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



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.

Post author correction


Article Subject: GI-Oncology



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

Article History


Financial support: None.
Conflict of interest: The authors have no conflict of interest to declare.
Trial registration: Clinical trial NCT02786342, version 1.1

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  • Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola (Forlì-Cesena) - Italy
  • Department of Medical Oncology, University Hospital Cagliari, Cagliari - Italy
  • Department of Oncology, San Bortolo General Hospital, ULSS 8 Berica, Vicenza - Italy
  • Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari - Italy
  • Department of Oncology, Pisa University Hospital, Pisa - Italy
  • Unit of Medical Oncology, Hospital of Faenza, AUSL Romagna, Faenza (Ravenna) - Italy
  • Center for the Study of Liver Diseases, Department of Medical Sciences M. Aresu, University of Cagliari, Cagliari - Italy
  • Department of Internal Medicine, University Hospital, Cagliari - Italy
  • Department of Oncology, G. Rummo Hospital, Benevento - Italy
  • Department of General Surgery, Morgagni-Pierantoni Hospiatal, AUSL Romagna, Forlì - Italy
  • Department of Medical and Surgical Sciences, University of Bologna, Bologna - Italy
  • Medical Oncology Unit, University Hospital, Parma - Italy
  • Ultrasound Unit for Infectious Diseases, AORN dei Colli, Cotugno Hospital, Naples - Italy
  • Unit of Internal Medicine, Hospital of Faenza, Faenza (Ravenna) - Italy
  • Medical Oncology 1, Istituto Oncologico Veneto IRCCS, Padua - Italy
  • Biosciences Laboratory, IRST IRCCS, Meldola (Forlì-Cesena) - Italy
  • Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola (Forlì-Cesena) - Italy
  • Medical Oncology Department, Campus Biomedico, University of Rome, Rome - Italy
  • Department of Oncology, Infermi Hospital, Rimini - Italy
  • Internal Medicine Department, Unit of Hepatology, Campus Biomedico, University of Rome, Rome - Italy
  • University Hospital of Modena, Modena - Italy

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