Substantial benefits persisted at 4-year follow-up and were also seen in patients who crossed over to trastuzumab.

The benefits of trastuzumab are well established for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (whether early or advanced). The current standard is 1 year of trastuzumab therapy, but the optimal duration of treatment in the adjuvant setting remains unknown. The Herceptin Adjuvant (HERA) trial is an ongoing international, multicenter, randomized, phase III trial involving >5000 women with HER2-positive, early stage breast cancer who completed local regional therapy (surgery with or without radiation therapy) and at least 4 cycles of chemotherapy (adjuvant, neoadjuvant, or both). Patients were randomly assigned to observation or trastuzumab for 1 or 2 years. At median follow-up of 1 year, disease-free survival (DFS) was significantly better in patients who received trastuzumab than in those who did not (hazard ratio, 0.54); thus, the trial protocol was amended to allow crossover for patients without recurrence who did not receive trastuzumab initially. Subsequent analysis at median follow-up of 2 years showed that, compared with chemotherapy alone, the addition of trastuzumab was associated with better DFS (HR, 0.64) and overall survival (OS; HR, 0.66; JW Oncol Hematol Feb 5 2007).

Now, HERA investigators report data on trastuzumab versus observation at median follow-up of 4 years in an analysis that incorporated the effect of crossover from observation to trastuzumab. The study population included 1698 patients initially randomized to observation and 1703 patients to trastuzumab for 1 year.

Intent-to-treat (ITT) analysis of DFS showed a substantial benefit in the trastuzumab group versus observation (4-year DFS: 78.6% vs. 72.2%; HR, 0.76); however, ITT analysis of OS showed no significant difference in risk for death (4-year OS: 89.3% and 87.7%; HR, 0.85). In all, 885 of 1698 patients in the observation group (52%) ultimately crossed over to trastuzumab, beginning treatment a median of 22.8 months after initial randomization. DFS outcomes in these patients were substantially better than in those who remained on observation.

Comment: These results reaffirm that the addition of trastuzumab significantly improves outcomes of patients with early stage, HER2-positive breast cancer. A more nuanced view discloses additional insights. Most trials have shown incremental improvement in survival with concurrent chemotherapy plus trastuzumab as opposed to the sequential approach in the HERA trial. The HERA trial also suggests that late administration of trastuzumab (i.e., long after adjuvant chemotherapy has been completed) can confer significant benefit to patients who did not receive trastuzumab at the outset of treatment. However, such an approach is unlikely to be adopted or tested in prospective clinical trials because standard of care dictates that anti-HER2 therapy be instituted soon after completion of local therapy.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology