This Phase III, randomized, open-label trial will determine whether the regimens of chemotherapy plus trastuzumab plus bevacizumab improve invasive disease-free survival (IDFS) relative to the regimens of chemotherapy plus trastuzumab. Secondary aims include determining whether the addition of bevacizumab to chemotherapy plus trastuzumab will improve disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), and distant recurrence-free interval (DRFI). The benefit of adding bevacizumab for IDFS, DFS, OS, RFI, and DRFI will also be evaluated for each of the two chemotherapy regimens. The cardiac and non-cardiac toxicities of each of the regimens will also be evaluated.~Following local determination that the tumor is HER2-positive for gene amplification by in situ hybridization or is IHC 2+ or 3+, a tumor sample must be submitted for HER2 testing by a designated central laboratory. If central testing confirms that the tumor is HER2-positive (either positive by FISH or IHC 3+) and all other eligibility criteria have been met, the patient will be randomized to a regimen of chemotherapy and trastuzumab with or without bevacizumab.~Patients in the trial will be enrolled in one of two chemotherapy regimen cohorts. One cohort will receive 6 cycles of docetaxel/carboplatin plus trastuzumab (TCH) with or without bevacizumab; the other cohort will receive 3 cycles of docetaxel plus trastuzumab given with or without bevacizumab followed by 3 cycles of 5-Fluorouracil, Epirubicin, Cyclophosphamide (TH-FEC). With both regimens, patients will continue trastuzumab with or without bevacizumab following chemotherapy to complete 1 year of targeted therapy. Following completion of chemotherapy, patients will also receive adjuvant radiotherapy and endocrine therapy as clinically indicated.~The trial will be conducted by investigators affiliated with the Cancer International Research Group (CIRG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP). CIRG and NSABP investigators will only enroll patients in the TCH regimen cohort. Additional investigators, referred to in the protocol as Independent Investigators, will enroll patients in both the TCH regimen or the TH-FEC regimen cohort depending on institutional preference for the one regimen that will be used by that institution for the duration of the trial.~Patients will be given the option of allowing their tumor samples to be used for the BETH translational research and correlative science studies. Also, patients will be asked to consent to the submission of blood and serum samples at scheduled time points during the study.~LVEF assessments will be performed before study entry and then at scheduled time points during therapy and at 18, 36, and 60 months following randomization.~The planned sample size for the trial is 3,000 patients randomized in the faster accruing cohort and a minimum of 3,500 patients overall.
The trial will determine the value of adding bevacizumab to chemotherapy plus trastuzumab in patients with resected node-positive or high risk node-negative, HER2-positive breast cancer.