Multicenter prospective proof-of-concept study of digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer

The presence of circulating tumor cell (CTC) clusters is associated with disease progression and reduced survival in a variety of cancer types. In breast cancer, preclinical studie showed that inhibitors of Na⁺/K⁺ ATPase suppress CTC clusters and block metastasis. A multicenter, prospective proof-of-concept trial in Switzerland evaluated the impact of treatment with the Na⁺/K⁺ ATPase inhibitor digoxin on mean CTC cluster size in women with metastatic breast cancer (mBC). In nine mBC patients treated daily with a maintenance digoxin dose (0.7-1.4 ng/ml serum level) the mean cluster size decreased with -2.2 cells per cluster upon treatment, meeting the primary endpoint of the study. Transcriptome profiling of CTCs highlighted downregulation of cell-cell adhesion and cell cycle-related genes upon treatment with digoxin. No treatment-related adverse events occurred. The authors conclude that these data provide a first-in-human proof-of-principle that digoxin treatment leads to a partial CTC cluster dissolution.