Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE-2 Study

• Published in: Targeted oncology Vol. 15; no. 1; pp. 115 - 126
• Main Authors: Faloppi, Luca, Puzzoni, Marco, Casadei Gardini, Andrea, Silvestris, Nicola, Masi, Gianluca, Marisi, Giorgia, Vivaldi, Caterina, Gadaleta, Cosmo Damiano, Ziranu, Pina, Bianconi, Maristella, Loretelli, Cristian, Demurtas, Laura, Lai, Eleonora, Giampieri, Riccardo, Galizia, Eva, Ulivi, Paola, Battelli, Nicola, Falcone, Alfredo, Cascinu, Stefano, Scartozzi, Mario
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2020; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis; Biomedicine; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Clinical outcomes; Female; Genotype; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Inhibitor drugs; Liver cancer; Liver Neoplasms - blood supply; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Male; Medicine; Medicine & Public Health; Middle Aged; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Oncology; Original Research Article; Polymorphism, Single Nucleotide; Prognosis; Retrospective Studies; Sorafenib - adverse effects; Sorafenib - therapeutic use; Studies; Targeted cancer therapy; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor Receptor-1 - genetics
• ISSN: 1776-2596; 1776-260X; 1776-260X
• DOI: 10.1007/s11523-020-00698-x

Background Sorafenib represents one of the therapeutic strongholds for advanced hepatocellular carcinoma (HCC), but unfortunately, predictive factors are lacking. We previously reported that the VEGF single nucleotide polymorphisms (SNPs) rs2010963 and rs4604006 might correlate with clinical outcomes in sorafenib-treated HCC patients. Objective The objective of the ALICE-2 study is to define a prognostic angiogenesis profile to better identify HCC patients who are more likely to benefit from sorafenib treatment. Patients and methods From 2008 to 2015, all consecutive HCC patients receiving sorafenib according to the Italian label were tested for specific HIF - 1α , VEGF , and VEGFR SNPs. Results from angiogenesis genotyping were then correlated with clinical outcome parameters. Results Globally, a total of 210 patients were enrolled. At multivariate analysis rs12434438 of HIF1α , rs2010963 of VEGF - A , and rs4604006 of VEGF - C were confirmed as independent predictive factors. At the combined analysis of significant SNPs, the presence of two favourable alleles of rs2010963 and rs4604006 of VEGF compared to only one or to none favourable alleles, was able to identify three separate patients populations with different time-to-progression (TTP) (10.8 vs. 5.6 vs. 3.7 months, respectively; p  < 0.0001) and overall survival (OS) (19.0 vs. 13.5 vs. 7.5 months, respectively; p  < 0.0001). Furthermore, the presence of the GG genotype of rs12434438 ( HIF - 1α ) seemed able to select a population with a particularly poor outcome, independently from the clinical effect of the two VEGF SNPs (TTP: 2.6 months, HR: 0.54, p  = 0.0374; OS: 6.6 months, p  = 0.0061, HR: 0.43). Conclusions Our findings show that polymorphism analysis of HIF - 1α , VEGF , and VEGFR genes may represent a prognostic panel to better identify HCC patients who are more likely to benefit from sorafenib treatment.