Luca Faloppi1,2, Marco Puzzoni2, Andrea Casadei Gardini3, Nicola Silvestris4, Gianluca Masi5, Giorgia Marisi3, Caterina Vivaldi5, Cosmo Damiano Gadaleta4, Pina Ziranu2, Maristella Bianconi6, Cristian Loretelli7, Laura Demurtas2, Eleonora Lai2, Riccardo Giampieri8, Eva Galizia1, Paola Ulivi3, Nicola Battelli1, Alfredo Falcone5, Stefano Cascinu9, Mario Scartozzi10,11. 1. Medical Oncology Unit, Macerata General Hospital, ASUR Marche AV3, Macerata, Italy. 2. Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. 3. Medical Oncology Unit, IRCSS-IRST, Meldola, Italy. 4. Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy. 5. Medical Oncology Unit, University of Pisa, Pisa, Italy. 6. Medical Oncology Unit, San Benedetto del Tronto Hospital, ASUR Marche AV5, San Benedetto del Tronto, Italy. 7. International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. 8. Oncology Department, Polytechnic University of Marche, Ancona, Italy. 9. Medical Oncology Unit, University of Modena, Modena, Italy. 10. Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. marioscartozzi@gmail.com. 11. Oncologia Medica, Azienda Ospedaliera Universitaria Cagliari, Presidio Policlinico Universitario "Duilio Casula", S.S. 554, Km 4,500 Bivio per Sestu, Monserrato, CA, 09042, Italy. marioscartozzi@gmail.com.
Abstract
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.
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.
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Authors: Dario Spanu; Andrea Pretta; Eleonora Lai; Mara Persano; Clelia Donisi; Stefano Mariani; Marco Dubois; Marco Migliari; Giorgio Saba; Pina Ziranu; Valeria Pusceddu; Marco Puzzoni; Giorgio Astara; Mario Scartozzi Journal: World J Hepatol Date: 2022-07-27