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The benefits of adding trastuzumab (Herceptin) to adjuvant chemotherapy for early HER2-positive breast cancer are durable, according to an updated analysis of two practice-changing phase III trials.
The new combined analysis of the North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trials shows the hazard of disease recurrence decreased by 52%, and the hazard of death decreased by 35% in women with resected breast cancer who had trastuzumab (Herceptin) added to adjuvant regimens.
Overall survival at 4 years was 92.6% with the addition of trastuzumab vs. 89.4% with chemotherapy alone (hazard ratio 0.65, P = .0007). Disease-free survival was 85.9% and 73.1%, respectively, at 4 years (HR 0.48, P less than .00001). The results are "dramatic," presenter Dr. Edith A. Perez, the Serene M. and Frances C. Durling Professor of Medicine, Mayo Clinic, Jacksonville, Fla., acknowledged.
The two trials were combined because both had a control arm of chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel) alone and a concurrent arm of chemotherapy plus 52 weeks of trastuzumab.
In the first joint analysis, trastuzumab was associated with a 33% reduction in the risk of death and a 52% reduction in risk of recurrence at 3 years (N. Engl. J. Med. 2005;353:1673-84). The 3-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes with trastuzumab was 4.1% in trial B-31, and 2.9% in trial N9831. The primary end point was disease-free survival.
The updated analysis included 3,968 patients. Accrual was completed in April of 2005. At that time, the interim results were unblinded because of the striking results, and patients in the chemotherapy-alone arms of the trials were permitted to cross over to trastuzumab. In all, 413 patients from both trials did so. The data cutoff for the updated analysis was January 2007, with a median follow-up of 2.9 years.
In the intent-to-treat analysis presented by Dr. Perez, there were 397 events and 210 deaths in 1,979 patients on chemotherapy alone, compared with 222 events and 147 deaths among 1,989 patients in the chemotherapy plus trastuzumab group. Cardiac toxicity remained the same in both the first and second joint analyses.
Women with estrogen receptor-positive and/or progesterone receptor-positive breast cancer had better disease-free survival than those with estrogen receptor- and progesterone receptor-negative disease: 89.4% vs. 81.7% with trastuzumab and 76.9% vs. 68.2% with chemotherapy alone.
Establishing correct HER2+ status in women under consideration for trastuzumab treatment is imperative, Dr. Perez said. Initially, both trials included women whose status was determined in local laboratories. After the first 100 patients, the protocols were revised to require confirmation by central testing. Women with tumors confirmed by central testing to be HER2 positive had a 53% improvement in disease-free survival with trastuzumab (P=< .0001), compared with women with HER2-negative tumors.
Genentech Inc., manufacturer of trastuzumab, provided trastuzumab and partial funding for both studies, but did not participate in the research under an agreement with the National Cancer Institute, which sponsored the studies.
Perez E.A. et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Abstract 512.
Commentary |
The benefits gained from addition of trastuzumab to anthracycline- and taxane-based chemotherapy for early stage, primarily node-positive, HER2 overexpressing breast cancer remain one of the most significant advances in the treatment of breast cancer since adjuvant hormonal therapy was discovered to benefit women with hormone receptor positive disease. Although we still need to understand the advantages of trastuzumab in lower-risk, node-negative disease, this updated analysis demonstrates a marked reduction in recurrence and death from breast cancer among women who received trastuzumab in the two combined trials. The data hold up with an additional 1 year of follow-up—and despite the fact that many women on the control arm went on to receive trastuzumab after the trials were unblinded. Data from the North Central Cancer Treatment Group study suggest that patients who tested positive locally but had subsequent negative testing upon central assessment benefited from the addition of trastuzumab. One interpretation is that a subset of patients whose tumors have lower expression of HER2 could benefit from HER2-directed therapy. It must be stressed that this intriguing evaluation is still very preliminary and requires validation in larger data sets before a change in treatment guidelines could be recommended. — Hope S. Rugo, M.D.
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