PD-010Multicentric prospective study of validation of angiogenesis-related gene polymorphisms in hepatocellular carcinoma patients treated with sorafenib: results of INNOVATE study

Introduction: Sorafenib, an oral multi-kinase inhibitor, represents the standard of care for advanced hepatocellular carcinoma (HCC), even if a large number of patients have limited efficacy with respect to toxic effects. Biomarkers of efficacy or resistance have yet to be identified. In two retrospective studies, we analyzed endothelial-derived nitric oxide synthase (eNOS) and angiopoietin-2 (ANGPT2) polymorphisms and at univariate analysis, patients with the eNOS-786TT genotype and ANGPT2rs55633437 TT/GT genotypes had significantly shorter median progression-free survival (PFS) and overall survival (OS) compared to those with other genotypes. On the basis of these preliminary results, our aim was to validate this data in a prospective study of patients with HCC treated with sorafenib (NCT02786342). Methods: This is a prospective Italian multicenter study, that included 137 HCC patients receiving sorafenib. We analyzed eNOS-786T>C and ANGPT2rs55633437G>T by Real Time PCR method or direct sequencing in relation to the primary endpoint (OS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. Results: One hundred thirty seven HCC patients (122 males and 15 females), prospectively treated with sorafenib from May 2015 to September 2018 were included. Median age was 69 years (range 28-88 years). A total of 120 patients had Child-Pugh A and 17 had Child-Pugh B7. Thirty-nine had BCLC-B and 98 patients had BCLC-C. At univariate analysis, we confirmed that the eNOS-786 TT genotype was significantly associated with a lower median OS than the other genotypes (8.8 vs 15.7 months; HR 1.57; 95% CI, 1.02-2.44; P = .0418). For ANGPT2 rs55633437 we highlighted no difference between GG versus TT-GT genotypes (HR 0.72; 95% CI, 0.37-1.42; P = .35). Following adjustment for clinical covariates (age, gender, etiology, BCLC stage, serum α-FP level, MELD score, eNOSand ANGPT2), multivariate analysis confirmed eNOS- 786 and portal vein thrombosis as independent prognostic factors predicting OS (TT vs TC+CC: HR 2.13; 95% CI, 1.08-4.22; P =.0291; Portal vein thrombosis, yes vs no: HR 2.39; 95% CI, 1.16-4.93; P = .0175). Conclusion: Our prospective study confirmed that the eNOS-786 TT genotype may be capable of identifying a subset of HCC patients who have a lower median OS than the other genotypes. ANGPT2 polymorphism was not confirmed as a predictor of outcome.