Benefit With Aromatase Inhibitors in the Adjuvant Setting for Postmenopausal Women With Breast Cancer

Henning T. Mouridsen, MD, PhD; Nicholas J. Robert, MD

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In This Article

Discussion

A number of adjuvant breast cancer trials are currently evaluating all 3 third-generation aromatase inhibitors relative to the current standard, tamoxifen for 5 years. In comparing efficacy and safety of these agents with tamoxifen, trials are evaluating efficacy by both short-term (eg, DFS) and long-term (OS) criteria, as well as short-term tolerability (immediate adverse events) and long-term consequences of pronounced estrogen deprivation (QOL, end-organ effects). Three different treatment strategies are currently under investigation to determine how to optimally improve upon tamoxifen: an aromatase inhibitor as a replacement for 5 years of tamoxifen (early adjuvant therapy); sequencing an aromatase inhibitor during the first 5 years of tamoxifen, with total treatment for 5 years (early sequential adjuvant therapy); and extension of adjuvant endocrine therapy with an aromatase inhibitor following the standard 5 years of tamoxifen (extended adjuvant therapy).

So far, results have been reported for the ATAC trial of anastrozole vs tamoxifen and the BIG 1-98 trial of letrozole vs tamoxifen as early adjuvant therapy; for the ICCG 96, ARNO and ITA trials in which exemestane or anastrozole were sequenced after 2 to 3 years of tamoxifen; and for the MA.17 trial of extended adjuvant letrozole following 5 years of tamoxifen. In all cases, significant improvements have been seen in short-term efficacy (time to recurrence or DFS). In addition, all 3 agents were generally well tolerated by short-term criteria, and, as expected from their mode of action, with a general trend of higher frequency of arthralgia, osteoporosis/fractures, and a lower frequency of thromboembolic events and gynecologic symptoms compared with tamoxifen or placebo. These efficacy and safety results support the use of each aromatase inhibitor in its respective treatment setting. In a recent data update, MA.17 did demonstrate the first significant long-term efficacy improvement for an aromatase inhibitor as adjuvant therapy: an improvement in OS for patients who were node-positive.[46] However, until all long-term efficacy and safety results become available, and until results are reported for the other ongoing trials of aromatase inhibitors, it is important for physicians to carefully evaluate current data in making treatment decisions among the existing options. Because the aromatase inhibitors differ in mode of action and potency,[50] which might influence clinical activity, comparison of results among the 7 trials reported to date is not valid.

The US Food and Drug Administration has approved anastrozole for adjuvant therapy on the basis of the ATAC trial results, which showed a 13% relative reduction in the risk of recurrence, and at 6 years a 3.7% absolute reduction in time to recurrence in receptor-positive tumors with anastrozole compared with tamoxifen.[27] However, several long-term issues remain to be resolved before anastrozole can be considered to have long-term superiority over tamoxifen. No survival benefit has yet been demonstrated; optimum duration of anastrozole treatment is not yet established; and long-term efficacy may be influenced by a carryover benefit following 5 years of tamoxifen treatment.[4,23,51] Establishing the long-term benefits of anastrozole over tamoxifen will require longer follow-up in the main ATAC trial, as well as in safety subprotocols, such as one that is examining bone mineral density, which showed progressive deterioration over the first 2 years of treatment with anastrozole.[29] Because of the lack of maturity of the ATAC data, anastrozole is being recommended by the American Society of Clinical Oncology and by the St. Gallen Consensus Panel in a limited context within the adjuvant setting, that is, for patients who either have contraindications to, or poorly tolerate, tamoxifen.[51,52]

Similar considerations relate to the up-front use of letrozole. The BIG 1-98 trial demonstrated significant superiority of early treatment with an aromatase inhibitor vs tamoxifen. Thus, with 25.8 months' median follow-up, letrozole was associated with a 19% reduction in the risk of an event, corresponding to an absolute risk reduction of 2.6% at 4 years. Moreover, time to distant recurrence was reduced by 27%.[32]

Treatment recommendations must also be limited with regard to early sequential adjuvant treatment with exemestane, based on ICCG 96 trial results, or with anastrozole, based on the ARNO and ITA trials. Long-term efficacy and safety data will be necessary before firm conclusions about superiority relative to tamoxifen can be drawn, and before optimum use of the aromatase inhibitor can be determined. In the ICCG 96 trial, the relative risk reduction was 32% and the estimated 3-year absolute reduction in risk of recurrence with exemestane vs tamoxifen was 4.7%.[37] Results of the ARNO trial for early sequential anastrozole were consistent with ICCG 96 in showing improvement (41% relative reduction in risk of recurrence) with sequencing of an aromatase inhibitor.[44]

MA.17 is the only trial to have reported on extended adjuvant therapy with an aromatase inhibitor. In interim results of MA.17, there was a 43% relative reduction, and a 4-year estimated absolute reduction of 6%, in risk of recurrence with letrozole compared with placebo.[45] Also, in a recent MA.17 update, for patients who were node-positive, letrozole achieved a significantly higher rate of OS than placebo,[46] the first evidence for a long-term survival benefit in any adjuvant aromatase inhibitor trial.

A key unresolved issue for all of the aromatase inhibitor trials is the optimum duration of treatment, either as a replacement for, or sequenced after, tamoxifen. The MA.17 trial will re-randomize patients who have completed 5 years of letrozole to either continue letrozole or switch to placebo. Another important issue is the optimum treatment schedule with aromatase inhibitors relative to tamoxifen -- ie, replacement of, or sequenced after, tamoxifen. Ongoing trials, particularly BIG 1-98, will address both issues, because it is directly comparing letrozole with tamoxifen as early adjuvant therapy, as well as early sequencing of letrozole after tamoxifen and tamoxifen after letrozole. Also, the amended TEAM trial will analyze the benefits with an aromatase inhibitor (exemestane) used upfront or sequenced after tamoxifen.

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