Abstract 4706: Biomarker selection defines a subgroup of hepatocellular carcinoma (HCC) patients with poor prognosis who are candidates for MET inhibition strategy
Authors: Tijeras-Raballand Annemilai , Albuquerque Miguel , Neuzillet Cindy , Colnot Nathalie , Bladt Friedhelm , Ihling Christian , Klevesath Manfred , Zheng Hongxia , Raymond Eric , Gramont Armand de , Faivre Sandrine , Paradis Valérie 
Published: May 2015

Abstract
Background: In HCC, acquired resistance to receptor tyrosine kinase receptors has been associated with an increased expression and activation of the c-MET pathway. In addition, initial data suggest that carbonic anhydrase 9 (CA9), a hypoxia marker, is associated with HCC development. The aim of this study was to correlate c-MET and CA9 expression levels by immunochemistry with clinicopathologic characteristics and disease-free survival (DFS) in patients with HCC.
Materials and Methods: One-hundred HCC resection specimens were evaluated by immunohistochemistry. Staining results were qualitatively and quantitatively assessed and correlated with clinicopathologic parameters. We elaborated our own dedicated macro, using ImageJ software, for automated evaluation. c-MET high and CA9 high expression were defined as moderate to strong staining. Univariate analyses were performed using Fisher's exact or chi square test, and multivariate analyses using Cox regression model. Median DFS were calculated by Kaplan-Meier method.
Results: Patients were mainly males (84%). Tumors were classified as BCLC A1 (92%), uninodular (53%), low-AFP-expressing (82%), moderately differentiated (63%), and with pathologic vascular invasion (71%). c-MET high expression was observed in 51% of tumors and was higher in patients with viral hepatitis-associated HCC (p=0.02) and in patients with AFP&gt;400UI/L (p=0.03). CA9 high expression was observed in 41% of tumors and was correlated with viral hepatitis (p=0.002), pathological vascular invasion (p=0.007), and poor differentiation (p=0.007). c-MET and CA9 expression levels significantly correlated with each other (p=0.008). Median DFS was shorter in the c-MET high (12.9 months, vs &gt;80 months in c-MET low patients; p=0.018) and CA9 high (10.2 months, vs 34.4 months in CA9 low patients; p=0.02) populations. Comparison of c-MET and CA9 status discriminated 3 groups with distinct prognosis. The shortest median DFS was 10.7 months in the c-MET high / CA9 high group, whereas median DFS was not reached in the c-MET low / CA9 low group (p=0.003). The group comprising c-MET high / CA9 low and c-MET low/ CA9 high expressing patients was defined as an intermediate risk populations (DFS=19 months). In a multivariate analysis, smaller tumor size (p=0.025), uninodular morphology (p=0.004), and CA9-low levels (p=0.007) were independently associated with a prolonged DFS. In addition, c-MET high expression level was significantly associated with shorter DFS when CA9 was excluded from the model (p=0.024). Data on c-MET amplification will be added.
Conclusion: c-MET expression is a useful prognostic marker in HCC that could be used for patient stratification. Patients with HCC overexpressing c-MET and CA9 represent a subgroup with a particularly poor prognosis who might benefit from therapy with c-MET inhibitors.
Citation Format: Annemilai Tijeras-Raballand, Miguel Albuquerque, Cindy Neuzillet, Nathalie Colnot, Friedhelm Bladt, Christian Ihling, Manfred Klevesath, Hongxia Zheng, Eric Raymond, Armand de Gramont, Sandrine Faivre, Valérie Paradis. Biomarker selection defines a subgroup of hepatocellular carcinoma (HCC) patients with poor prognosis who are candidates for MET inhibition strategy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4706. doi:10.1158/1538-7445.AM2014-4706