The evidence for adding trastuzumab to the above regimen in HER-2 positive patients comes from the combined results of 2 trials, the B-31 trial and the N9831 trial, that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER 2 positive (FISH+ or IHC3+) breast cancer.rr
The National Surgical Adjuvant Breast and Bowel Project B-31 trial enrolled node positive women and compared the following 2 regimens:
- Group 1: 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by 4 cycles of paclitaxel every 3 weeks (or weekly x 12) (n=1046)
- Group 2: 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by 4 cycles of paclitaxel every 3 weeks (or weekly x 12) plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (n=1055)
The North Central Cancer Treatment Group N9831 trial enrolled node positive and high risk node negative women and compared 3 regimens:
- Group A: 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by weekly paclitaxel x 12 (n=971)
- Group B: 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by weekly paclitaxel x 12 followed by 52 weeks of trastuzumab (initiated after paclitaxel) (n=1216)
- Group C: 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by weekly paclitaxel plus 52 weeks of trastuzumab (initiated concurrently with paclitaxel) (n=973)
The studies were combined to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel.
The primary end point was disease free survival (DFS) and secondary end points included overall survival (OS), time to distant recurrence, death from breast cancer, contralateral breast cancer and other second primary cancers.
Link to Breast adjuvant/neoadjuvant paclitaxel weekly protocol for additional evidence supporting the use of weekly paclitaxel in adjuvant breast cancer.r
Efficacy
After a median follow-up of 3.9 years, women randomly assigned to the trastuzumab arm had a significantly increased DFS (86% v 74%, HR 0.52, 95% CI 0.45 to 0.60; p<0.001) and OS (93% v 86%, HR 0.61, 95% CI 0.50 to 0.75; p<0.001) compared with women randomly assigned to the control arm.
Kaplan-Meier estimates of (A) disease-free survival and (B) overall survivalr
© Journal of Clinical Oncology 2011
Summary of efficacyr
© Journal of Clinical Oncology 2011
Toxicity
The principal adverse event associated with trastuzumab therapy among patients with prior exposure to anthracycline is cardiac dysfunction.
In the B-31 trial, the 7-year cumulative incidence of cardiac events (symptomatic congestive heart failure or probable or definite cardiac death) was 1.3% in the control group and 4.0% in the concurrent trastuzumab group.r The relative risk of a cardiac event was 3.30 in trastuzumab treated patients versus patients in the control arm.r
In the N9831 trial, at a median follow-up of 3.75 years, the 3-year cumulative incidence of cardiac events (symptomatic congestive heart failure or probable or definite cardiac death) was 0.3% in the control group and 3.3 % in the concurrent trastuzumab group.r
Other adverse events which appeared to be related to trastuzumab included rare cases of interstitial pneumonitis. In the B-31 trial, 4 patients in the trastuzumab group had interstitial pneumonitis, 1 of whom died.r In the N9831 trial, 5 patients in the trastuzumab group had greater than or equal to grade 3 pneumonitis or pulmonary infiltrates, 1 of whom died.r