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

• Grant number: 21/01045-4
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2022
• End date: June 30, 2024
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Ludmilla Thomé Domingos Chinen
• Grantee: Ludmilla Thomé Domingos Chinen
• Host Institution: Hospital do Coração (HCor). Associação do Sanatório Sírio. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Celso Abdon Lopes de Mello ; Felipe José Fernandez Coimbra ; Guilherme Yazbek ; Nora Manoukian Forones ; Rachel Simões Pimenta Riechelmann ; Rubens Chojniak ; Victor Hugo Fonseca de Jesus ; Virgílio Souza e Silva

Abstract

Venous thromboembolism (VTE) is a common complication in patients with active cancer. Patients with cancer have a 4 to 7 times higher risk of developing VTE compared to the general population. VTE is associated with an annual recurrence rate of 21% and a bleeding risk of 12%. This often leads to the need for prolonged anticoagulation therapy and interruption of chemotherapy. Chemotherapy itself increases the risk of VTE, and breast cancer is a malignancy with a high incidence of VTE. Generally, higher rates of VTE are observed in patients with more advanced stages of cancer. Currently, there are no validated methods capable of predicting VTE in cancer patients.In 2007, Khorana et al published a predictive model for thrombosis validation in patients undergoing chemotherapy, utilizing the aforementioned variables. Circulating Tumor Cells (CTCs) may play a role in coagulation activation as they express tissue factor (TF), which initiates the coagulation cascade. On the other hand, platelets and fibrin networks form a "coat" around CTCs, shielding them from natural killer (NK) cell lysis. Microemboli composed of CTCs and platelets facilitate adhesion to the endothelium. Platelets and neutrophils serve as predictive markers for thromboembolic events.Primary Objective: To assess the association of VTE in patients with advanced/metastatic breast and gynecological tumors with the presence of Circulating Tumor Microemboli (CTMs) and CTCs in blood samples at the onset of treatment.Secondary Objectives:Evaluate the presence of CTCs and CTMs at the time of VTE diagnosis.Examine the variation of CTC and CTM levels with the introduction of anticoagulant therapy.Assess the correlation between baseline CTC and CTM levels at the time of thrombosis with progression-free and overall survival.Investigate the expression of glycosphingolipids in CTCs and CTMs and their correlation with the presence of thromboembolic events.Compare the performance of Khorana's model with and without CTCs.This prospective, observational, longitudinal study will involve the collection of complete blood samples and clinical data from patients with locally advanced or metastatic breast and gynecological tumors. Blood samples will be collected at up to three points: at the beginning of systemic treatment, upon detection of thrombosis by any indicator (clinical or incidental imaging findings), and for patients with thrombosis, after one month of anticoagulant treatment. The estimated sample size is 200 patients. Blood samples (10 mL) will be collected in tubes containing EDTA and filtered using ISET technology. Following filtration, the membranes will be examined, and CTCs will be characterized through cytopathological analysis. Immunocytochemistry will be employed for marker analysis on CTCs. Laboratory data, including total neutrophil count, lymphocyte count, platelet count, tumor markers, albumin levels, and C-reactive protein (CRP) levels, will be obtained at the same time points as CTC collections.We hope that by utilizing CTCs and CTMs as biomarkers, we can assist physicians in preventing thromboembolic events in their patients, leading to cost savings and improved patient survival. Additionally, if CTC and CTM levels decrease after anticoagulant use, we may use these tools as predictors of treatment success. (AU)