk of developing breast cancer of 1.7%, treatment with 60 mg of raloxifene for 5.6 years resulted in a 44% reduction in incidence of invasive breast cancer and a 55% reduction in incidence of invasive ER-positive breast cancer (11
). Treatment did not reduce the incidence of invasive ER-negative breast cancer or of noninvasive breast cancer. Raloxifene appeared to be most effective in reducing the incidence of breast cancer during the first 4 years of treatment. Moreover, the effect of treatment appeared to be similar across subgroups defined by age, reproductive history, and breast cancer risk status.
The reduction in incidence of invasive breast cancer and invasive ER-positive breast cancer in the RUTH trial confirms the findings of the MORE randomized trial, which assessed the effects of 60 and 120 mg of raloxifene on fractures in 7705 postmenopausal women with osteoporosis (9
). After 4 years of follow-up in the MORE trial, the incidence of invasive breast cancer was 72% lower among women assigned to raloxifene compared with women assigned to placebo and the incidence of ER-positive breast cancer was 84% lower (9
). By comparison, in the Breast Cancer Prevention Study, a randomized trial of 13 388 women with greater than 1.66% 5-year risk of breast cancer, treatment with 20 mg of tamoxifen daily reduced the incidence of invasive breast cancer by 50% after 4 years (7
). Similar to the effect of raloxifene in the MORE and RUTH trials, the reduction in risk of breast cancer associated with tamoxifen was confined to ER-positive tumors (7
). The effects of raloxifene and tamoxifen on breast cancer risk were compared directly in the Study of Tamoxifen and Raloxifene (STAR), a randomized trial in which 19 747 women with a 4% average 5-year risk of developing breast cancer were randomly assigned to treatment with 20 mg tamoxifen or 60 mg raloxifene daily for 4 years. In the STAR trial, there were no differences between the two active treatments in the incidence of either invasive breast cancer or ER-positive invasive breast cancer (15
Raloxifene and tamoxifen are SERMs that bind to ERs and have estrogenic activity in some tissues and antiestrogenic activity in others. Both are thought to reduce the incidence of breast cancer by interfering with the effects of estrogen on the initiation, promotion, and/or proliferation of ER-positive cancers (16
). A reduction in incidence of invasive breast cancer was observed in the RUTH trial within 2 years of beginning treatment. Given that several years are required from initiation to clinical detection of breast cancer (17
), the RUTH findings are most consistent with an effect of raloxifene on estrogen-related tumor promotion or proliferation. A similar pattern of early reduction in incidence of breast cancer was observed in the MORE trial with raloxifene (14
) and in the Breast Cancer Prevention Trial with tamoxifen (7
Noninvasive breast cancers constituted only 7% of all breast cancers in the RUTH trial (0.2 cases per 1000 woman-years). Among women over 50 years old in the United States, the rate of noninvasive breast cancer is 0.85 per 1000, accounting for about 25% of all breast cancers (18
). RUTH was an international trial, with the majority of participants in Europe. The low rate of noninvasive breast cancer in the RUTH trial may be due to a longer mammographic screening interval or to lower rates of detection of noninvasive breast cancer outside the United States. Noninvasive breast cancer is generally detected on screening mammography (19
), which is commonly performed annually in the United States and biannually outside the United States. Following European standards, mammography was performed biannually in the RUTH trial, and detection of noninvasive cancer depended on local readings.
Treatment with raloxifene reduced the incidence of invasive breast cancer to a similar degree regardless of tumor stage, lymph node status, or tumor grade. Although there was a statistically significant interaction of treatment and tumor size, there was no consistent association of the effect of raloxifene on risk for invasive breast cancer by increasing tumor size (P for linear trend = .82).
