Trastuzumab trial results stunning’ in early-stage HER2-positive breast cancer
Results from recent published trials have shown much promise in the use of trastuzumab (Herceptin) plus adjuvant chemotherapy in patients with HER2-positive early-stage breast cancer.
Patients are considered HER2-positive if they have overexpression of the HER2 protein, amplification of the HER2 gene, or both, researchers say. This occurs in about 15-25% of breast cancers, and is an aggressive form of the disease.
The results of these trials were published in the Oct. 20 issue of the New England Journal of Medicine. The first Phase III trial, HERA, involved women with HER2-positive early-stage invasive breast cancer who completed therapy (surgery with or without radiotherapy) and a minimum of four courses of chemotherapy. Endocrine therapy, primarily tamoxifen, was given after chemotherapy to women with hormone receptor-positive disease unless contraindicated.
Researchers randomly assigned 1,694 women to two years of treatment with trastuzumab, 1,694 women to one year of trastuzumab, and 1,693 women to observation. The published findings, however, report only the results of treatment with trastuzumab for one year or observation.
As compared with observation after primary therapy, trastuzumab given after primary therapy reduced the rate of recurrence by approximately 50%. A total of 127 disease-free survival events were reported in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for the risk of an event in the trastuzumab group, as compared with the observation group, corresponded to an absolute benefit in disease-free survival of 8.4 percentage points at two years. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity, a possible side effect of the drug, developed in 0.5% of the women who were treated with trastuzumab.
The second article presents the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.
The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every three weeks (Group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (Group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (Group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (Group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (Group C). The studies were amended 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 researchers say.
The results included 2,043 patients enrolled in trial B-31, 1,736 of whom with at least one follow-up evaluation. In trial N9831, 1,633 patients had been enrolled in Groups A and C; 1,615 of these patients had follow-up data submitted.
The median follow-up was 2 years (2.4 years in trial B-31 and 1.5 years in trial N9831). There were 261 events in the control group and 133 events in the trastuzumab group. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12% at three years. Trastuzumab therapy was associated with a 33% reduction in the risk of death. (There were 62 deaths in the trastuzumab group, as compared with 92 deaths in the control group.) The three-year cumulative incidence of Class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1% in trial B-31 and 2.9% in trial N9831.
Results might change treatment plans
The results of the studies are stunning, says Gabriel N. Hortobagyi, MD, professor of medicine and chairman of the department of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. His comments appeared in an editorial accompanying the trial results.
"On the basis of these results, our care of patients with HER2-positive breast cancer must change today," he writes. "Certainly, patients with lymph node-positive, HER2-positive breast cancer should receive trastuzumab as part of optimal adjuvant systemic therapy, unless the antibody is clearly contraindicated. Patients with negative lymph nodes, whose estimated risk of recurrence after optimal chemotherapy and endocrine therapy comfortably exceeds the risk of the cardiac toxic effects of trastuzumab, should also be offered the antibody. Since most HER2-positive tumors have other adverse prognostic factors, this risk-benefit scenario is likely to apply to many patients with node-negative breast cancer."
The results do raise some questions, Hortobagyi says. What is the optimal schedule for therapy with trastuzumab: Should it be given with or after chemotherapy? More research should also determine how to deal with the trastuzumab-induced heart problems that trastuzumab can cause, he adds.
The results of these studies are not "evolutionary but revolutionary," concludes Hortobagyi. "The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow. However, trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer."
Results from recent published trials have shown much promise in the use of trastuzumab (Herceptin) plus adjuvant chemotherapy in patients with HER2-positive early-stage breast cancer.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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