Evaluation of circulating tumor cells in association with platelets as a manner to identify and prevent tromboembolic events

Abstract

Venous thromboembolism (VTE) is a common complication in patients with active cancer. Cancer patients are at risk of developing a VTE 4 to 7 times higher than the general population, and it is associated with an annual recurrence rate of 21%, bleeding risk of 12%, leading to the need for anticoagulation for a long period and cessation of chemotherapy. Chemotherapy increases the risk of VTE. The neoplasms with the highest incidence of VTE are the pancreas and stomach. In general, higher rates are observed in patients with more advanced stages. There are no validated methods capable of predicting VTE in cancer patients. In 2007, Khorana et al published the validation of a predictor model for thrombosis in patients undergoing chemotherapy, with the aforementioned variables. Circulating Tumor Cells (CTCs) may be involved in the activation of coagulation, as they express tissue factor (TF), which activates the coagulation cascade. On the other hand, platelets and fibrin mesh form a "coating" around the CTCs, protecting them from lysis by NK cells. CTCs and platelet microemboli facilitate adhesion to the endothelium. Platelets and neutrophils represent predictive markers of thromboembolic events. Primary objective: to assess the incidence of VTE in patients with advanced gastric or pancreatic cancer and to correlate with the presence of CTM ( circulating tumor microemboli) and CTCs in blood samples at the beginning of treatment. Secondary objectives: - to assess the presence of CTC and CTM at the time of diagnosis of VTE; - verify the variation of CTCs and CTM levels with institution of anticoagulant therapy; - to assess the correlation between CTCs and CTM levels at baseline and at the time of thrombosis with progression-free and global survival; - to verify the expression of glycosphingolipids in CTCs and CTMs and its correlation with the presence of thromboembolic events; - compare the performance of the Khorana model with and without CTCs. This will be a prospective study, with two centers (ACCamargo Cancer Center and UNIFESP), observational, longitudinal to be carried out through the collection of whole blood and clinical data from patients with gastrointestinal tumors (patients with locally advanced or metastatic pancreatic cancer and patients with metastatic gastric cancer). Blood collection will be performed at up to three times: at the beginning of systemic treatment, at the detection of thrombosis by any indicator (clinical or by an incidental finding of imaging) and for the patients with thrombosis, after three months of treatment with oral anticoagulants. The sample was estimated at 100 patients with these two tumors, which are the most associated with VTE. Blood samples (10 mL) will be collected in tubes containing EDTA, and filtered by ISET technology. After filtration, membranes will be examined and CTCs characterized by cytopathological analysis. For analysis of markers in CTCs we will do immunocytochemistry. Laboratory data, including total number of neutrophils, lymphocytes, platelet count, tumor markers, albumin and C-reactive protein (CRP) levels will be obtained at the same time as the CTCs collections. We hope to be able to help clinicians prevent thromboembolic events in their patients by using CTCs and CTMs as biomarkers, which will bring benefits in terms of costs and patient survival. Also, if CTCs and CTM levels decrease after the use of oral anticoagulants, we can use these tools as predictors of treatment success. (AU)