In an international, multicenter, randomized trial , women with HER2-positive breast cancer were assigned to either one or two years of treatment with trastuzumab (a recombinant monoclonal antibody against HER2; n=3388) or to observation (n=1693). Eligible patients had histologically confirmed, completely excised invasive breast cancer with HER2 overexpression or amplification, and had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group was 0.54 (95% CI 0.43 to 0.67; p<0.0001), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab.
After median follow-up of 23.5 months (range 0–48 months) 97/ 1698 (5.7%) patients randomised to observation alone and 58/1703 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up . 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47–0.91; p=0.0115, NNT 37). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54–0.76; p<0.0001, NNT 15.8).
The combined results of two trials comparing 52 weeks of trastuzumab either in combination with or after paclitaxel, following a regimen of doxorubicin and cyclophosphamide, included follow-up data of 3351 women with surgically removed HER2-positive breast cancer. Of the 394 events (recurrent, second primary cancer, or death before recurrence) triggering the first scheduled interim analysis, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; p<0.0001). The result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (p=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 2.9–4.1 percent.