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

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

Disclosures
In This Article

Extended Adjuvant Therapy

The MA.17 Trial

Study Design. This trial randomized 5187 postmenopausal women with primary breast cancer that was predominantly ER+ and/or PgR+ to receive either letrozole or placebo for 5 years; receptor status was unknown in only 2% of patients. Women had to be disease-free following approximately 5 years of tamoxifen therapy. Patients were stratified according to receptor status, nodal status, and prior adjuvant chemotherapy, and then randomized to receive letrozole (2.5 mg/d) or placebo, with treatment planned for 5 years (Figure 4).

The primary end point of the MA.17 trial was DFS, based on the first recurrence of the original cancer, either locally or as distant metastasis, or occurrence of a new primary cancer in the contralateral breast. Secondary end points included OS, the rate of contralateral breast cancer, long-term safety and tolerability, and QOL. Two companion trials were included to evaluate bone metabolism and lipid metabolism during therapy.[22]

Results. Patient characteristics were well-balanced between the 2 groups ( Table 10 ).[45] The MA.17 trial was unblinded at the first planned interim analysis, after 171 events (median follow-up 2.4 years), due to a significant difference in events that favored the letrozole arm and far exceeded predefined unblinding boundaries. Letrozole decreased the risk of breast cancer recurrence (local or metastatic recurrence or new contralateral breast cancer) by 43% vs placebo (HR 0.57, P = .00008). Throughout 4 years of treatment, DFS was progressively improved with letrozole compared with placebo, with estimated 4-year DFS of 93% vs 87%, respectively (P < .001) (Figure 5). The significant increase in DFS was observed irrespective of whether patients were node-positive or node-negative ( Table 11 ).[45] There were fewer breast cancer-associated deaths in the letrozole group than in the placebo group (9 vs 17, respectively, at 4 years), and improved OS did not reach statistical significance (96% for letrozole vs 94% for placebo; P = .25).[45]

Final MA.17 efficacy and safety results recently have been made available and largely confirmed those of the initial interim analysis.[46] However, at a median follow-up of 2.5 years, node-positive patients on letrozole showed a significant OS benefit compared with those on placebo. In this high-risk population, characterized by an incrementally larger overall number of events, letrozole decreased mortality by 39% compared with placebo (P = .04). A 39% reduction in risk of distant metastatic recurrences -- which are usually fatal -- was demonstrated overall, an improvement that was seen both in node-negative and node-positive patients.

Letrozole therapy was generally well tolerated and most adverse events were mild (grade 1 or 2).[45] Letrozole therapy was associated with significantly less vaginal bleeding compared with placebo, and patients in the placebo group had significantly fewer hot flashes and less muscle and bone pain ( Table 12 ). There were small but nonsignificant increases in patient-reported new-onset osteoporosis and clinical fractures in the letrozole group.[45] In QOL assessment, global physical and mental health measurements did reveal small to moderate differences of questionable clinical significance that favored placebo over letrozole in some domains. Overall, letrozole did not show a substantial adverse effect on QOL relative to placebo.[47,48]

The results of this pivotal trial led to the approval of letrozole as extended adjuvant treatment of early breast cancer in postmenopausal women who had received standard adjuvant tamoxifen therapy in the United States and in several European countries.

NSABP B-33

Study Design. In this phase 3 trial, patients were disease-free postmenopausal women with early stage ER+ and/or PgR+ breast cancer who had completed approximately 5 years of tamoxifen therapy. They were enrolled within 6 months of discontinuing tamoxifen and randomized to receive either exemestane (25 mg/d) or placebo for 5 years. A total accrual of 3000 patients was planned.[49]

Results. The placebo arm was closed in October 2003[49] due to the results of MA.17. No trial results have been reported.

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