The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice

ESSENTIALS: Factor Xa (FXa)‐targeting direct oral anticoagulants (DOACs) reduce venous thromboembolism (VTE). The effects of FXa‐targeting DOACs on cancer progression remain to be studied. In xenograft models, a FXa‐targeting DOAC did not inhibit breast cancer growth and metastasis. A thrombin‐targeting DOAC, dabigatran, also did not inhibit breast cancer growth and metastasis. ABSTRACT: BACKGROUND: Factor Xa‐targeting DOACs were recently found to reduce recurrent VTE efficiently in cancer patients when compared to the standard treatment with low‐molecular‐weight heparins (LMWHs). While the anticancer effects of LMWHs have been extensively studied in preclinical cancer models, the effects of FXa‐targeting DOACs on cancer progression remain to be studied. OBJECTIVE: We investigated whether the FXa‐targeting DOAC rivaroxaban and the thrombin‐targeting DOAC dabigatran etexilate (DE) affected human breast cancer growth and metastasis in orthotopic xenograft models. METHODS/RESULTS: Mice that were put on a custom‐made chow diet supplemented with rivaroxaban (0.4 or 1.0 mg/g diet) or dabigatran etexilate (DE) (10 mg/g diet) showed prolonged ex vivo coagulation times (prothrombin time [PT] and activated partial thromboplastin time [aPTT] assay, respectively). However, rivaroxaban and DE did not inhibit MDA‐MB‐231 tumor growth and metastasis formation in lungs or livers of 7‐week‐old fully immunodeficient NOD/SCID/ƴ(C) (−/−) (NSG) mice. Comparable data were obtained for rivaroxaban‐treated mice when using NOD‐SCID mice. Rivaroxaban and DE treatment also did not significantly inhibit tumor growth and metastasis formation when using another human triple negative breast cancer (TNBC) cell line (HCC1806) in NOD‐SCID mice. The FXa and thrombin‐induced gene expression of the downstream target CXCL8 in both cell lines, but FXa and thrombin, did not significantly stimulate migration, proliferation, or stemness in vitro. CONCLUSION: Although effectively inhibiting coagulation, the DOACs rivaroxaban and DE did not inhibit orthotopic growth and metastasis of human TNBC. It remains to be investigated whether DOACs exert antitumorigenic effects in other types of cancer.