Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00

Abstract

Purpose: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer.

Patients and methods: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths.

Results: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%).

Conclusion: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

Trial registration: ClinicalTrials.gov NCT00022516.

Fig 1.

CONSORT diagram. The flow diagram shows the intent-to-treat population of 1,081 patients included in the primary efficacy analysis of cyclophosphamide + methotrexate (CM) maintenance compared with no CM and the 473 patients included in the treatment/safety population for CM maintenance in International Breast Cancer Study Group (IBCSG) Trial 22-00.

Fig 2.

Kaplan-Meier estimates of disease-free survival (DFS) according to treatment assignment (A) for the intent-to-treat population of International Breast Cancer Study Group Trial 22-00, for the cohort with triple-negative breast cancer (B), and for the cohort with triple-negative, node-positive breast cancer (C). CM, cyclosphosphamide + methotrexate; HR, hazard ratio. P represents the stratified log-rank test P value.

Fig 3.

Results of Cox proportional-hazards models for the comparisons of disease-free survival (DFS) according to treatment assignment among all the patients and according to baseline characteristics. The solid vertical line at 0.84 indicates the overall hazard ratio (HR) estimate for DFS. The P value is a test of heterogeneity of the treatment effect across subgroups, by using a test of treatment-by-variable interaction from a stratified Cox model with unknown omitted from the test. The size of the squares is inversely proportional to the standard error of the HR. CM, cyclosphosphamide + methotrexate; CMF, cyclophosphamide + methotrexate + fluorouracil; HER2, human epidermal growth factor receptor 2.

Fig 4.

Landmark analysis to illustrate relationship between adherence to cyclophosphamide + methotrexate (CM) maintenance and disease-free survival (DFS) for the trial population (A) and for the triple-negative cohort (B), with groupings for CM maintenance at 75% or greater of the scheduled dose; CM maintenance less than 75% of the scheduled dose; and no CM. The 75% dose threshold was prospectively selected to have approximately one third of evaluable CM maintenance patients in the higher-dose group. The landmark population included patients who were alive, in follow-up, and free of a DFS event at the landmark time of 365 days (scheduled duration of CM maintenance) plus 56 days (random assignment window allowance) since the first day of last cycle adjuvant chemotherapy.