NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

associated with significant increases in both DFS (HR, 0.66; 95% CI, 0.44–1.00; P = .049) and OS (HR, 0.0.53; 95% CI, 0.28–0.99; P = .045). 282 A meta-analysis of ABCSG 8, ARNO 95, and ITA studies showed significant improvement in OS (HR, 0.71, 95% CI, 0.5200.98; P = .04) with a switch to anastrozole. 300 The TEAM trial compared sequential treatment of exemestane alone versus sequential therapy of tamoxifen for 2.5 to 3.0 years followed by exemestane to complete 5 years of hormone therapy. 301 At the end of 5 years, 85% of patients in the sequential group versus 86% in the exemestane group were disease free (HR, 0.97; 95% CI, 0.88–1.08; P = .60). This is consistent with the data from the BIG 1-98 trial, 295 in which tamoxifen followed by letrozole or the reverse sequence of letrozole followed by tamoxifen was not associated with significant differences in efficacy versus letrozole monotherapy after a median follow-up of 71 months. Results of the MA-17 trial in 5187 women who had completed 4.5 to 6 years of adjuvant tamoxifen demonstrated that extended therapy with letrozole provides benefit in postmenopausal women with hormone receptor-positive, early breast cancer. 283,302 At a median follow-up of 2.5 years, the results showed fewer recurrences or new contralateral breast cancers with extended letrozole (HR, 0.58; 95% CI, 0.45– 0.76; P < .001). No difference in OS was demonstrated (HR, 0.82; 95% CI, 0.57– 1.19; P = .3), although there was a survival advantage in the subset of patients with ALN-positive disease (HR 0.61; 95% CI, 0.38–0.98; P = .04). In a separate cohort analysis of the MA-17 trial, the efficacy of letrozole versus placebo was evaluated after un-blinding of the study in the 1579 women who had been randomly assigned to placebo after 4.5 to 6 years of tamoxifen. 303,304 The median time since completion of tamoxifen was 2.8 years. Both DFS and distant DFS were significantly improved in the group receiving letrozole, thereby providing some

evidence for the efficacy of letrozole in patients who had received 4.5 to 6 years of tamoxifen therapy followed by no endocrine therapy for an extended period. A formal quality-of-life analysis demonstrated reasonable preservation of quality of life during extended endocrine therapy, although women may experience ongoing menopausal symptoms and loss of bone mineral density. 305,306 No data are available regarding use of aromatase inhibitors for more than 5 years or long-term toxic effects from extended treatment. In addition, the ATLAS trial data does not provide clear direction for treatment of postmenopausal women. 265 There are no data available to suggest that an aromatase inhibitor for 5 years is better for long-term benefit than 10 years of tamoxifen. In the extension study of ABCSG trial 6, hormone receptor-positive postmenopausal patients received 5 years of adjuvant tamoxifen and were randomized to 3 years of anastrozole or no further therapy. 307 At a median follow-up of 62.3 months, women who received anastrozole (n = 387) were reported to have a statistically significantly reduced risk of recurrence compared with women who received no further treatment (n = 469; HR, 0.62; 95% CI, 0.40– 0.96; P = .031). 307 The differences in design and patient populations among the studies of the aromatase inhibitors do not allow for the direct comparison of the results of these studies. A meta-analysis of adjuvant trials of aromatase inhibitors versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented lower recurrence rates with the aromatase inhibitor-containing regimen, with no clear impact on OS. 308 It is not known whether initial, sequential, or extended use of adjuvant aromatase inhibitors is the optimal strategy.

The optimal duration of aromatase inhibitor treatment is also not known, nor is the optimal use vis-à-vis chemotherapy established. Further, the

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