title: 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 progression-free 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.
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casadei Gardini
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Marisi
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Faloppi
authors.affiliation: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.affiliation: DPT Internal Medicine, Faenza Hospital, AUSL Romagna, Faenza, Italy.
authors.forename: Francesco Giuseppe
authors.initials: FG
authors.lastname: Foschi
authors.affiliation: A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Iavarone
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Internal Medicine "G. Baccelli", University of Bari "A. Moro", Bari, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Lauletta
authors.affiliation: Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy.
authors.forename: Jody
authors.initials: J
authors.lastname: Corbelli
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Valgiusti
authors.affiliation: A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Della Corte
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Luca Maria
authors.initials: LM
authors.lastname: Neri
authors.affiliation: Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tamberi
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.affiliation: Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Nanni
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tenti
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Frassineti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: angiogenesis; biomarkers; endothelial nitric oxide synthase; hepatocellular carcinoma; single nucleotide polymorphisms