ecent Advances With Targeted Therapies in the Treatment of Breast Cancer— Targeting HER2 in Breast Cancer: Current Results and Future Potential
Source: Recent Advances With Targeted Therapies in the Treatment of Breast Cancer
By: Edith A. Perez, MD
Joint Analysis of NSABP B-31 and NCCTG N9831
A joint analysis of the combined results of 2 large trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 and the North Central Cancer Treatment Group (NCCTG) trial N9831, was undertaken to determine the clinical benefit of adding concurrent trastuzumab to adjuvant chemotherapy in women with surgically resected HER2-positive breast cancer, as determined by either IHC (HER2, 3+) or FISH (
Capsule Summary).[15] Disease-free survival was the primary endpoint of this analysis.
The B-31 trial randomized patients to either doxorubicin/cyclophosphamide every 3 weeks for 4 cycles followed by paclitaxel every 3 weeks for 4 cycles vs an identical regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel. In the 3-arm N9831 trial, patients in arm A received doxorubicin/cyclophosphamide every 3 weeks for 4 cycles followed by weekly paclitaxel for 12 weeks; patients in arm B received the same regimen followed by 52 weeks of trastuzumab given after completion of paclitaxel; and patients in arm C received the same regimen as arm B, except that trastuzumab was given concurrently with paclitaxel instead of sequentially. In the joint analysis the chemotherapy-only group from B-31 and the control group (arm A) from N9831 were compared with the chemotherapy-trastuzumab group from the former study and the arm C from the latter. Data from arm B of the N9831 study were excluded from this analysis since trastuzumab was given sequentially rather than concurrently with paclitaxel.[15]
Patient age, the number of positive nodes, and hormone receptor characteristics were equally distributed among the control and the trastuzumab groups in both trials (
Table 2).[15] The majority of patients were younger than 60 years of age. The B-31 trial did not have any patients with node-negative breast cancer, compared with approximately 12% of patients in the N9831 trial who did. For both N9831 treatment groups analyzed, more than 48% of patients had 1-3 positive nodes, and less than 15% of patients had more than 10 positive nodes.
Both trials opened to enrollment in 2000 and by early 2005, a total of 394 events had been reported, prompting the first interim analysis.[15] Observed adverse events included recurrent disease, second primary cancer, or death before recurrence. In the trastuzumab groups, 133 adverse events were reported, compared with 261 events in the control group (hazard ratio [HR] for first event in trastuzumab groups vs control: 0.48;
P < .0001). Disease-free survival (defined as percentage of patients alive and disease-free at 3 years) was 87.1% for the trastuzumab group and 75.4% for the control group, for an absolute difference of 12% at 3 years. This difference increased to 18% at 5 years (
Figure 2). Treatment with trastuzumab also resulted in a 33% reduction in the risk of death (
P = .015). Trastuzumab was generally well tolerated, with cardiotoxicity occurring in 4.1% of B-31 trial patients and 2.9% of N9831 trial patients.
These data strongly support the addition of trastuzumab and paclitaxel after chemotherapy with doxorubicin/cyclophosphamide to improve clinical outcome in patients with early-stage, HER2-positive breast cancer.[15]
Cross-Study Comparison of N9831/B-31 With HERA( the European adjuvant Herceptin trial)
Although cross-study comparisons must be interpreted with caution, it may be useful to look at results from the 2 large national studies and the international trial with trastuzumab. In all 3 trials, the addition of trastuzumab to chemotherapy improved clinical outcome despite the fact that only 6% of patients in the B-31/N9831 trials were node negative vs 33% of patients in the HERA trial.[15,16] Concurrent administration of trastuzumab with chemotherapy showed early benefits (92% DFS at 2 years), but with longer treatment duration (2.6 to 3.0 years) there was no difference in concurrent vs sequential trastuzumab therapy (87% vs 86% DFS, respectively) (
Table 3). Interestingly, a 2-year DFS of only 77% in the chemotherapy-only arm was observed in the HERA study, despite the presence of node-negative disease in one third of patients.[16] This outcome will likely change with longer follow-up, but it may suggest that the chemotherapy used in the HERA trial has a different effect on clinical outcome, compared with the treatments used in the B-31 and N9831 studies, in patients with HER2-positive breast cancer. It is also possible that the hormone therapy given to patients in the HERA study may account for this discrepancy.
note: Both articles above are by E. Perez. from a very recent Clinical Care Options CME.
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