Maintenance Regimen Fails to Improve DFS in HR-Negative Early Breast Cancer

Maintenance therapy with low-dose cyclophosphamide and methotrexate in women with hormone receptor-negative early breast cancer did not improve disease-free survival.

Maintenance therapy with low-dose cyclophosphamide and methotrexate (CM) in women with hormone receptor (HR)-negative early breast cancer did not improve disease-free survival (DFS), according to results of a randomized phase III trial. There was suggestion of benefit in women with triple-negative, node-positive disease.

“There are conflicting results on antitumor activity for chemotherapy administered for a prolonged time,” wrote study authors led by Marco Colleoni, MD, of the European Institute of Oncology in Milan. “Preclinical and clinical studies support the notion that less-toxic, low-dose continuous chemotherapy, also called metronomic chemotherapy, is of clinical value.”

The study tested whether maintenance therapy with such a prolonged, low-dose regimen might be of benefit in 1,086 women (1,081 in the intent-to-treat population) with estrogen receptor– and progesterone receptor–negative early breast cancer with any nodal and HER2 status. The women were randomized to either CM maintenance (542 patients) or to no CM (539 patients) at any point between primary surgery and 56 days after the first day of the last course of adjuvant chemotherapy.

Women in the CM group received oral cyclophosphamide 50 mg/day continuously along with oral methotrexate 2.5 mg twice daily on days 1 and 2 of each week for 1 year. The results were published in the Journal of Clinical Oncology.

After a median follow-up of 6.9 years, the 5-year DFS rate was 78.1% among patients treated with CM, and 74.7% among patients who did not receive CM. The reduction in DFS was not significant, with a hazard ratio (HR) of 0.84 (95% CI, 0.66–1.06; P = .14). A multivariate analysis adjusting for tumor size, nodal status, and use of trastuzumab did not change that result.

The study included 814 patients with triple-negative disease; among those patients, the DFS rate at 5 years was 78.7% with CM therapy and 74.6% without CM therapy. Though the reduction was greater, it still did not reach significance, with an HR of 0.80 (95% CI, 0.60–1.06). The most promising results occurred in those with triple-negative, node-positive disease (340 patients), in whom the 5-year DFS rate was 72.5% with CM and 64.6% without CM, for an HR of 0.72 (95% CI, 0.49–1.05).

There was also a hint that therapy nonadherence could have influenced the results. Patients who received 75% or more of the scheduled CM dose had an HR of 0.62 (95% CI, 0.39–1.0) in favor of CM, while there was no hazard reduction in those who received less than 75% of the dose compared with the group who did not receive CM.

A safety population of 473 patients in the CM group were available for analysis. A total of 64 patients (14%) experienced a grade 3 or 4 treatment-related adverse event. The most frequent event was elevated serum transaminases (which was reversible) (7%), followed by leukopenia (2%).

“We conclude that the addition of CM maintenance treatment should not be recommended for women with HR-negative early breast cancer,” the authors wrote. However, they added, “The trend suggests a positive effect on selected subpopulations,” noting that these results support additional studies of maintenance approaches in high-risk triple-negative patients.