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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Local ablative therapies are established treatment modalities in the treatment of early- and intermediate-stage hepatocellular carcinoma (HCC). Systemic effects of local ablation on circulating immune cells may contribute to patients’ response. Depending on their activation, myeloid cells are able to trigger HCC progression as well as to support anti-tumor immunity. Certain priming of monocytes may already occur while still in the circulation. By using flow cytometry, we analyzed peripheral blood monocyte cell populations from a prospective clinical trial cohort of 21 HCC patients following interstitial brachytherapy (IBT) or radiofrequency ablation (RFA) and investigated alterations in the composition of monocyte subpopulations and monocytic myeloid-derived suppressor cells (mMDSCs) as well as receptors involved in orchestrating monocyte function. We discovered that mMDSC levels increased following both IBT and RFA in virtually all patients. Furthermore, we identified varying alterations in the level of monocyte subpopulations following radiation compared to RFA. (A) Liquid biopsy liquid biopsy of circulating monocytes in the future may provide information on the inflammatory response towards local ablation as part of an orchestrated immune response.

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

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