NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

cardiac dysfunction appears to be related to both age and baseline left ventricular ejection fraction. An analysis of data from N9831 showed the 3-year cumulative incidence of CHF or cardiac death to be 0.3%, 2.8%, and 3.3% in the arms of the trial without trastuzumab, with trastuzumab following chemotherapy, and with trastuzumab initially combined with paclitaxel, respectively. 347 The acceptable rate of significant cardiac toxicity observed in the trastuzumab adjuvant trials in part reflects rigorous monitoring for cardiac dysfunction. Furthermore, concerns have been raised regarding the long-term cardiac risks associated with trastuzumab therapy based on results of follow-up evaluations of cardiac function in patients enrolled in some of these trials. 349,350 A third trial (HERA) (N = 5081) tested trastuzumab for 1 or 2 years compared to none following all local therapy and a variety of standard chemotherapy regimens in patients with node-positive disease or node-negative disease with tumor ≥1 cm. 222 At a median follow-up of one year, a 46% reduction in the risk of recurrence was reported in those who received trastuzumab compared with those who did not (HR 0.54; 95%, CI 0.43–0.67; P < .0001), no difference in OS, and acceptable cardiac toxicity were reported. The 2-year data indicate that 1 year of trastuzumab therapy is associated with an OS benefit when compared with observation (HR for risk of death = 0.66; 95% CI, 0.47– 0.91; P = .0115). 351 After this initial analysis, patients randomized to chemotherapy alone were allowed to cross over to receive trastuzumab. Intent-to-treat analysis including a crossover patient was reported at 4-year median follow-up. 346 The primary endpoint of DFS continued to be significantly higher in the trastuzumab-treated group (78.6%) versus the observation group (72.2; HR 0.76; 95%, CI 0.66–0.87; P < .0001). At a median follow-up of 8 years, the study reported no significant difference in DFS, a secondary endpoint, in patients treated with

Adjuvant HER2-Targeted Therapy The panel recommends HER2-targeted therapy in patients with HER2 positive tumors (see Principles of HER2 Testing ). Trastuzumab is a humanized monoclonal antibody with specificity for the extracellular domain of HER2. 343 Results of several randomized trials testing trastuzumab as adjuvant therapy have been reported. 221-226,344-346 NSABP B-31 patients with HER2-positive, node-positive breast cancer were randomly assigned to 4 cycles of AC every 3 weeks followed by paclitaxel for 4 cycles every 3 weeks or the same regimen with 52 weeks of trastuzumab commencing with paclitaxel. In the NCCTG N9831 trial, patients with HER2-positive breast cancer that was node-positive, or node-negative, with primary tumors greater than 1 cm in size if ER- and PR-negative or greater than 2 cm in size if ER- or PR-positive, were similarly randomized except that paclitaxel was given by a low-dose weekly schedule for 12 weeks and a third arm delayed trastuzumab until the completion of paclitaxel. The B-31 and NCCTG N9831 trials have been jointly analyzed with the merged control arms for both trials compared with the merged arms using trastuzumab begun concurrently with paclitaxel. There were 4045 patients included in the joint analysis performed at 3.9 years median follow-up. A 48% reduction in the risk of recurrence (HR 0.52; 95% CI, 0.45–0.60; P < .001) and a 39% reduction in the risk of death (HR 0.61; 95% CI, 0.50–0.75; log-rank P = .001) were documented. 345 Similar significant effects on DFS were observed when results of the NSABP B-31 and NCCTG N9831 trials were analyzed separately. Cardiac toxicity was increased in patients treated with trastuzumab. 224,347,348 In the adjuvant trastuzumab trials, the rates of grade III/IV congestive heart failure (CHF) or cardiac-related death in patients receiving treatment regimens containing trastuzumab ranged from 0% (FinHer trial) to 4.1% (NSABP B-31 trial). 221,222,224,226,347,348 The frequency of

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