Abstract 3010: Broad reduction in cancer incidence in patients treated with warfarin: a prospective cohort study

Abstract

Abstract BACKGROUND Evidence shows that the vitamin K-antagonist warfarin, a popular anti-coagulant in clinical use for decades, has anti-tumor activity. This is recently attributed to disruption of post-translational modification of Gas6, the common ligand of the Axl receptor tyrosine kinase family. Gas6-Axl signaling is associated with malignancy and is required for tumoriogenesis and progression in several preclinical cancer models. Warfarin is shown to inhibit Axl signaling-dependent malignant traits and enhance anti-tumor immune responses at doses that do not achieve anticoagulation. The objective of this study is to investigate the association between warfarin use and cancer incidence in a large unselected Norwegian cohort. Our results reveal a remarkable reduction in cancer incidence associated with warfarin use across a wide range of tumor types. METHODS A cohort selected from the Norwegian population registry included all persons born between 1924-1954, living in Norway 2006-2012 (n=1 256 725). We cross-referenced this cohort using the unique Norwegian National ID Number to: 1) the Cancer Registry of Norway and retrieved information on all cancer cases 2006-2012; 2) information on filled warfarin prescriptions (ATC: B01AA03) from the Norwegian Prescriptions Database (2004-2012). Warfarin-use was defined > 6 months and minimum 2 years between first warfarin prescription and cancer diagnosis. We also performed a subgroup analysis on persons prescribed warfarin for atrial fibrillation/flutter (n=33 313) compared to non-users. Mantel-Haenzel method was used to calculate the incidence rate ratio (IRR), adjusting for sex and age. RESULTS In this cohort, 92 942 persons were classified as warfarin users, and we observed 132 687 cancer cases in the 7-year study period. We observed a significantly lower sex and age-adjusted risk for cancer development across all malignancy types in the warfarin user group compared to the non-user group (IRR: 0.842, 95% CI, 0.824-0.861). The association was similar among many cancers including major types (prostate IRR: 0.687,95% CI 0.653-0.722; lung IRR: 0.801, 95% CI 0.749-0.856; breast IRR: 0.903, 95% CI 0.817-0.998). Given the expected confounding effect of thrombotic disease on cancer incidence, we conducted a subgroup analysis among patients prescribed warfarin for atrial fibrillation/flutter (AF-group), a subgroup with reduced comorbidity. Warfarin users in the AF-group showed a stronger overall cancer risk reduction (IRR: 0.619, 95%CI 0.592-0.646), including all major cancer types, particular lung cancer. (Prostate, IRR: 0.604, 95%CI 0.552-0.662; Lung IRR: 0.391, 95%CI 0.332-0.460; Breast IRR: 0.720, 95%CI 0.594-0.871) CONCLUSION We show that warfarin use is associated with a broad cancer protective effect in a large unselected patient cohort. Subgroup analysis of arrhythmia patients to reduce confounders reinforced the notion that warfarin exerts important anti-tumor effects. Citation Format: Gry S. Haaland, Ragnhild S. Falk, Oddbjørn Straume, James B. Lorens. Broad reduction in cancer incidence in patients treated with warfarin: a prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3010. doi:10.1158/1538-7445.AM2017-3010