Abstract
Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence (
P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported.
Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment.
Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms
breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]).
Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status (
P < 0.001), and there was a significant (39%) improvement in as in node-positive patients (
P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS (
P < 0.001), a 72% improvement in distant DFS (
P = 0.002), and a 47% improvement in as (
P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival,
P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy.
Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.
