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Originally published as JCO Early Release 10.1200/JCO.2007.10.9447 on June 11 2007 © 2007 American Society of Clinical Oncology.
Optimal Use of Aromatase Inhibitors: To Lead or to Follow?
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Just more than a decade ago, investigators launched a series of large, randomized trials of aromatase inhibitors (AIs) as adjuvant therapy for postmenopausal women with hormone receptor–positive, early-stage breast cancer. Collectively, these studies have evaluated the use of an first-line AI (Arimidex, Tamoxifen, Alone or in Combination [ATAC], Breast International Group [BIG] 1-98), a sequential approach after 2 to 3 years of tamoxifen (Intergroup Exemestane Study [IES], Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8, Arimidex-Nolvadex [ARNO] 95, Italian Tamoxifen Arimidex [ITA]), or extended therapy (MA.17).1-6 In each of these trials, incorporation of an AI in the adjuvant setting resulted in significant improvements in disease-free survival (DFS) compared with the reference arm of 5 years of tamoxifen alone. In this issue of the Journal of Clinical Oncology, Kaufmann et al7 report that switching to anastrozole after a 2-year course of tamoxifen led to a significant reduction in the risk of disease recurrence with the suggestion of a small advantage in overall survival. The study does have two important limitations that should be considered. First, as with other trials of sequential therapy, DFS and overall survival were counted only from the time of random assignment, which occurred after completion of 2 years of tamoxifen. Therefore, results of this study cannot be compared directly with trials of first-line AIs, in which random assignment occurred at the time of initial therapy. Second, follow-up data was not updated from that previously collected for the combined analysis with ABCSG trial 8.4 Thus, the median duration of exposure to anastrozole remains only 26.8 months, and less than half of patients had completed the planned 5 years of adjuvant endocrine therapy by the data cutoff point of September 2004. Given the long natural history of estrogen receptor (ER) –positive breast cancer, it will be important to assess whether the reported differences in outcomes hold up over time. Despite these limitations, this trial adds to the growing literature supporting the use of AIs in the adjuvant setting. The Kaufmann et al trial, and others like it, raise a number of questions. Perhaps the most critical is whether one should recommend an first-line AI or a sequential approach with a 2- to 3-year course of tamoxifen followed by an AI. If our only goal were to minimize recurrences in the first 2 to 3 years of therapy, the answer would be obvious—an first-line AI will result in a small decrease in early recurrence. It is noteworthy, however, that in the ATAC and BIG 1-98 trials the absolute difference in DFS between the tamoxifen and the AI arms was only 1.6% and 1.5%, respectively, at 3 years. A substantial number of these events are local recurrences, and there has been no reported difference in overall survival in either trial.8 Because our ultimate objective is to maximize overall survival and quality of life, it may be reasonable to accept a small, short-term disadvantage in DFS with the real hope that the sequential use of two, noncross-resistant agents will lead to an improvement in long-term outcomes. If we look to the metastatic setting, it is clear that resistance to either tamoxifen or AIs can occur, and that disease response and stabilization can be seen with a switch to the other agent.9 Although cross-trial comparisons are both problematic and risky, they can be a source of information when randomized comparisons are not available. With this caveat in mind, it is noteworthy that the hazard ratios (AI v tamoxifen) for DFS have been consistently more favorable in sequential studies than in the up-front studies. Moreover, an overall survival advantage has been seen in this study, in the node-positive subset of MA.17, in the large ER–positive/unknown subset of the IES study, and in one meta-analysis of sequential AI studies, but in neither of the first-line AI trials to date.10-12 While these observations could be consistent with a priming effect of tamoxifen, with the exception of ABCSG trial 8, all of the sequential studies enrolled patients who were disease free after 2 to 3 years of tamoxifen. Thus, there is a selection bias toward women with hormonally sensitive disease, as women who developed recurrences in the first 2 to 3 years on tamoxifen were excluded. In short, the differences in hazard ratios may be due to underlying differences in the patient populations, and not because of any true benefit from using tamoxifen before an AI. In an effort to overcome these limitations, several groups have applied modeling approaches to predict the most favorable overall strategy, with somewhat conflicting results.13,14 Ultimately, the debate will likely not be settled until results of BIG 1-98 are available, as this is the only trial designed to directly compare an first-line AI versus a sequential approach. If one is planning to use a sequential strategy, what is the optimal duration of AI therapy? The natural history of ER–positive breast cancer is very long. In women treated with tamoxifen, over half of all recurrences occur 6 to 15 years after diagnosis.15 Based on results from MA.17, we know that extended endocrine therapy with a 5-year course of an AI after a 5-year course of tamoxifen is effective. From this study and others, it is also known that a 5-year course of an AI is generally well-tolerated. In the absence of significant toxicity, we think it is reasonable to consider up to 5 years of an AI for women treated with a 2 to 3 year course of tamoxifen. In light of the monotonic risk of relapse in women with ER–positive disease, the ability to extend therapy beyond 5 years is one of the appealing aspects of a crossover strategy. However, we must acknowledge that this approach has not been specifically studied in the context of controlled clinical trials. Another approach to extended therapy would be to initiate therapy with an AI and simply continue beyond 5 years. Unfortunately, we