Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study

Purpose: After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of NOS3 and ANGPT2 polymorphisms in HCC patients treated with sorafenib [NCT02786342]. Experimental Design: This prospective multicenter study was conducted at 10 centres in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437).The primary outcome was progression free survival (PFS), while secondary outcomes included overall survival (OS) and disease-control rate (DCR). Results:165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 vs 2.4 months, HR 0.43, p=0.0007) and OS (15.7 vs 8.6 months, HR 0.38, p<0.0001) compared to TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS(2.4 vs 5.7 months, HR 1.93,p=0.0833) and OS(15.1 vs 13.0 months, HR 2.68,p=0.55) when compared to the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR 0.50, p=0.0128) and OS (HR 0.29,p=0.0041). Conclusions:The INNOVATE study met the primary endpoint, confirming that advanced HCC patients with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients