P18.07.A MODULATION OF CIRCULATING EXTRACELLULAR VESICLE LEVELS IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA BY BEVACIZUMAB: A SECONDARY ANALYSIS OF THE ARTE TRIAL

Abstract BACKGROUND The use of blood-derived extracellular vesicles (EV) for non-invasive monitoring of response to therapy and outcome in patients with glioblastoma has gained significant attention in recent years. However, many factors, such as age or treatment regimens, may affect the yield and quality of isolated EV, potentially limiting the diagnostic information that can be derived from such liquid biopsies. Here, we investigated the effect of bevacizumab (AvastinΤΜ), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), on total and tumour-derived EV from serum of patients with newly diagnosed glioblastoma undergoing hypofractionated radiotherapy in the ARTE trial (NCT01443676). Despite the absence of a survival benefit beyond subgroup analyses in any randomized clinical trial, bevacizumab remains, in some countries, one of the few approved treatments for patients with glioblastoma. MATERIAL AND METHODS We conducted a retrospective analysis of patient serum samples from the control (Arm B, n = 21) and experimental (Arm A, n = 30) arm of the randomised, open-label, phase II ARTE clinical trial. EV were isolated from 500 μL of serum with size exclusion chromatography. Isolated EV were characterised using nano-particle tracking analysis and flow cytometry. Total EV number and tumour-derived EV proportion, based on EV-associated tumor markers, were compared between the two arms as well as between baseline and progression. Additionally, EV counts and proportions were correlated to available clinical parameters, including tumour volume. RESULTS There were treatment-related changes in total EV numbers between baseline and progression. Examining different timepoints, we observed a steady increase in total EV count from baseline to progression in arm B (control), while in arm A (experimental) a decrease of total EV count was observed. In addition, the proportion of tumour-derived EV positively correlated with enhancing tumour volume as well as necrosis and edema volume in both groups. Similarly, a negative correlation between tumour-derived EV proportion and progression free survival was identified. CONCLUSION Bevacizumab, an anti-angiogenic agent, reduces total and tumour-derived EV numbers in blood, most likely via its interference with the growth and permeability of blood vessels at the tumour site, illustrating that co-medications need to be considered as confounding factors when assessing for the diagnostic performance of liquid biopsy approaches.