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

Abstract

AbstractPurpose: SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) 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 nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, 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 IHC 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 nonresponders 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 2.23 × 10−5, 2.22 × 10−5, and 2.23 × 10−5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 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 8.34 × 10−5 and 7.98 × 10−4, 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-only treatment in patients with advanced HCC of metabolic origin.

Authors 14

1. Timothy Wai Ho Shuen

   National Cancer Centre Singapore

   Affiliation as printed

   Division of Medical Oncology, National Cancer Centre Singapore, Singapore

2. Marianna Alunni‐Fabbroni

   LMU Klinikum · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Radiology, University Hospital, LMU Munich, Munich, Germany

3. Elif Öcal

   LMU Klinikum · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Radiology, University Hospital, LMU Munich, Munich, Germany

4. Peter Malfertheiner

   LMU Klinikum · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Medicine II, University Hospital, LMU Munich, Munich, Germany

   Department of Radiology, University Hospital, LMU Munich, Munich, Germany

5. Moritz Wildgruber

   LMU Klinikum · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Radiology, University Hospital, LMU Munich, Munich, Germany

6. Regina Schinner

   LMU Klinikum · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Radiology, University Hospital, LMU Munich, Munich, Germany

7. Maciej Pech

   University Hospital Magdeburg · Otto-von-Guericke-Universität Magdeburg

   Affiliation as printed

   Department of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany

8. Julia Benckert

   Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of Hepatology and Gastroenterology, Charit e University Hospital, Berlin, Germany

9. Bruno Sangro

   Clinica Universidad de Navarra

   Affiliation as printed

   Liver Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain

10. Christiane Katharina Kuhl Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    University Hospital of RWTH Aachen, Aachen, Germany

11. Antonio Gasbarrini

    Università Cattolica del Sacro Cuore · Agostino Gemelli University Polyclinic

    Affiliation as printed

    Internal Medicine, Gastroenterology and Hepatic Disease Unit, IRCCS Fondazione; Policlinico Universitario A. Gemelli, Universit a Cattolica del Sacro Cuore, Rome, Italy

12. Pierce K. H. Chow

    National University of Singapore · Singapore General Hospital · SingHealth Duke-NUS Academic Medical Centre · Duke-NUS Medical School · National Cancer Centre Singapore

    Affiliation as printed

    Division of Surgery and Surgical Oncology, Department of Hepatopancreatobiliary and Transplantation Surgery, National Cancer Centre Singapore and Singapore General Hospital, Singapore

    Surgery Academic Clinical Program, Duke-NUS Medical School Singapore, Singapore

13. Han Chong Toh

    National Cancer Centre Singapore

    Affiliation as printed

    Division of Medical Oncology, National Cancer Centre Singapore, Singapore

14. Jens Ricke corresponding

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Radiology, University Hospital, LMU Munich, Munich, Germany