Research Papers:
eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study
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Abstract
Andrea Casadei Gardini1,*, Giorgia Marisi2,*, Luca Faloppi3, Emanuela Scarpi4, Francesco Giuseppe Foschi5, Massimo Iavarone6, Gianfranco Lauletta7, Jody Corbelli8, Martina Valgiusti1, Floriana Facchetti6, Cristina della Corte6, Luca Maria Neri9, Stefano Tamberi8, Stefano Cascinu3, Mario Scartozzi10, Dino Amadori1, Oriana Nanni4, Elena Tenti1, Paola Ulivi2,**, Giovanni Luca Frassineti1,**
1Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
2Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
3Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
4Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
5DPT Internal Medicine, Faenza Hospital, AUSL Romagna, Faenza, Italy
6A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
7Department of Biomedical Sciences and Human Oncology, Internal Medicine “G. Baccelli”, University of Bari “A. Moro”, Bari, Italy
8Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy
9Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
10Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
*These first authors contributed equally to this work
**These authors have contributed equally to this work
Correspondence to:
Giorgia Marisi, e-mail: [email protected]
Keywords: hepatocellular carcinoma, endothelial nitric oxide synthase, single nucleotide polymorphisms, biomarkers, angiogenesis
Received: February 08, 2016 Accepted: March 28, 2016 Published: April 4, 2016
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.
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PII: 8569