Tamoxifen has been shown to reduce the risk of contralateral breast cancer in women with invasive breast cancer and DCIS (12
). The benefit appears to be very durable. After 2 to 5 years of adjuvant tamoxifen, the contralateral breast cancer reduction continued through at least 15 years of follow-up (2
). In primary prevention trials of tamoxifen in women at risk for the future development of breast cancer, 5 to 8 years of tamoxifen significantly reduced the incidence of invasive breast cancer, and this benefit persisted for at least 7 to 12 years (6
Raloxifene has also been shown to reduce the incidence of primary invasive breast cancer (compared with placebo). The Multiple Outcomes of Raloxifene Evaluation (MORE) trial randomized 7,704 postmenopausal women with osteoporosis; with a median follow-up of 45 months, raloxifene (given for 4 years) reduced the incidence of breast cancer by 76% (RR = 0.24; 95% CI, 0.13–0.44) (7
). In the Raloxifene Use for the Heart (RUTH) trial, 10,101 postmenopausal women with coronary heart disease or multiple risk factors for this disease were assigned to either raloxifene (60 mg/d) or placebo. With 5.6 years median follow-up, raloxifene reduced the incidence of invasive breast cancer by a significant 44% (hazard ratio [HR] = 0.56; 95% CI, 0.38–0.83) (17
). As detailed in the initial report of STAR, after a median follow-up of 47 months, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer. The updated results reported here demonstrate that, after a median follow-up of 81 months, which represents 60 months of treatment plus an additional 21 months of follow-up, raloxifene no longer appears to be as effective as tamoxifen in preventing primary invasive breast cancer. Raloxifene does appear, however, to retain approximately 76% of tamoxifen’s effectiveness, which represents as much as a 38% reduction in invasive breast cancer (compared with an untreated group). The initial STAR report also suggested that raloxifene may not be as effective as tamoxifen in preventing the development of noninvasive breast cancers (LCIS and DCIS combined). The updated results show that the difference between the treatment groups has narrowed, and, much like its effect against invasive breast cancer, raloxifene is about 78% as effective as tamoxifen in reducing the risk of noninvasive breast cancer. Patients with a history of LCIS or atypical hyperplasia of the breast have a 4-fold to 10-fold increased risk of subsequent invasive disease, and tamoxifen and raloxifene were equally effective in reducing this risk in the initially reported STAR results. The current analyses indicate that this equality is no longer the case for STAR women with a history of atypical hyperplasia (RR = 1.48; 95% CI=1.06–2.09), although results for the LCIS group remain similar to those reported originally (RR = 1.13; 95% CI, 0.76–1.69).
Only a slight difference was evident between treatment groups in the cumulative incidence of both invasive and noninvasive breast cancer () through the first 20 months of the study. After 30 months, a clear separation of the treatment curves was observed, with a higher cumulative incidence of both invasive and noninvasive breast cancer in the raloxifene group. Why are we seeing this apparent diminution of raloxifene’s benefits with longer follow-up? When the initial STAR results were published, all participants were notified of the results, and women who were still receiving tamoxifen were offered the option of crossing over to raloxifene therapy for the remainder of their 5 years of treatment. Only 879 women (9%) chose this option. The cross-over is unlikely to fully explain our updated findings.
Is nonadherence with the medication an issue? Only about 2% of orally administered raloxifene becomes bioavailable, and the biological half-life of raloxifene is much shorter than that of tamoxifen. Missing a day or 2 of raloxifene may result in a greater reduction of effectiveness than will similarly skipped doses of tamoxifen. However, overall adherence to protocol medication, as measured by pill counts, was similar in the two groups, and the protocol medication drop-off rates were higher in the tamoxifen group (38.9% vs 27.4%), which indicates that nonadherence or drop-offs in the raloxifene group do not provide the answer. Raloxifene may simply be less potent than is tamoxifen. It was originally developed as a drug to treat breast cancer but was less effective than was tamoxifen in that setting as well (18
The superiority of tamoxifen over raloxifene in reducing breast cancer risk comes with a cost: significantly more endometrial cancers, hysterectomies for benign disease, thromboembolic events, and cataracts. These toxicities may be acceptable for the treatment of breast cancer but have proved to be a barrier to the use of tamoxifen for preventing primary breast cancers. It is important to point out that, unlike raloxifene, tamoxifen is approved for use in premenopausal women, and the BCPT (NSABP P-1) showed no excessive risk of endometrial cancers or thromboembolic events in the tamoxifen-treated premenopausal group compared with the placebo group. For premenopausal women at increased risk, particularly those with biopsy-proven risk factors such as LCIS or atypical hyperplasia, tamoxifen has a positive risk/benefit ratio and should be presented as a treatment option. A similar risk/benefit ratio may exist in younger postmenopausal women with elevated Gail scores and a prior hysterectomy.
