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Originally published as JCO Early Release 10.1200/JCO.2002.06.617 on July 1 2002 © 2002 American Society for Clinical Oncology
A Rose Is No Longer a RoseUniversity of California, San Francisco, San Francisco, CA GERTRUDE STEIN’S famous poem, "Rose is a rose is a rose,"1 has, for many years, been an apt exemplar for teaching a fundamental principle about the management of metastatic breast cancer: Endocrine therapy is an endocrine therapy is an endocrine therapy. Until a few years ago, randomized comparisons of different forms of endocrine therapy rarely demonstrated superiority of one over another. There was no advantage for combining endocrine treatments, and patients whose tumors regressed with one endocrine therapy often responded to another form of hormone treatment at the time of tumor regrowth. For this reason, endocrine treatments have been given sequentially (the "endocrine cascade") as patients responded and then progressed, with the order being determined by the toxicity of each agent, the least toxic being used first. A typical sequence for postmenopausal patients used before 1990 and before the widespread use of adjuvant tamoxifen is shown in Fig 1.
In the 1990s, these sequences began to change and they are still changing. A new generation of aromatase inhibitors, including anastrozole, letrozole, and exemestane, have replaced aminoglutethimide for postmenopausal women with metastases. Not only are all of these considerably less toxic than aminoglutethimide, each has been shown to be more effective than megestrol acetate,2-5 and two have been shown to be more effective than tamoxifen.6,7 The end points that were statistically significant varied in these studies, but in all of the comparisons with megestrol acetate, aromatase inhibitor treatment resulted in either a significantly better survival or a strong trend toward improved survival. In comparisons with tamoxifen, the aromatase inhibitors have not yet been shown to significantly improve survival, but it is unlikely that the mature results of these studies, especially those of the letrozole trial, will show survival inferiority from use of the aromatase inhibitors as first-line treatment.8 As a result of these trials, aromatase inhibitors are now clearly the treatment of choice for patients with newly diagnosed metastases from hormone-sensitive tumors (Fig 2). They are effective in both tamoxifen-naive patients as well as those who have responded and then progressed while or after receiving adjuvant tamoxifen.
It is not clear at the present time that one aromatase inhibitor is more effective than the others. Letrozole has been shown to reduce estrogen levels to a greater degree than the other aromatase inhibitors.9,10 Anastrozole has been shown to have greater selectivity for aromatase,11 but it remains to be shown that these laboratory correlates should affect clinical decisions in the choice between these drugs. The first randomized trial comparing anastrozole and letrozole enrolled 713 postmenopausal patients who had relapsed after treatment with tamoxifen.12 The receptor status was know for only 48% of the patients, so it is likely that many of the patients were receptor negative and might not have benefited from either treatment. Letrozole resulted in a significantly better response rate than anastrozole, and there was also a trend favoring letrozole in clinical benefit from treatment. However, there were no differences in time to tumor progression, duration of response, or duration of clinical benefits. Exemestane is the most recently introduced aromatase inhibitor. Fewer clinical data are available to evaluate its role, and it is not as widely used at this time. Exemestane differs from letrozole and anastrozole in that it is a steroidal, nonreversible aromatase inhibitor, but it is not clear that this is clinically important. Exemestane has been shown to induce response and result in clinical benefit (objective response or stable disease for > 6 months) for 24% of patients previously treated with a nonsteroidal aromatase inhibitor.13 In a preclinical rat model, exemestane was shown to prevent or substantially reduce loss of bone mineral density, increase in pyridinoline (a biochemical serum marker of bone resorption), and increase in osteocalcin (a biochemical serum marker of bone formation) after ovariectomy.14 Since the beneficial effects of tamoxifen on bone are one of its main advantages over anastrozole and letrozole, this similarity in the effects of tamoxifen and exemestane may become very important if the results of the preclinical studies can be reproduced in clinical trials. Two other antiestrogens are similar to, but have no proven advantages over, tamoxifen. Toremifene has been shown in randomized trials to be equivalent in efficacy.15 No direct comparisons have been made between raloxifene and tamoxifen, and the United States Food and Drug Administration has not approved raloxifene for the treatment of breast cancer. Neither has been shown to be very effective in patients resistant to tamoxifen. Cross-resistance between tamoxifen and toremifene has been demonstrated in a double-blind cross-over trial.16 A randomized trial (the Anastrozole, Tamoxifen Alone of in Combination [ATAC] trial) comparing anastrozole, tamoxifen, or a combination of anastrozole and tamoxifen as adjuvant therapy in 9,366 women has been reported to demonstrate a highly significant improvement in the disease-free and distant disease-free survival of those randomized to anastrozole alone compared with either of the other two arms.17 There was also a very substantial and significant relative reduction in contralateral breast cancers. There are relatively few deaths to date, and no survival differences have emerged. The median follow-up on this study is still only 34 months, and most of the patients are still on study. In general, the toxicity profile was better for anastrozole than for tamoxifen. An important exception was the lower incidence of skeletal complications and bone fractures among patients treated with tamoxifen. Approximately one fifth of the patients (1,995) had received adjuvant chemotherapy before they were randomized on this trial, and in this group, there was no difference between anastrozole and tamoxifen. The results of the trial seem so promising that many physicians now use anastrozole as adjuvant therapy. However, an ad hoc committee of the American Society of Clinical Oncology has recommended that tamoxifen still be considered the standard adjuvant treatment until additional evidence of