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© The Author 2007. Published by Oxford University Press.
EDITORIALS |
Tamoxifen: An Enduring Star
Affiliations of authors: Scientific Director's Office (UV) and Divisions of Chemoprevention (AD) and Epidemiology and Biostatistics (PM), European Institute of Oncology, Milan, Italy; Division of Medical Oncology, Galliera Hospital, Genoa, Italy (AD)
Correspondence to: Umberto Veronesi, MD, Scientific Director's Office, European Institute of Oncology, via Ripamonti, 435, 20141 Milan, Italy (e-mail: umberto.veronesi{at}ieo.it).
In this issue of the Journal, two placebo-controlled studies (1,2) provide long-term results from trials of tamoxifen for the primary prevention of breast cancer in high-risk women. Cuzick et al. (1) expand on the first International Breast Cancer Intervention Study (IBIS-I), showing after a median follow-up of 8 years and 337 breast cancer events that tamoxifen statistically significantly reduces breast cancer by 29% with no attenuation of benefit after completion of the 5-year treatment schedule. Importantly, their data reveal a greater benefit from tamoxifen on estrogen receptor (ER)–positive disease in the follow-up period and an appreciable tapering of adverse events after the active treatment period, such that the risk–benefit ratio improved with longer follow-up. Similarly, Powles et al. (2) update the pioneering Royal Marsden trial after a median follow-up of 13 years and 186 events, reporting a non–statistically significant 22% reduction of breast cancer with tamoxifen but a statistically significant 39% reduction of ER-positive disease. The reduction in ER-positive disease was not readily apparent during the 8-year treatment period but became statistically significant with longer follow-up. Tamoxifen had no effect on ER-negative breast cancer in either trial. Notably, in both trials, the incidence of (early-stage) endometrial cancers and the development of venous thromboembolic events were only slightly increased during the entire time spans of both studies. Overall, tamoxifen was less active in reducing breast cancer risk, and also less toxic, in these two mostly European investigations compared with the American National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial (3).
The results of both studies support previous evidence from the meta-analysis of adjuvant trials (4) and from the follow-up data of the NSABP P-1 trial (3) of a durable—and possibly permanent—preventive effect of tamoxifen on ER-positive breast cancer that extends well beyond treatment cessation (e.g., 10 years in the adjuvant treatment meta-analysis). These findings, coupled with the superiority of tamoxifen over raloxifene for the prevention of ductal carcinoma in situ (DCIS) observed in the Study of Tamoxifen and Raloxifene (STAR) trial (5), underline the need to continue to follow the women in the STAR trial to discern whether raloxifene is truly equally effective at preventing invasive breast cancer with longer follow-up. Moreover, these results illustrate how an old and presumably superseded drug like tamoxifen (yet, a clever example of target therapy!) continues to spawn new insights and challenges for those scientists and clinicians subscribing to evidence-, rather than business-, based medicine.
Both trials share several findings that have important research and clinical implications. First, the increasing benefit of tamoxifen on ER-positive disease with longer follow-up in IBIS-I (1) and its clear manifestation after the 8-year active treatment phase in the Royal Marsden trial (2) suggest a true preventive effect and not merely a transient risk reduction. Second, the greater protective effect of tamoxifen in women aged 50 years or younger compared with older women in the IBIS-I trial (1) and the similar protective effect seen in premenopausal women in the Royal Marsden trial (2) highlight its favorable risk–benefit ratio in younger women, among whom severe toxicity is rare. By contrast, the NSABP P-1 trial (3) documented a trend toward a greater reduction in risk of breast cancer with increasing age. Third, the substantial number of hormone replacement therapy (HRT) users who underwent treatment in the two trials gave rise to mixed findings: whereas no benefit of tamoxifen was noted in the IBIS-I in current HRT users, a trend toward a risk reduction was detected in past users (1). In the Royal Marsden trial (2), concomitant use of HRT had no impact on the benefit of tamoxifen in the posttreatment phase, thus leaving the potential of HRT/tamoxifen combination treatment an open issue that is currently being addressed in the HRT opposed to low-dose tamoxifen (HOT) study (6). Fourth, both studies paint a reassuring picture in terms of safety, with a limited excess of endometrial cancer in the IBIS-I trial (1) that was statistically significant only during the active treatment period (12 cases in the tamoxifen arm versus 3 in the placebo arm, P = .02) but not overall (17 versus 11 cases) and a difference of borderline statistical significance in the Royal Marsden trial (13 versus 5 cases, P = .06). As for venous thromboembolic events, there was a twofold increase in deep-vein thrombosis, pulmonary embolism, and retinal thrombosis only in IBIS-I (1), which was statistically significant only in the active treatment phase, and no excess of cerebrovascular or cardiac events in either study (1,2). There were slightly fewer myocardial infarctions, more gynecologic and vasomotor symptoms, no excess of cataracts, and, surprisingly, no effect on bone fractures in the tamoxifen arms of both trials (1,2).