Our results demonstrate that raloxifene (compared with tamoxifen) retains substantial benefit in reducing the risk of invasive breast cancer with fewer life-threatening side effects, including significantly fewer endometrial cancers, and these results are in keeping with those in the placebo-controlled raloxifene trials. We saw no significant increases in other primary cancers, although there were numerically more ovarian cancers and thyroid cancers. Neither of these tumors was noted to be of concern in the other raloxifene trials, but we plan to continue to follow STAR patients with particular attention to all potential long-term side effects.
The 5-year duration of therapy in STAR was a carryover from the P-1 trial of tamoxifen versus placebo, in which 5 years of tamoxifen was chosen based on the duration of treatment in adjuvant trials. In the combined results of MORE and the Continuing Outcomes Relevant to Evista (CORE) trial, which involved as much as 8 years of raloxifene therapy, a 66% reduction in the incidence of invasive breast cancer was seen in the raloxifene-treated group compared with the placebo group (HR = 0.34; 95% CI, 0.22–0.50). The women in the MORE/CORE studies were not selected based on breast cancer risk, and the majority had Gail scores below 1.66%, although some high-risk women were included.
Laboratory studies demonstrate that the antitumor actions of raloxifene and related hydroxylated SERMs depend on the duration of administration (19
). In other words, longer administration periods are necessary to control tumorigenesis with short-acting SERMs with poor bioavailability (20
). It may be that the long-term benefit of tamoxifen in controlling tumorigenesis after stopping the 5-year treatment continues because of the development of a sophisticated (phase II) antihormone-resistant disease that is vulnerable to the apoptotic actions of physiologic estrogen (22
). In contrast, the evolution of acquired antihormone resistance may not advance as quickly with raloxifene as with tamoxifen, and raloxifene only remains therapeutically effective as long as it is given (8
). It is unlikely that the optimual duration of raloxifene for chemoprevention will be evaluated in a breast cancer prevention setting; however, the use of raloxifene in treating and preventing osteoporosis is approved for an indefinite period of time. Therefore, continuing raloxifene therapy beyond 5 years might be an approach that would preserve its chemopreventive activity.
Large randomized cancer-prevention trials with long-term clinical follow-up of a carefully characterized population of individuals provide a valuable resource beyond the primary aims of the study. In the NSABP STAR (P-2) and BCPT (P-1), baseline blood samples have been collected and stored from more than 30,000 women at an increased risk for breast cancer, as have tumor specimens from breast cancer events. Various studies have already been conducted using these resources, and others are underway, including a genome-wide-association study by NSABP in collaboration with the National Institutes of Health Pharmacogenetics Research Network (PGRN) and the RIKEN Yokohama Institute Center for Genomic Medicine; this study includes a detailed evaluation of cytochrome P450–2D6 (CYP2D6) status ([refs. 23
; access to these data and specimens is not restricted to NSABP members; the pathology section of the NSABP Web site (http://www.nsabp.pitt.edu
) describes the process by which one can submit applications for such projects).
In conclusion, with a median follow-up of 81 months, our long-term, updated results show that raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease, and this level of effectiveness grew closer over time to that of tamoxifen (78% as effective) in preventing noninvasive disease, and that raloxifene remained far less toxic (e.g., now with highly statistically significantly fewer endometrial cancers). These relative effects of the drugs in the longer term—including greater potency of tamoxifen in preventing invasive and noninvasive disease and significantly less endometrial toxicity with raloxifene—are more consistent with the profiles that were expected on the basis of findings from other published studies. With deep public-health implications, these results help to clarify that both raloxifene and tamoxifen are good preventive choices for higher-risk postmenopausal women, depending largely on a woman’s personal risk factors for breast cancer. For postmenopausal women with elevated risk, these results should encourage widespread acceptance of raloxifene for breast cancer risk reduction, especially in women with an intact uterus who also face a risk of osteoporosis and fracture. The results should also promote greater acceptance of tamoxifen (given its greater efficacy) by premenopausal women who are at very high risk for breast cancer. Such increased acceptances of both SERMs for breast cancer risk reduction ultimately would reduce the public health burden of the disease.