Multicenter prospective study of angiogenesis polymorphism validation in HCC patients treated with sorafenib. An INNOVATE study protocol.

Andrea Casadei‐Gardini ,Luca Faloppi,Giorgio Ercolani,Jody Corbelli,Nicola Silvestris,Alessandro Leonetti,Daniele Santini,Giuseppe Aprile,Davide Tassinari,Daniele Bruno,Caterina Vivaldi,Vincenzo Dadduzio,Mario Scartozzi,Emanuela Scarpi,Chiara Caparello,Luchino Chessa,Vittorina Zagonel,Giovanni Luca Frassineti,Giorgia Marisi,Marianna Silletta,Lorenzo Calvetti,Flavia Pagan,Gianluca Masi,Emiliano Tamburini,Francesco Giuseppe Foschi,Oronzo Brunetti,Arianna Lanzi,Stefano Cascinu,Francesca Negri ,Umberto Vespasiani Gentilucci ,G De Stefano ,Nunzia Farella

doi:10.5301/tj.5000704

Abstract

Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.

Highlights

Sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet
Overall, our data may suggest that polymorphism analysis of the vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), Hypoxia-inducible factor (HIF) and endothelium-derived nitric oxide synthase (eNOS)
This nonpharmacological, interventional, prospective multicenter study is aimed at determining whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, progression-free survival (PFS) and overall survival (OS) of advanced HCC patients treated with sorafenib

Summary

Introduction

Sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS). Patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. In the ALICE-1 study [8], in univariate analysis VEGF-A alleles. Allele C of rs2010963 and allele T of rs4604006 of VEGF-A proved to be independent factors influencing both PFS and OS. In the ALICE-2 study [9], single nucleotide polymorphisms (SNPs) of HIF-1α were analyzed. The GG genotype of rs12434438 characterized a population with a poor outcome regardless of the clinical

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