Abstract 3436: Mechanisms of paraneoplastic thrombocytosis in ovarian carcinoma

Abstract

Abstract Objective: The observation that thrombocytosis (platelet count >450,000/μL) occurs in patients with solid malignancies was made over 100 years ago. However, the underlying mechanisms and clinical implications of paraneoplastic thrombocytosis in epithelial malignancies such as ovarian carcinoma are poorly understood and are the focus of the current study. Methods: Following IRB approval, clinical parameters and initial complete blood counts (CBC) were evaluated in 608 epithelial ovarian cancer patients. Plasma levels of key megakaryopoietic factors thrombopoietin, IL-1α, IL-3, IL-4, IL-6, IL-11, G-CSF, GM-CSF, stem cell factor, and FLT-3 ligand were assayed in a subset of 150 patients at the time of initial diagnosis with advanced stage, high grade epithelial ovarian cancer using a Luminex immunobead-based cytokine profiling platform. For animal studies, CBCs were measured in control mice as well as syngeneic (2 cell lines) and orthotopic (3 cell lines) mouse models of ovarian cancer. Megakaryocytes in spleen and bone marrow were quantified by bright-field microscopy. Results: Human study: Thirty-two percent of patients had thrombocytosis at initial diagnosis. Compared to patients with normal platelet counts, women presenting with thrombocytosis were significantly more likely to have advanced stage disease (p=0.013) and poor mean progression-free (1.29 vs 2.73 years, p<0.001) and overall survival (3.01 vs 6.05 years, p<0.001). On multivariate analysis, thrombocytosis remained an independent predictor of decreased overall survival. Plasma levels of megakaryopoietic factors IL-6 and G-CSF significantly correlated with platelet counts (r=0.33, p<0.01 and r=0.18, p=0.03). Animal study: Paraneoplastic thrombocytosis was recapitulated in both syngeneic and orthotopic mouse models of ovarian cancer. Platelet counts were increased by 27-200% in mice bearing invasive ovarian tumors compared to controls (p<0.01) and platelet counts significantly correlated with tumor burden (r=0.61, p<0.05). Thrombocytosis was accompanied by a non-significant increase in leukocytes and decrease in red blood cells. Mean platelet count in the peripheral blood strongly correlated with mean megakaryocyte counts in spleen and bone marrow (r=0.95, p<0.05). Conclusions: Our data provide additional insight into the clinical significance and etiology of paraneoplastic thrombocytosis in ovarian cancer patients. In vivo studies evaluating the effect of silencing tumor cell production of IL-6 and G-CSF on paraneoplastic thrombocytosis using human-specific siRNA sequences are ongoing. Paraneoplastic thrombocytosis and the interaction between platelets and cancer cells could be targets for developing novel therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3436.