Abstract 794: Prognostic value of high c-Met expression in patients with poor prognosis pancreatic adenocarcinoma following surgical resection: comparison of three c-Met scoring methods and exploration of underlying mechanisms of c-Met overexpression
Authors: Neuzillet Cindy , Tijeras-Raballand Annemilaï , Raffenne Jérôme , de Gramont Armand , Bedossa Pierre , Paradis Valérie , Sauvanet Alain , Bachet Jean-Baptiste , Raymond Eric , Hammel Pascal , Couvelard Anne , Cros Jérôme 
Published: August 2015

Abstract
Context: The HGF/c-Met pathway is an hypoxia-inducible pathway involved in tumor-stroma interactions and invasion in pancreatic ductal adenocarcinoma (PDAC). Assessment of c-Met expression is a critical issue as c-Met inhibitors are under clinical development and are suggested to display antitumor activity only in high c-Met tumors. We aimed to assess the prognostic value of c-Met overexpression in PDAC and explore underlying mechanisms (hypoxia, gene amplification, post transcriptional deregulation).
Patients and methods: Patients (Pts) with resected PDAC who had received no perioperative chemo/radiotherapy were retrospectively selected. c-Met immunostaining was graded using a simplified score (high c-Met: ≥20% of cancer cells with 3+ staining) and compared to a standard scale combining staining surface and intensity (SI score) and to the MetMab score. Concordance between entire section and tissue microarray (TMA) was assessed and a computer-assisted quantification algorithm was developed (Aperio® software). Hypoxia was assessed by visual grading of HIF-1α/CA9 immunostaining, necrosis, and automated microvascular density (Aperio®). c-Met gene copy number was assessed by fluorescent in situ hybridization (FISH) and Taqman® based copy number variation (CNV) assay. c-Met mRNA levels were quantified using reverse transcription PCR (RT-PCR). c-Met pathway activation was assessed by immunostaining of phospho-c-Met, phospho-GAB1 and downstream signaling (pAKT, pERK, and pSTAT3) and graded visually. Clinical, pathological, and molecular biomarkers were correlated with disease-free (DFS) and overall (OS) survivals.
Results: Thirty-seven Pts were analyzed. The simplified c-Met score displayed the best prognostic value and reproducibility vs both the SI score and the MetMab score; using this score: (a) high c-Met (7/37) was associated with shorter DFS (6.3 vs 33.0 months, HR: 3.456, p = 0.0035) and OS (10.8 vs 39.0 months, HR: 4.257, p = 0.0006); and (b) the kappa index was 0.773±0.122. In multivariate analysis, high c-Met was independently associated with both DFS and OS. c-Met expression was concordant on entire section and TMA in 87.9% of cases, and quantifiable using a specific computer-assisted algorithm. There was no correlation between hypoxia-related markers and c-Met expression. FISH and CNV analysis did not show c-Met gene amplification. mRNA quantification and downstream pathway activation data will be presented.
Conclusion: c-Met is an independent prognostic marker in resected PDAC that may help identifying Pts at high risk of recurrence and poor survival. High c-Met expression was not associated with hypoxia or gene amplification in this study. The simplified c-Met scale is a robust and reproducible scoring method that could be used for ongoing larger studies on TMA.
Citation Format: Cindy Neuzillet, Annemilaï Tijeras-Raballand, Jérôme Raffenne, Armand de Gramont, Pierre Bedossa, Valérie Paradis, Alain Sauvanet, Jean-Baptiste Bachet, Eric Raymond, Pascal Hammel, Anne Couvelard, Jérôme Cros. Prognostic value of high c-Met expression in patients with poor prognosis pancreatic adenocarcinoma following surgical resection: comparison of three c-Met scoring methods and exploration of underlying mechanisms of c-Met overexpression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 794. doi:10.1158/1538-7445.AM2015-794