Abstract
Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312-5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448-4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.
Highlights
For patients who were treated with transarterial chemoembolization (TACE)
(2) We focused on proteins on which high-throughput experiments and highly focused biochemical studies have been performed in the 50,208 proteins (Reliability score Ն 3). [3] we selected 1683 proteins that were secreted or might be secreted, per UniProt Knowledgebase (UniProtKB, http://www.uniprot.org/) database
The principal findings of this study relate to the prediction of a good response to sorafenib, based on a quantitative proteomics approach
Summary
For patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy. Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) and Asia-Pacific trials, was the first systemic chemotherapeutic agent that was found to lengthen the survival of patients with unresectable (intermediate to advanced) HCC [5, 6]. These trials demonstrated a modest survival benefit of ϳ3 months over placebo, and several patients with advanced HCC remained refractory to sorafenib [5,6,7]. The response to alpha-fetoprotein (AFP) and a decrease in vascular endothelial growth factor were independent predictors of responsiveness to sorafenib, alone or in combination [12, 13] These on-treatment biomarkers fail to identify who will benefit from sorafenib before treatment is commenced. These studies included a narrow range of candidate proteins in the biomarker discovery stage
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