benefit, especially a survival benefit, has been demonstrated. The exceptions to this are patients who cannot tolerate or have contraindications to treatment with tamoxifen.18 Tamoxifen has been evaluated in women without breast cancer but who are at high risk of developing the disease by virtue of age, family history, prior biopsies, parity, and age of menarche.19-22 In randomized trials comparing 5 years of tamoxifen use to placebo, there was a decrease in the incidence of breast cancer during the first 4 to 5 years of follow-up. This suggests that the onset of the disease can at least be delayed. Whether this strategy will prevent breast cancer or decrease mortality will require substantially longer follow-up. The most recent entrant into the new pantheon of drugs for the treatment of breast cancer is the pure antiestrogen fulvestrant. The first results from randomized trials evaluating fulvestrant appear in this issue of the Journal of Clinical Oncology.23,24 Fulvestrant downregulates and degrades the estrogen receptor, causes a reduction in progesterone receptor, and has only estrogen antagonistic effects. This is in contrast to tamoxifen, which has partial agonist effects, and the aromatase inhibitors, which reduce the estrogen available to the cancer cell. Both of these trials enrolled women who had previously received endocrine therapy, primarily tamoxifen, in either the adjuvant or metastatic setting and whose disease had progressed while they were receiving or after they had completed the therapy. Many of the patients were known to have responded and then progressed. Fulvestrant was at least as effective as the comparator, anastrozole, and response durations may have been longer. Preclinical data suggest that fulvestrant may be more effective than tamoxifen,25 and it might work in patients who are initially resistant to tamoxifen. It is possible that combinations of fulvestrant and aromatase inhibitors will be effective, in contrast to the outcome of the ATAC trial, where there was no advantage to combining tamoxifen and anastrozole. The endocrine cascade has grown much more complex over the past 10 years, and these recent studies suggest that this complexity will continue to grow (Fig 3). While these new therapies may be confusing to clinicians and patients at this time, they also offer promise of much more effective, nontoxic treatment that will both palliate symptoms and prolong the lives of patients with breast cancer.
NOTES This editorial was published ahead of print at www.jco.org. REFERENCES 1. Stein G, Dupee FW, Van Vechten C (eds): Selected Writings of Gertrude Stein. Vintage Books, 1990 2. Buzdar AU, Jonat W, Howell A, et al: Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: Results of a survival update based on a combined analysis of data from two mature phase III trials—Arimidex Study Group. Cancer 83: 1142-1152, 1998[CrossRef][Medline] 3. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453-461, 1998[Abstract]
4. Buzdar A, Douma J, Davidson N, et al: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19: 3357-3366, 2001
5. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial—The Exemestane Study Group. J Clin Oncol 18: 1399-1411, 2000 6. Bonneterre J, Buzdar A, Nabholtz JM, et al: Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92: 2247-2258, 2001[CrossRef][Medline]
7. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19: 2596-2606, 2001
8. Cohen MH, Johnson JR, Li N, et al: Approval summary: Letrozole in the treatment of postmenopausal women with advanced breast cancer. Clin Cancer Res 8: 665-669, 2002 9. Boeddinghaus IM, Dowsett M: Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors. J Steroid Biochem Mol Biol 79: 85-91, 2001[CrossRef][Medline] 10. Bernardi A, Zamagni C, Di Fabio F, et al: Randomized comparative study on estrogen suppression induced by 3 different aromatase inhibitors in postmenopausal patients with advanced breast cancer. Proc Am Soc Clin Oncol 21: 55a, 2002 (abstr 217) 11. Buzdar AU: A summary of second-line randomized studies of aromatase inhibitors. J Steroid Biochem Mol Biol 79: 109-114, 2001[CrossRef][Medline] 12. Rose C, Vtoraya O, Pluzanska A, et al: Letrozole (Femara) vs. anastrozole (Arimidex): Second-line treatment in postmenopausal women with advanced breast cancer. Proc Am Soc Clin Oncol 2002; 21:34a, 2002 (abstr 131)
13. Lonning PE, Bajetta E, Murray R, et al: Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 18: 2234-2244, 2000 14. Goss P, Grynpas M, Qi S, et al: The effects of exemestane on bone and lipids in the ovariectomized rat. Presented at the 24th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, 2001 15. Pyrhonen S, Ellmen J, Vuorinen J, et al: Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer. Breast Cancer Res Treat 56: 133-143, 1999[Medline] 16. Stenbygaard LE, Herrstedt J, Thomsen JF, et al: Toremifene and tamoxifen in advanced breast cancer: A double-blind cross-over trial. Breast Cancer Res Treat 25: 57-63, 1993[CrossRef][Medline] 17. Baum M on behalf of the ATAC Trialists’ Group: The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post-menopausal (PM) women. Presented at the 24th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, 2001
18. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor–positive breast cancer: Status report 2002. J Clin Oncol 20: 3317-3327, 2002
19. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for pre-vention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90: 1371-1388, 1998 20. Powles T, Eeles R, Ashley S, et al: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352: 98-101, 1998[Medline] 21. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women—Italian Tamoxifen Prevention Study. Lancet 352: 93-97, 1998[Medline] 22. Cuzick J: First presentation of results from IBIS I (International Breast Intervention Study I) and a meta-analysis of the IBIS 1 results with updated data from the Italian and Royal Marsden studies. Presented at the 3rd European Breast Cancer Conference, Barcelona, Spain, March 19-23, 2002
23. Osborne CK, Pippen J, Jones SE, et al: A double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: Results of a North American trial. J Clin Oncol 20: 3386-3395, 2002
24. Howell A, Robertson JFR, Quaresma Albano J, et al: Fulvestrant (formerly ICI 182,780) is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20: 3396-3403, 2002
25. Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, et al: Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87: 746-750, 1995 This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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