Kurzeder, ChristianNguyen-Sträuli, Bich DoanKrol, IlonaRing, AlexanderCastro-Giner, FrancescNüesch, ManuelAsawa, SimranZhang, Yu WeiBudinjas, SelinaGvozdenovic, AnaVogel, MarenKöhler, AngelaKuhar, Cvetka GrašičSchwab, Fabienne D.Heinzelmann‐Schwarz, ViolaWeber, William P.Rochlitz, ChristophVorburger, DeniseFrauchiger-Heuer, HeikeWitzel, IsabellWicki, AndreasKuster, Gabriela M.Vetter, MarcusAceto, Nicola2025-05-272025-05-272025-05-242025-01-2410.1038/s41591-024-03486-6https://infoscience.epfl.ch/handle/20.500.14299/250641The 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 studies showed that inhibitors of the Na + /K + ATPase suppress CTC clusters and block metastasis. Here we conducted a prospective, open-label, proof-of-concept study in women with metastatic breast cancer, where the primary objective was to determine whether treatment with the Na + /K + ATPase inhibitor digoxin could reduce mean CTC cluster size. An analysis of nine patients treated daily with a maintenance digoxin dose (0.7–1.4 ng ml −1 serum level) revealed a mean cluster size reduction of −2.2 cells per cluster upon treatment ( P = 0.003), meeting the primary endpoint of the study. Mechanistically, transcriptome profiling of CTCs highlighted downregulation of cell–cell adhesion and cell-cycle-related genes upon treatment with digoxin, in line with its cluster-dissolution activity. No treatment-related adverse events occurred. Thus, our data provide a first-in-human proof of principle that digoxin treatment leads to a partial CTC cluster dissolution, encouraging larger follow-up studies with refined Na + /K + ATPase inhibitors and that include clinical outcome endpoints. ClinicalTrials.gov identifier: NCT03928210 .entext::journal::journal article::research article