Investigating Aspirin and Ticagrelor for the prevention of tumour cell-induced platelet aggregation

Abstract

Background:Tumour-cell induced platelet aggregation (TCIPA) increases the metastatic potential ofcancer. Mechanisms include protection of tumour cells from immune destruction,interaction of platelet receptors with tumour ligands to facilitate adhesion, andenrichment of the tumour microenvironment, promoting extravasation andproliferation. Use of antiplatelet agents could reduce TCIPA, resulting in reducedmetastatic progression and increased patient survival. Ticagrelor, a P2Y12 antagonist, isan antiplatelet medication used in cardiovascular disease. To date, this has not beeninvestigated for the reduction of TCIPA in cancer patients. This study investigated theeffects of Ticagrelor and aspirin as monotherapy and dual therapy in metastatic breastand colorectal cancer patients.Method:Blood was collected from healthy volunteers and patients with metastatic cancer. Theinitial study focused on assay development, and in vitro experiments investigatingplatelet activation. An interventional study investigated platelet activation in healthydonors and patients with metastatic breast or colorectal cancer. Participants wererandomised to receive aspirin or Ticagrelor for 2 weeks, followed by a 2-week washoutand crossover to the other monotherapy, before completing 2 weeks of dualtherapy. Blood samples were taken at baseline and the end of each treatment. Lighttransmission aggregometry assessed platelet reactivity in terms of spontaneousaggregation and aggregation response to agonists. Flow cytometry measured theactivation status of the platelets by the amount of P-selectin expression, fibrinogenbinding and Annexin-V binding. Extracellular vesicles were quantified by flowcytometry, and cell-free DNA by qPCR; these were explored as potential biomarkers.Results:17 healthy volunteers and 57 metastatic cancer patients provided blood samples for theinitial study. Cancer patients had significantly higher amounts of spontaneousaggregation and levels of P-selectin expression compared to healthy volunteers. 20healthy people, 10 breast and 6 colorectal cancer patients started the interventionalstudy. Colorectal patients had higher spontaneous aggregation at baseline, which couldbe significantly reduced by Ticagrelor. Breast patients had higher amounts of fibrinogenbinding at baseline, and this was significantly reduced by Ticagrelor.Conclusion:Platelets from cancer patients are hyperreactive, as evidenced by their ability tospontaneously aggregate, and the higher expression of platelet activation markers.These platelets have a high sensitivity to P2Y12 inhibition, and Ticagrelor reduced theactivation of platelets with a low incidence of patient adverse outcomes. This warrantslarger studies into Ticagrelor as an adjunct to anticancer treatment and potentialprophylactic treatment for cancer-associated venous thromboembolism.