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Integrative Biomarker Analyses Indicate Etiological Variations in c-Met and Tsc2 Alterations in Hepatocellular Carcinoma

Zhu, Andrew and Chen, David and He, Wei and Kanai, Masayuki and Voi, Maurizio and Chen, Li-Tzong and Daniele, Bruno and Vogel, Arndt and Chiang, Derek (2016) Integrative Biomarker Analyses Indicate Etiological Variations in c-Met and Tsc2 Alterations in Hepatocellular Carcinoma. Journal of Hepatology, 65 (2). pp. 296-304. ISSN 1600-0641

Abstract

Background & Aims: The purpose of this study was to identify potential prognostic biomarkers from baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial, a randomized phase 3 study of everolimus in hepatocellular carcinoma (HCC).

Methods: Circulating plasma levels of bFGF, PLGF, VEGF, VEGF-D, c-Kit, collagen IV, sVEGFR1 and VEGFR2 were measured by ELISA (N=503). Protein levels of IGF-1R, c-Met, mTOR, Tsc2 were assayed by immunohistochemistry (N=125). Genomic DNA sequencing was conducted on a panel of 287 cancer-related genes (N=69).

Results: Patients with baseline plasma concentrations of VEGF or sVEGFR1 above the cohort median had significantly shorter overall survival. These plasma biomarkers retained prognostic significance in a multivariate Cox regression model with geographic region, macroscopic vascular invasion and AFP levels. Membranous c-Met protein levels were significantly lower for Asian patients, as well as for hepatitis B viral etiology. The prevalence of genetic changes were similar to previous reports, along with a trend towards higher PTEN and TSC2 mutations among Asians.

Conclusions: The angiogenesis biomarkers VEGF and sVEGFR1 were independent prognostic predictors of survival in patients with advanced HCC. Potential differences in c-Met and mTOR pathway activation between Asian and non-Asian patients should be considered in future clinical trials.

Item Type: Article
Keywords: everolimus, mTOR, PI-3 kinase pathway, next-generation sequencing
Date Deposited: 12 Aug 2016 00:45
Last Modified: 12 Aug 2016 00:45
URI: https://oak.novartis.com/id/eprint/28603

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