Raloxifene did not reduce the risk of noninvasive breast cancer (11
). In fact, more noninvasive breast cancers occurred in the raloxifene than in the placebo group (11 vs 5, HR = 2.17, 95% CI = 0.75 to 6.24), although the number of noninvasive breast cancers was small and this difference was not statistically different. There was also no reduction in the incidence of noninvasive breast cancer with raloxifene treatment in the MORE trial (HR = 0.90, 95% CI = 0.30 to 2.69) (9
) or in the Continuing Outcomes Relevant to Evista (CORE) trial (HR = 1.78, 95% CI = 0.37 to 8.61) (10
). In contrast, treatment with tamoxifen in the Breast Cancer Prevention Trial resulted in a 50% reduction in the incidence of both invasive and noninvasive breast cancer (7
). In the STAR trial, in which raloxifene and tamoxifen were compared directly, there was no difference in the effect of tamoxifen and raloxifene on incidence of invasive breast cancer, but women assigned to raloxifene had a 40% higher incidence of noninvasive breast cancer than women in the tamoxifen group (HR = 1.40, 95% CI = 0.98 to 2.00) (15
It is not clear why tamoxifen appears to reduce incidence of noninvasive breast cancer whereas raloxifene does not. One possible explanation is that tamoxifen may be more effective than raloxifene in preventing the development of noninvasive disease because it has a greater binding affinity for ERβ (20
). Compared with proliferative lesions and noninvasive breast cancer, invasive disease is characterized by greater expression of ERα and less expression of ERβ (21
), which appears to protect against tumor progression (21
The effect of raloxifene on the incidence of invasive breast cancer was similar across subgroups. Because we examined a total of 20 subgroups, the borderline interaction between treatment effect and ovariectomy likely occurred by chance.
If SERMs such as tamoxifen and raloxifene are used for prevention of breast cancer, it is important to determine the optimal duration of treatment. Among women with lymph node–negative ER-positive breast cancer, a reduced risk of recurrence of cancer persists for up to 15 years after 5 years of treatment with tamoxifen (27
). However, women treated with tamoxifen for longer than 5 years do not have improved outcomes (7
). After 4 years of follow-up, 92% of women who received 5 years of tamoxifen treatment and were then randomly assigned to placebo were alive and free of breast cancer, compared with 86% of women randomly assigned to continue tamoxifen (P
= .003) (28
). These data resulted in the recommendation that adjuvant therapy with tamoxifen in women with breast cancer be discontinued after 5 years. In the Breast Cancer Prevention Trial, treatment with tamoxifen reduced risk of invasive breast cancer during each year of 6 years of follow-up (7
In a post hoc analysis, the effect of raloxifene treatment on incidence of invasive breast cancer did not differ by year, although in years 5–7, the hazard ratios were close to 1. In the MORE trial, 4 years of treatment with raloxifene resulted in a 72% reduction of risk of invasive breast cancer (9
), and in the CORE trial, after treatment was interrupted for an average of 11 months, an additional 4 years of blinded treatment with raloxifene resulted in a 59% reduction in risk of invasive breast cancer (HR = 0.41, 95% CI = 0.24 to 0.71) (10
). These data from MORE and CORE provide the longest observation of the use of an SERM for breast cancer prevention. Taken together with the main finding in RUTH, that breast cancer risk was reduced over 5.6 years of treatment, it seems reasonable to conclude that treatment with raloxifene for up to 8 years is safe and effective in reducing breast cancer risk.
Participants in the RUTH trial were selected because they either had known coronary disease or were at high risk for coronary disease. Thus, it is possible that the findings of the RUTH trial may not be able to be generalized to women who are not at high risk for coronary disease. However, 41% of RUTH participants had a 5-year predicted risk of breast cancer of 1.66% or greater, which would have made them eligible for the Breast Cancer Prevention and STAR trials. In addition, the effectiveness of raloxifene in reducing risk of breast cancer did not vary by baseline risk for breast cancer ().
Which women might consider taking raloxifene to reduce the risk of breast cancer? Although treatment with raloxifene in the RUTH trial reduced the incidence of breast cancer and vertebral fracture, it also increased the incidence of venous thromboembolic events and fatal stroke (11
). Assuming that the relative risks from the RUTH trial apply to women in the general population, the best benefit to risk ratio would occur in women at high risk of breast cancer and osteoporosis and low risk of venous thrombosis and stroke. In the STAR trial, which directly compared the effects of 4 years of treatment with tamoxifen or raloxifene among women at high risk of breast cancer, rates of invasive breast cancer were the same, but women assigned to raloxifene had lower rates of venous thromboembolic events (HR = 0.70, 95% CI = 0.54 to 0.91), uterine cancer (HR = 0.62, 95% CI = 0.35 to 1.08), and cataracts (HR = 0.79, 95% CI = 0.68 to 0.92) compared with tamoxifen. The rates of stroke, fatal stroke, coronary events, and fractures did not differ in the two treatment groups.