ENOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: Final results of the ePHAS Study

Abstract

Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progressionfree survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.Oncotarget 27989 www.impactjournals.com/oncotarget

ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

“…With regard to NOS3 , we conducted an updated follow-up of our previously described case series [6] and we added seven patients. By univariate analysis we confirmed that patients with at least one copy of the minor allele C for NOS3 rs2070744T > C polymorphisms had a significantly better outcome, with higher median PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) and OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) than those of patients homozygous for the T allele (Table 3 and Figure 3).…”

“…The selection of three NOS3 polymorphisms ( NOS3 rs2070744; VNTR 4a/b and NOS3 rs1799983) and genotyping analyses of these were described in our previous study [6].…”

“…In our previous retrospective study, we analyzed three endothelium-derived nitric oxide synthase ( NOS3 ) polymorphisms located inside the NOS3 gene on chromosome 7. We demonstrated that patients with the NOS3 rs2070744 ( NOS3-786 ) TT genotype had significantly shorter median progression-free survival (PFS) and overall survival (OS) when compared to those with other genotypes [6].…”

Is the era of sorafenib over? A review of the literature

“…Scientists have showed that polymorphisms of ATP binding cassette (ABC) subfamily B member 1 ( ABCB1 ), ATP binding cassette subfamily G member 2 ( ABCG2 ), endothelial nitric oxide synthase ( eNOS ), and solute carrier family 15 member 2 ( SLC15A2 ) may be associated with the effect of sorafenib. 10–12 Silvia et al showed that using β-caryophyllene oxide can inhibit ABC proteins and induce the chemosensitization of HCC cells to sorafenib. 13 However, there is insufficient evidence indicating an exact relationship between these factors and the response to sorafenib.…”

Multicenter prospective study of angiogenesis polymorphism validation in HCC patients treated with sorafenib. An INNOVATE study protocol

“…In the ePHAS study (14), a training cohort of 41 HCC patients and a validation cohort of 87 patients receiving sorafenib were analyzed. At univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS (2.6 vs. 5.8 months, p<0.0001) and OS (3.2 vs.14.6 months, p = 0.024) than those with other haplotypes.…”