Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial

Abstract

Purpose: SORAMIC is a randomized controlled trial in advanced HCC patients undergoing sorafenib+/- selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction. Experimental Design: The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib-alone. Patients were classified as responders or non-responders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by liquid chromatography-mass spectrometry, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by immunohistochemical staining of liver and tumor tissues and transcriptomics of blood cells. Results: Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and non-responders receiving SIRT+sorafenib and sorafenib-alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP1 were identified as candidate biomarkers at baseline from the 13 responders to SIRT+sorafenib with statistically significant AUC=1 for all and bootstrap p-values 2.23x10-5, 2.22x10-5, and 2.23x10-5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6-9 weeks after combined treatment with significant AUC and bootstrap p-values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC=0.9697 and 0.9192 as well as bootstrap p-values 8.34x10-5 and 7.98x10-4, respectively. HCC tumor was the likely origin of circulating EVs. Conclusions: In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib treatment in patients with advanced HCC of metabolic origin.

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Transarterial Chemoembolization Plus Sorafenib versus Transarterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma: An Umbrella Review of Meta-Analyses and Systematic Reviews

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Research Progress of Extracellular Vesicles-Loaded Microneedle Technology

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