Abstract 3824: c-MET as a prognostic biomarker and therapeutic target in patients with poor prognostic pancreatic adenocarcinoma following surgical resection
Authors: NEUZILLET Cindy , CROS Jérôme , TIJERAS-RABALLAND Annemilaï , MOROCH Julien , MESTIER Louis DE , BEDOSSA Pierre , PARADIS Valérie , SAUVANET Alain , BACHET Jean-Baptiste , GRAMONT Armand DE , CVITKOVIC Esteban , RAYMOND Eric , HAMMEL Pascal , COUVELARD Anne 
Published: May 2015

Abstract
Context: Pancreatic ductal adenocarcinoma (PDAC) displays a prominent desmoplastic stromal reaction, leading to tumor hypoxia and driving a selective pressure towards cancer cells with aggressive phenotype. Activation of the HGF/c-MET pathway is involved in tumor-stroma interactions and promotes PDAC cells proliferation, invasion, EMT, and stem cellness. As a background for identifying tumors that could benefit from MET inhibitors, we set a study looking at c-MET expression in PDAC and its association with clinical/pathological features, hypoxia, and survival.
Patients and methods: Patients who underwent curative surgical resection for PDAC and received no adjuvant chemotherapy (“pure” prognostic value) were selected for this study. c-MET expression was assessed using immunochemistry and graded on a scale (combining the intensity of staining and the % of stained cells) from 0 to 4, along with the microenvironment characteristics as defined by HIF-1α and CA9 immunostaining (hypoxia), CD31 expression (microvascular density [MVD]), and stroma abundance. Clinical, pathological, and molecular biomarkers have been correlated with disease-free (DFS) and overall (OS) survivals.
Results: thirty-seven patients have been analyzed in this study. Twenty-seven percent of tumors (10/37) were c-MET high (score ≥ 3). High c-MET expression was associated with moderate/poor differentiation (p = 0.017), presence of isolated tumor cells in the stroma (p = 0.023), and low stroma abundance (r = -0.445, p = 0.0074), but not with hypoxia-related markers (HIF-1α, CA9, or MVD). High c-MET expression was associated with shorter DFS (median: 7.7 vs 33.0 months, HR = 2.207, p=0.025) and OS (median: 12.1 vs 38.9 months, HR = 2.207, p=0.0099) than low c-MET expression in PDAC. High c-MET expression combined with tumor size &gt; 20 mm and lymph node ratio (defined as the ratio of lymph nodes with tumor metastasis to the total lymph nodes dissected) &gt; 0.20 predicted risk of early local or distant recurrence (RFS &lt; 12 months) with an AUC = 0.833. Results of computer-assisted evaluation of c-MET expression, and correlation between c-MET expression assessed on entire tumor section and tissue microarray will be presented.
Conclusion: c-MET appears to be a strong prognostic marker in resected PDAC that may help to identify patients at high risk of early recurrence. c-MET was not correlated with hypoxia in this study, but was associated with aggressive tumor features (poor differentiation, isolated tumor cells in the stroma, low stroma abundance). PDAC overexpressing c-MET may represent a subgroup candidate for intensified adjuvant treatment or clinical trials with MET inhibitors.
Citation Format: Cindy NEUZILLET, Jérôme CROS, Annemilaï TIJERAS-RABALLAND, Julien MOROCH, Louis DE MESTIER, Pierre BEDOSSA, Valérie PARADIS, Alain SAUVANET, Jean-Baptiste BACHET, Armand DE GRAMONT, Esteban CVITKOVIC, Eric RAYMOND, Pascal HAMMEL, Anne COUVELARD. c-MET as a prognostic biomarker and therapeutic target in patients with poor prognostic pancreatic adenocarcinoma following surgical resection. [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 3824. doi:10.1158/1538-7445.AM2014-3824