SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib ± selective internal radiation therapy (SIRT). A team led by researchers at the National Cancer Centre Singapore and the University Hospital, LMU Munich investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction.
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.
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.
Identification of predictive EV proteins for SIRT+sorafenib treatment
A, Venn diagram of proteins detected from the EV samples. B, Heatmap of the differential abundance of the 16 EV proteins identified in the SIRT+sorafenib responders. Responders and nonresponders were clustered according to average linkage algorithm using Euclidean distance. Relative expression levels are represented in red and green in the heatmap. C, Abundance of EV-ACTR3 detected from responders and nonresponders from the SIRT+sorafenib group. Mann–Whitney test was used. D, Survival analysis of the patients based on the EV-ACTR3 abundance by log-rank (Mantel–Cox) test. E, ROC analysis of EV-ACTR3 for SIRT+sorafenib treatment.