Low-dose oral cyclophosphamide plus methotrexate maintenance therapy yielded no disease-free survival benefit in women with hormone receptor–negative early breast cancer, according to the phase III International Breast Cancer Study Group (IBCSG) 22-00 trial. Some evidence of benefit was observed in patients with triple-negative, node-positive disease. Marco Colleoni, MD, of the European Institute of Oncology, Milan, Italy, and colleagues reported these findings in the Journal of Clinical Oncology.
In the open-label trial, 1,081 patients with estrogen receptor– and progesterone receptor–negative early breast cancer and any nodal and HER2 status were randomized between primary surgery and 56 days after the first day of the last course of adjuvant chemotherapy to cyclophosphamide/methotrexate maintenance (n = 542; cyclophosphamide at 50 mg/d continuously and methotrexate at 2.5 mg twice/d on days 1 and 2 of every week for 1 year) or to no cyclophosphamide/methotrexate (n = 539).
Patients were enrolled from 32 sites in the United States, Europe, and elsewhere between November 2000 and December 2012. The primary endpoint was disease-free survival.
Median follow up was 6.9 years. Disease-free survival at 5 years was 78.1% in the cyclophosphamide/methotrexate group vs 74.7% in the no-cyclophosphamide/methotrexate group (hazard ratio [HR] = 0.84, P = .14). Five-year disease-free survival was 78.7% vs 74.6% among 814 patients with triple-negative disease (HR = 0.80, 95% confidence interval [CI] = 0.60–1.06) and 72.5% vs 64.6% among 340 patients with triple-negative and node-positive disease (HR = 0.72, 95% CI = 0.49–1.05).
Overall, 13% of patients randomized to receive cyclophosphamide/methotrexate maintenance did not start cyclophosphamide/methotrexate. Among patients receiving at least 75% of the scheduled cyclophosphamide/methotrexate maintenance, the disease-free survival hazard ratio was 0.62 (95% CI = 0.39–1.0) vs the no-cyclophosphamide/methotrexate group.
Among the 473 patients who received at least one cyclophosphamide/methotrexate maintenance dose, grade 3 or 4 treatment-related adverse events occurred in 14%, with the most common being elevated serum transaminases (7%) and leukopenia (2%). Two patients in the cyclophosphamide/methotrexate group developed acute myeloid leukemia.
The investigators concluded: “Cyclophosphamide plus methotrexate maintenance did not produce a significant reduction in [disease-free survival] events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the triple-negative, node-positive subgroup supports additional exploration of this strategy in the triple-negative, higher-risk population.”
The study was supported by the IBCSG, Swedish Cancer League, Cancer Council Australia, Australia and New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Swiss Cancer League/ Oncosuisse, and U.S. National Cancer Institute. ■
Colleoni M, et al: J Clin Oncol. June 20, 2016 (early release online).