NEW ORLEANS—Addition of trastuzumab(Drug information on trastuzumab) (Herceptin) to standard anthracycline-containing chemotherapy in the neoadjuvant setting led to a dramatic increase in the frequency of pathological complete remissions in patients with operable HER-2-positive breast cancer. Aman Buzdar, MD, professor of breast medical oncology, M.D. Anderson Cancer Center, presented the results of the phase III trial at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 520).
In the study, eligible patients with histologically confirmed invasive breast cancer (T1-3, N0-1, M0) were identified as HER-2-positive by immunocytochemistry or fluorescence in situ hybridization (FISH), and randomized to a control arm involving a regimen of four cycles of paclitaxel, followed by four cycles of fluorouracil(Drug information on fluorouracil)/epirubicin/cyclophosphamide (FEC) or, in the experimental arm, to the same regimen plus weekly trastuzumab 2 mg/kg. All drugs were given intravenously, and the total duration of the chemotherapy was 24 weeks.
The principal endpoint of the trial was pathological complete response (CR), defined as the absence of tumor in the breast and axilla, determined by surgery at the end of the chemotherapy.
The trial aimed at an enrollment of 162 patients, but was terminated at an intermediate point by an independent Data Monitoring Committee, with only 42 participants enrolled, when it became clear from a completed analysis of 34 of these patients that the trastuzumab arm was clearly superior; the Bayesian predictive probability of reaching the same conclusion if the trial were continued to its initial planned enrollment was 95%.
Pathological Complete Response
Among the 42 patients, pathological CR was achieved in 26.3% of patients (5 of 19) in the control arm, and 65.2% (15 of 23) in the trastuzumab arm (P = .016). "In patients treated with trastuzumab, residual disease in the breast was significantly smaller, compared with the chemotherapy-alone group," Dr. Buzdar said. Similarly, a higher proportion of patients treated with trastuzumab had either no residual disease in the nodes or only one to three positive nodes, but this trend did not reach significance (see Table). Subgroup analysis indicated that this superiority obtained for both ER-positive and ER-negative patients.
Adverse Events
The only significant difference in adverse events between treatment and control arms was a higher incidence of grade 4 neutropenia among patients in the trastuzumab arm (91% vs 58%; P = .03), but the incidence of fever during neutropenia was the same (47%) for both arms.
The data regarding cardiac function were especially encouraging, as combined trastuzumab/chemotherapy regimens had been found to contribute to cardiac toxicity in earlier work, and the anthracyclines in particular are known to carry this risk. Epirubicin(Drug information on epirubicin) (Ellence) was, in fact, chosen as the anthracycline component for this study, as it is somewhat less cardiotoxic than other members of this drug class.
Decrease in cardiac ejection fraction (greater than 10%) was seen in six and four patients in the control and trastuzu-mab arms, respectively, but returned to normal in subsequent follow-up. Most importantly, no patients experienced any clinically relevant cardiotoxicity.
Dr. Buzdar concluded that the improvement in pathological CR in this trial was most likely the result of employing two sequential therapeutic regimens (FEC plus trastuzumab) as neoadjuvant treatment. Currently, all patients with HER-2-positive local breast cancer at M.D. Anderson are being offered this combination as neoadjuvant therapy. While the control arm of the trial has been suspended, efficacy and toxicity data continue to be collected from new HER-2-positive patients who follow this protocol. Subsequent follow-up will be required to establish whether this approach contributes to increased patient survival, Dr. Buzdar said.