Together, these results tell us that tamoxifen is an effective drug for breast cancer prevention and, at least in premenopausal women, tolerably safe. Intriguingly, Cuzick et al. suggest a potential strategy of sequential combination of tamoxifen in late premenopausal women followed by an aromatase inhibitor when women become postmenopausal. In the adjuvant treatment of early ER-positive breast cancer, the concept of the tamoxifen–aromatase inhibitor switch has gained ground and is being aggressively investigated, with one trial already achieving favorable results on overall survival (7). Given its enduring efficacy after active treatment completion, another research implication could be its intermittent administration (e.g., 2 years on, 2 years off) for repeated cycles to retain the benefits while reducing the risks.
A remarkable difference between the results of the American breast cancer prevention trials [NSABP P-1 (3) and STAR (5) where indirect comparison with no treatment is made using predicted events by the Gail model] and the predominantly European studies [IBIS-I (1), Royal Marsden (2), and the Italian trial (Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al.: unpublished data)] is the higher risk reduction (approximately 50%) observed in the former trials versus the 20%–30% risk reduction noted in the latter trials. This difference cannot be explained by a different proportion of ER-negative subjects among the study populations because the percentage of ER-negative breast cancers in the four placebo arms was similar: 16.8% (42 out of 250) in the P-1 trial (3), 21.1% (35 out of 166) in the IBIS-I (1), 16.3% (17 out of 104) in the Royal Marsden trial (2), and 25.7% (19 out of 74) in the Italian trial (Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al.: unpublished data). As already noted, the estrogenic effects of tamoxifen were also more frequent in the US trials (3,5), thus resulting, for instance, in more endometrial cancers, more venous thromboembolic events, and fewer bone fractures than in the European studies (1,2 and Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al.: unpublished data). Although the explanations for these differences may entail pharmacogenetic factors and gene–environment interactions, one readily apparent conclusion is that tamoxifen was less (yet still!) active but safer in the European trials. Consequently, the toxicity noted in the two American trials should not persuade European regulatory authorities to deny tamoxifen to high-risk individuals, especially premenopausal women or women with intraepithelial neoplasia (including atypical ductal hyperplasia and lobular carcinoma in situ), in whom the drug's risk–benefit ratio is extremely favorable.
Because use of tamoxifen for breast cancer prevention has been limited, strategies to improve its cost–benefit ratio are needed. One approach would be to refine instruments to identify women at high risk of developing ER-positive tumors. The Gail model was developed to predict the overall risk of breast cancer but not the risk of specific subtypes of breast cancer (8). Several recent studies have attempted to identify specific risk factors for ER-positive and ER-negative breast cancers (9–12). One interesting finding is the strong association of risk for ER-positive/progesterone receptor– positive tumors in women with elevated circulating levels of sex steroid hormones (13). Information from such studies could be used for developing a new model to identify an optimal target population for breast cancer prevention with tamoxifen. Along this line, we have recently developed a simple risk score based on a restricted set of characteristics (ovary conservation, age at menarche, parity, age at first birth, and height) that makes it possible to identify a subset of women at high risk of breast cancer due to hormone-related risk factors (14). In this special "high-risk" group, the risk reduction attributed to tamoxifen was huge (hazard ratio = 0.18, 95% confidence interval = 0.05 to 0.62), providing the rationale for further attempts to develop models that maximize the likelihood of response to tamoxifen intervention.
By the same token, women at slightly increased risk of developing adverse events associated with tamoxifen should be excluded from using tamoxifen to prevent breast cancer. Ancillary studies of the Italian tamoxifen trial singled out risk factors associated with the development of venous thromboembolic events or nonalcoholic steatohepatitis during tamoxifen treatment (15,16). In the initial report of the IBIS-I trial (17), a higher incidence of venous thromboembolic events was seen in women on tamoxifen undergoing surgery or subjected to prolonged immobilization, illustrating an example of a group of subjects in whom tamoxifen treatment must be withdrawn to reduce the risk of these events.
