Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways. What's new? The tyrosine kinase inhibitor sorafenib, which is directed against vascular endothelial growth factor (VEGF), is considered to be the standard of treatment for hepatocellular carcinoma (HCC). Nevertheless, some tumors fail to respond to the drug, possibly owing to variations in the VEGF gene. Here, investigation of single nucleotide polymorphisms (SNPs) in VEGF and VEGFR in HCC patients who received sorafenib reveals that certain SNPs are significant predictors of progression free survival and overall survival. The identified SNPs may represent valuable assets in the identification of HCC patients who are likely to benefit from sorafenib treatment. © 2014 UICC.

VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib : The ALICE-1 study / M. Scartozzi, L. Faloppi, G. Svegliati Baroni, C. Loretelli, F. Piscaglia, M. Iavarone, P. Toniutto, G. Fava, S. De Minicis, A. Mandolesi, M. Bianconi, R. Giampieri, A. Granito, F. Facchetti, D. Bitetto, S. Marinelli, L. Venerandi, S. Vavassori, S. Gemini, A. D’Errico, M. Colombo, L. Bolondi, I. Bearzi, A. Benedett, S. Cascinu. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - 135:5(2014 Sep 01), pp. 1247-1256. [10.1002/ijc.28772]

VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib : The ALICE-1 study

C. Loretelli;F. Facchetti;S. Vavassori;
2014

Abstract

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways. What's new? The tyrosine kinase inhibitor sorafenib, which is directed against vascular endothelial growth factor (VEGF), is considered to be the standard of treatment for hepatocellular carcinoma (HCC). Nevertheless, some tumors fail to respond to the drug, possibly owing to variations in the VEGF gene. Here, investigation of single nucleotide polymorphisms (SNPs) in VEGF and VEGFR in HCC patients who received sorafenib reveals that certain SNPs are significant predictors of progression free survival and overall survival. The identified SNPs may represent valuable assets in the identification of HCC patients who are likely to benefit from sorafenib treatment. © 2014 UICC.
angiogenesis; hepatocellular carcinoma; rs2010963; rs4604006; single nucleotide polymorphisms; sorafenib; VEGF; Adult; Aged; antineoplastic agents; carcinoma, hepatocellular; cell proliferation; disease-free survival; drug resistance, neoplasm; female; genotype; humans; liver neoplasms; lymphangiogenesis; male; middle aged; neovascularization, pathologic; niacinamide; phenylurea compounds; polymorphism, single nucleotide; protein kinase inhibitors; retrospective studies; treatment outcome; vascular endothelial growth factor a; vascular endothelial growth Factor C; vascular endothelial growth Factor Receptor-1; vascular endothelial growth Factor Receptor-2; vascular endothelial growth Factor Receptor-3; oncology; cancer research
Settore MED/06 - Oncologia Medica
Settore MED/04 - Patologia Generale
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/13 - Biologia Applicata
Settore MED/03 - Genetica Medica
1-set-2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/570219
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