Nonanthracycline Regimen Plus Trastuzumab Effective in Early Breast Cancer Irrespective of TOP2A Status
Available data suggest that docetaxel plus cyclophosphamide improves disease-free survival and overall survival compared with doxorubicin plus cyclophosphamide in early-stage breast cancer. Other findings suggest that amplification of TOP2A, the gene positioned next to HER2, is predictive of response to anthracyclines. In a phase II study reported in The Lancet Oncology, Stephen E. Jones, MD, of US Oncology Research, and colleagues assessed the addition of 1 year of trastuzumab (Herceptin) to a nonanthracycline regimen of docetaxel/cyclophosphamide as adjuvant therapy in patients with HER2-positive early-stage breast cancer and evaluated the effect of the regimen in TOP2A-amplifed vs TOP2A-nonamplified disease. Similar disease-free survival and overall survival were found in TOP2A-amplifed and TOP2A-nonamplified disease.
Study Details
In this open-label, single-group study, 493 patients aged 18 to 75 years with HER2-positive early-stage breast cancer received four 21-day cycles of docetaxel at 75 mg/m² plus cyclophosphamide at 600 mg/m² plus trastuzumab at 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab at 6 mg/kg every 3 weeks for the remainder of 1 year.
Patients had to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, operable histologically confirmed invasive carcinoma of the breast, and adequate tumor specimen available for fluorescence in situ hybridization analysis of TOP2A status. The primary endpoint was 2-year disease-free survival in TOP2A-amplified and TOP2A-nonamplified patients.
Patients had a median age of 55 years, 87% had ECOG performance status of 0, 58% had stage I disease, 79% had no positive nodes, 22% had tumor size ≤ 1 cm, 65% had estrogen receptor–positive disease, and 47% had progesterone receptor–positive disease.
Disease-Free Survival and Overall Survival
After a median follow-up of 36.1 months, overall 2-year disease-free survival and overall survival rates were 97.8% and 99.2% and overall 3-year disease-free survival and overall survival rates were 96.9% and 98.7%.
Among 190 patients with TOP2A-amplified disease, 2-year disease-free survival was 97.8% (95% confidence interval [CI] = 94.2–99.2) and 2-year overall survival was 99.5% (95% CI = 96.2–99.9); 3-year disease-free survival and overall survival were 97.2% and 98.9%. Among 248 patients with TOP2A-nonamplified disease, 2-year disease-free survival was 97.9% (95% CI = 94.9–99.1) and 2-year overall survival was 98.8% (95% CI = 96.2–99.6); 3-year disease-free survival and overall survival were 96.4% and 98.3%. TOP2A status could not be determined in 55 patients. Among 95 patients with negative nodes and tumor size ≤ 1 cm, disease-free survival and overall survival at 2 and 3 years was 100%.
Toxicity
The most common adverse events of any grade were fatigue (58%), neutropenia (51%), and nausea (45%). The most common grade 3 or 4 adverse events were neutropenia (47%), febrile neutropenia (6%), fatigue (4%), and diarrhea (3%). Dose reductions occurred in 8% of patients, and 8% discontinued study treatment due to study-related adverse events. Two patients died from treatment-related causes, one from aspiration and one from pulmonary infiltration.
Cardiac dysfunction occurred in 6% of patients (grade 3 in 0.4%), and 16 patients (3.3%) stopped trastuzumab due to cardiac dysfunction. Decreases in left-ventricular ejection fraction were mainly asymptomatic. Approximately 5% of patients exhibited a decrease in left-ventricular ejection fraction to less than 50% and almost a quarter had a decrease of 10%, with one patient having congestive heart failure. Other cardiac events were rare.
The investigators concluded, “A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status.”
The study was funded by Sanofi.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
