Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00

Abstract Purpose: To explore whether specific triple-negative breast cancer (TNBC) molecular subtypes are predictive for a benefit from maintenance low-dose cyclophosphamide and methotrexate (CM) in the adjuvant IBCSG 22–00 phase III clinical trial. Experimental Design: RNA sequencing was performed on a selection of 347 TNBC formalin-fixed paraffin-embedded (FFPE) tumor samples following a case–cohort-like sampling. TNBC subtypes were computed on gene expression data. The association between TNBC subtypes and treatment outcome was assessed using a Cox proportional-hazards interaction test. Results: Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM [disease-free survival (DFS): HR, 0.5; 95% confidence interval (CI), 0.28–0.89; Pinteraction = 0.018 and HR, 0.49; 95% CI, 0.27–0.9; Pinteraction = 0.021]. Moreover, a high expression of regulatory T-cell immune signature was associated with a better prognosis in the CM arm, in line with a potential immunomodulating role of cyclophosphamide. In contrast, a worse outcome was observed in tumors with a mesenchymal (M) subtype treated with low-dose CM (DFS: HR, 1.9; 95% CI, 1.2–3; Pinteraction = 0.0044). Conclusions: Our results show a differential benefit of low-dose CM therapy across different TNBC subtypes. Low-dose CM therapy could be considered as a potential strategy for TNBC tumors with IM subtype in the early-disease setting.