Background: Preclinical data suggested that significant HCC growth is dependent on angiogenesis.In the ALICE-2 we study patients (PT) receiving sorafenib(S) for HIF-1α,VEGF-A and VEGF-C SNPs.At multivariate analysis rs12434438 of HIF-1α,rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors for PFS and OS. At the combined analysis of significant SNPs the presence of 2 favourable alleles of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS(respectively:10.8 vs. 5.6 vs. 3.7 months,p < 0,0001)and OS(respectively:19.0vs13.5vs7.5months;p < 0,0001).Furthermore the presence of GG genotype of rs12434438 (HIF-1α)select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs(PFS: 2.6 months,p < 0,0001;OS:6.6 months,p < 0,0001).In ePHAS we study PT homozygous for a specific haplotype(Ht1:T-4b at eNOS-786/eNOS VNTR)showed a lower median PFS(2.1vs6.2 months,p < 0.0001)and OS(5.0vs14.9 months, p < 0.0001)compared to other genotypes.Data confirmed in multivariate. On the basis of these data we want to validate in a prospective study the potential role of VEGF,VEGFR,HIF-1,Ang2 and eNOS SNPs in PT with HCC treated with S. Trial design: This is a prospective non pharmacological study. The study population consisted of PT with advanced-stage HCC and PT not eligible for locoregional treatments or liver transplantation.The primary aim of the study is to validated the prognostic or predictive role of eNOS,Ang2,HIF-1, VEGF and VEGFR SNPs in relation to clinical outcome of PT treated with S. The secondary aim of the study is to verify the prognostic value of the basal level of ldh, blood pressure, plasma level of Ang2 and plasma level of VEGF in relation to clinical outcome (progression-free survival and overall survival) of patients treated with S. The study was planned to have a 90% power at the 5% significance level (two-sided) to detect a 42% relative reduction in the progression rate (absolute increase in PFS of 2.5 months). Assuming a 24-month accrual period and a 12-month follow-up, 160 patients were required.
Multicentric prospective study of validation of angiogenesis polymorphisms in HCC patients treated with sorafenib. INNOVATE study / Gardini, A. Casadei; Faloppi, L.; Daniele, B.; Cascinu, S.; Lonardi, S.; Masi, Gabriele; Negri, F.; Santini, D.; Silvestris, N.; Zagonel, V.; Scartozzi, M.. - 27:(2016). (Intervento presentato al convegno ESMO tenutosi a Copenhagen nel 07/10/2016) [10.1093/annonc/mdw371.100].
Multicentric prospective study of validation of angiogenesis polymorphisms in HCC patients treated with sorafenib. INNOVATE study
Gardini, A. Casadei;Cascinu, S.;MASI, GABRIELE;Santini, D.;Scartozzi, M.
2016
Abstract
Background: Preclinical data suggested that significant HCC growth is dependent on angiogenesis.In the ALICE-2 we study patients (PT) receiving sorafenib(S) for HIF-1α,VEGF-A and VEGF-C SNPs.At multivariate analysis rs12434438 of HIF-1α,rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors for PFS and OS. At the combined analysis of significant SNPs the presence of 2 favourable alleles of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS(respectively:10.8 vs. 5.6 vs. 3.7 months,p < 0,0001)and OS(respectively:19.0vs13.5vs7.5months;p < 0,0001).Furthermore the presence of GG genotype of rs12434438 (HIF-1α)select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs(PFS: 2.6 months,p < 0,0001;OS:6.6 months,p < 0,0001).In ePHAS we study PT homozygous for a specific haplotype(Ht1:T-4b at eNOS-786/eNOS VNTR)showed a lower median PFS(2.1vs6.2 months,p < 0.0001)and OS(5.0vs14.9 months, p < 0.0001)compared to other genotypes.Data confirmed in multivariate. On the basis of these data we want to validate in a prospective study the potential role of VEGF,VEGFR,HIF-1,Ang2 and eNOS SNPs in PT with HCC treated with S. Trial design: This is a prospective non pharmacological study. The study population consisted of PT with advanced-stage HCC and PT not eligible for locoregional treatments or liver transplantation.The primary aim of the study is to validated the prognostic or predictive role of eNOS,Ang2,HIF-1, VEGF and VEGFR SNPs in relation to clinical outcome of PT treated with S. The secondary aim of the study is to verify the prognostic value of the basal level of ldh, blood pressure, plasma level of Ang2 and plasma level of VEGF in relation to clinical outcome (progression-free survival and overall survival) of patients treated with S. The study was planned to have a 90% power at the 5% significance level (two-sided) to detect a 42% relative reduction in the progression rate (absolute increase in PFS of 2.5 months). Assuming a 24-month accrual period and a 12-month follow-up, 160 patients were required.
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