lack both efficacy and safety data to support such a strategy. Can we use tumor or host factors to guide our recommendations for individual patients? Although there was initial enthusiasm that the progesterone receptor or human epidermal growth factor receptor 2 might predict AI benefit, analysis of BIG 1-98 and updated analysis of ATAC do not support a differential effect of AIs versus tamoxifen according to either marker.16,17 In fact, the hazard reductions associated with AIs appear to be similar across subgroups. Nevertheless, patients with human epidermal growth factor receptor 2–positive or progesterone receptor–negative tumors face a higher rate of relapse within the first few years of diagnosis compared with other patients with ER–positive disease. Such patients, and others who might be at higher than average risk of early recurrence, may derive a greater absolute benefit from an first-line AI, particularly if their underlying risk of recurrence declines in subsequent years. In addition to tumor-specific factors, there is growing recognition that host factors may be critically important predictors of efficacy and toxicity. Polymorphisms in CYP2D6 correlate with levels of the active metabolite of tamoxifen. In a retrospective study, patients with the *4/*4 genotype (so-called poor metabolizers) experienced an increased risk of recurrence compared with women who were heterozygous or homozygous for the wild-type allele.18 Conversely, the distribution of polymorphisms of the aromatase gene (CYP19) varies across ethnic groups, and may influence the risk-benefit profile of AIs.19,20 Though each of these potential predictors will require confirmation in larger data sets, they illustrate the general concept that host factors can and probably do play an important role. Host factors may also modify the risk of adverse effects. For example, the presence of Factor V Leiden may predispose women receiving tamoxifen to thromboembolic events.21 With regard to AIs, correlative substudies within the large adjuvant trials may help to identify genetic and/or environmental predictors of skeletal complications. It is plausible, but unknown at this time, that the use of sequential therapy will result in a lower overall toxicity burden than the use of AIs alone. AIs unquestionably have a role in the optimal adjuvant endocrine therapy in postmenopausal women. Based on the available evidence, either an first-line or sequential approach is reasonable. Results of BIG 1-98 are eagerly awaited, although one study alone may not answer all the relevant questions. It is uncertain at this time if we will settle on a single strategy that can be applied uniformly to all postmenopausal women with hormone receptor–positive disease. Our bias is that a uniform approach will not be the answer, and efforts to optimize therapy for individual women will require continued collaborations between clinicians, trialists, laboratory scientists, and women with breast cancer. These endeavors will require substantial research funding and a willingness to maintain an open mind. As we look back in 2011, 4 years from now and 15 years after the first trials of the AIs in the adjuvant setting were initiated, we hope that tools will exist to provide more individualized care than is possible today, with the goal of allowing women with breast cancer to lead longer and better lives. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Eric P. Winer, AstraZeneca, Pfizer Stock: N/A Honoraria: N/A Research Funds: Eric P. Winer, AstraZeneca Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Nancy U. Lin, Eric P. Winer Manuscript writing: Nancy U. Lin, Eric P. Winer Final approval of manuscript: Nancy U. Lin, Eric P. Winer NOTES published online ahead of print at www.jco.org on June 11, 2007. REFERENCES 1. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 2. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 3. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 4. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline] 5. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 23:5138-5147, 2005 6. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003 7. Kaufmann M, Jonat W, Hilfrich J, et al: Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: The Arno 95 Study. J Clin Oncol 25:2664-2670, 2007 8. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline] 9. 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 10. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005 11. Coombes RC, Paridaens R, Jassem J, et al: First mature survival analysis of the Intergroup Exemestane Study: A randomized trial in disease-free, postmenopausal patients with early breast cancer randomized to continue tamoxifen or switch to exemestane following an initial 2-3 years of adjuvant tamoxifen. J Clin Oncol 24:9s, 2006 (LBA 527)[CrossRef] 12. Jonat W, Gnant M, Boccardo F, et al: Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: A meta-analysis. Lancet Oncol 7:991-996, 2006[CrossRef][Medline] 13. Punglia RS, Kuntz KM, Winer EP, et al: Optimizing adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer: A decision analysis. J Clin Oncol 23:5178-5187, 2005 14. Cuzick J, Sasieni P, Howell A: Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen? Br J Cancer 94:460-464, 2006[CrossRef][Medline] 15. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 16. Viale G, Regan M, Dell'Orto P, et al: Central review of ER, PgR, and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005 17. Dowsett M, Allred C: Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial. Breast Cancer Res Treat 100:S21, 2006 (abstr 48) 18. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005 19. Ma CX, Adjei AA, Salavaggione OE, et al: Human aromatase: Gene resequencing and functional genomics. Cancer Res 65:11071-11082, 2005 20. Moy B, Tu D, Pater JL, et al: Clinical outcomes of ethnic minority women in MA.17: A trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Ann Oncol 17:1637-1643, 2006 21. Garber JE, Halabi S, Kaplan E, et al: Factor V Leiden (FVL) mutations and thromboembolic events (TE) in women with breast cancer on adjuvant tamoxifen. J Clin Oncol 23:6S, 2005 (abstr 508) Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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