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

Abstract

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 nitric oxide synthase <i>3</i> (<i>NOS3</i>) and <i>ANGPT2</i> polymorphisms in patients with HCC treated with sorafenib [NCT02786342]. This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for <i>NOS3</i> (rs2070744) and <i>ANGPT2</i> SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate. A total of 165 patients were enrolled between March 2016 and June 2018. <i>NOS3</i> rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; <i>P</i> = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; <i>P</i> < 0.0001) compared with TT genotype. There was no statistically significant association between <i>ANGPT2</i> rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; <i>P</i> = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; <i>P</i> = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed <i>NOS3</i> as an independent prognostic factor for PFS (HR = 0.50; <i>P</i> = 0.0128) and OS (HR = 0.29; <i>P</i> = 0.0041). The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with <i>NOS3</i> rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.