Optimal Use of Aromatase Inhibitors: To Lead or to Follow?

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). 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 al 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. 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 2to 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. 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. 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 upfront 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 metaanalysis of sequential AI studies, but in neither of the first-line AI trials to date. 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. 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. 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 19 JULY 1 2007