Another potential strategy to improve the risk–benefit ratio of tamoxifen is a dose reduction (18) or a weekly, rather than daily, administration based on its prolonged half-life (19). Although the therapeutic dose of 20 mg/day tamoxifen has been used in all the phase III chemoprevention trials, there is compelling evidence that a lower dose, e.g., 5 mg/day or even less, could have the same protective effect while also lowering the drug's estrogenic effects, thereby potentially reducing the risks of endometrial cancer and venous thromboembolic events (20). A dose of 5 mg/day is currently being used in the HOT study, which is a phase III placebo-controlled trial in which tamoxifen is given together with HRT in an attempt to retain the benefits of each agent while reducing the related risks (6). The study is based on previous findings of a statistically significant effect of tamoxifen in the subset of HRT users (current or past) and on the notion that HRT users have adequate hormone levels that mimic premenopausal levels, a hormone milieu in which tamoxifen is less toxic. In a randomized dose-ranging trial (Decensi A, Gandini S, Serrano D, Cazzaniga M, Pizzamiglio M, Maffini F, et al.: unpublished data), we found that low-dose tamoxifen, including a weekly dose of 10 mg, favorably modulates biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms.
Importantly, mortality has not been shown to be reduced by tamoxifen in any individual study. Although an updated meta-analysis will better address this issue, it is reasonable to assume that the prevention of ER-positive breast cancers, which tend to have a good prognosis, does not translate into a substantial mortality reduction up to 10 years. Longer follow-up is needed to assess the effect of tamoxifen on the ultimate endpoint for prevention, i.e., breast cancer mortality, but the current evidence of a 40% durable reduction of ER-positive breast cancer is still very important in terms of a reduction of the clinical and psychological morbidity that accompanies a diagnosis of breast cancer and possibly also in terms of cost savings.
The long-term results of these two important trials (1,2) reinforce the notion that tamoxifen is effective with an acceptable safety profile in reducing the risk of—and perhaps truly preventing—ER-positive breast cancer in high-risk individuals. The cost–benefit ratio becomes extremely favorable in premenopausal women, particularly with precursor lesions otherwise defined as intraepithelial neoplasia. For instance, the initial findings (21) and the 7-year follow-up (3) of the NSABP P-1 trial showed a 86%–75% risk reduction of invasive breast cancer in women with prior atypical ductal hyperplasia taking tamoxifen. With the long-term data from the IBIS-I trial and the Royal Marsden study, we are now in a position to readdress the general negative perception of tamoxifen for standard breast cancer prevention. The results of these two trials, together with the findings from the NSABP P-1 trial (3) and the poor efficacy of raloxifene compared with tamoxifen in preventing DCIS (5), convincingly move tamoxifen beyond the proof-of-principle stage and underscore its worth as a viable standard option for preventing ER-positive breast cancer in high-risk women.
We admit a naive awareness that medical practice is increasingly influenced by external, namely financial, pressures, including shareholders’ concerns and legal issues; nevertheless, tamoxifen is a telling example of an effective agent with an unprecedented body of clinical evidence that has thus far had little appeal in the prevention setting mainly because of its poor commercial interest (the drug is cheap and off patent). However, cancer chemoprevention is a difficult arena for drug testing, as recently demonstrated by the failure of COX-2 inhibitors in the prevention of colorectal adenomas due to their unexpected cardiovascular events after prolonged intervention (22,23). The selection of drugs with extensive postmarketing surveillance in different clinical settings via a joint effort between academia and drug companies may therefore be one good strategy to accelerate the field of cancer prevention. We urge the community of scientists and clinicians to rethink its priorities and move toward choices driven more by public health concerns than by market interests. Unless we envision medical care exclusively for an elite, the resulting escalation of health care costs will become unaffordable.
NOTES
It is a pleasure to acknowledge the Italian National Research Council, the Italian Association for Research on Cancer, the Italian Foundation for Research on Cancer, the American-Italian Cancer Foundation, and the Italian League Against Cancer.
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J Natl Cancer Inst 2007 99: 272-282.
J Natl Cancer Inst 2007 99: 257.
J Natl Cancer Inst 2007 99: 257.
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