Abstract A107: c-Met overexpression as an independent prognostic biomarker and therapeutic target in patients with poor prognostic pancreatic adenocarcinoma following surgical resection
Authors: Neuzillet Cindy , Cros Jérôme , Tijeras-Raballand Annemilaï , Gramont Armand De , Moroch Julien , Mestier Louis De , Bedossa Pierre , Paradis Valérie , Sauvanet Alain , Bachet Jean-Baptiste , Cvitkovic Esteban , Raymond Eric , Hammel Pascal , Couvelard Anne 
Published: October 2015

Abstract
Context: Hypoxia-induced activation of the HGF/c-Met pathway is 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 in PDAC.
Patients and methods: Patients with resected PDAC and no perioperative chemotherapy/radiotherapy were retrospectively selected to assess the “pure” prognostic value of molecular biomarkers. c-Met immunostaining was graded using a standard visual scale combining surface (S) and intensity (I) (SI) or a simplified score (high c-Met: ≥20% of cancer cells with strong staining). Hypoxia was assessed by HIF-1α and CA9 immunostainings, CD31 expression (microvascular density), and necrosis. Clinical, pathological, and molecular biomarkers were correlated with disease-free (DFS) and overall (OS) survivals. Computer-assisted classification was performed using Aperio® software. Patients with resected PDAC who had received adjuvant treatment (chemotherapy and/or radiotherapy) were selected for the validation step of c-Met score on tissue microarrays (TMA).
Results: Thirty-seven patients were analyzed. The simplified score had the best prognostic value and reproducibility. Using this score, high c-Met expression (7/37) was associated with shorter DFS (6.3 vs 33.0 months, HR: 3.456, p=0.0036) and OS (10.8 vs 39.0 months, HR: 4.257, p=0.0004). In multivariate analysis, high c-Met expression was independently associated with both DFS (p=0.030) and OS (p=0.004). c-Met expression was concordant on entire section and TMA in 87.9%, and quantifiable using a specific computer-assisted algorithm (36/37 tumors were correctly classified). There was no correlation between hypoxia-related markers and c-Met expression in this study. In the validation cohort (n=94), patients with c-Met high tumors had significantly shorter DFS (9.4 vs 18.4 months, HR: 1.830, p=0.0198).
Conclusion: c-Met is an independent prognostic marker in resected PDAC that may help identifying patients at high risk of recurrence and poor survival. The simplified c-Met scale is robust and reproducible, and could be used as reliable scoring method for routine use and larger prognostic and predictive studies on TMA. Patients with PDAC overexpressing c-Met may represent a subgroup candidate for intensified adjuvant treatment or clinical trials with c-Met inhibitors.
Citation Format: Cindy Neuzillet, Jérôme Cros, Annemilaï Tijeras-Raballand, Armand De Gramont, Julien Moroch, Louis De Mestier, Pierre Bedossa, Valérie Paradis, Alain Sauvanet, Jean-Baptiste Bachet, Esteban Cvitkovic, Eric Raymond, Pascal Hammel, Anne Couvelard. c-Met overexpression as an independent prognostic biomarker and therapeutic target in patients with poor prognostic pancreatic adenocarcinoma following surgical resection. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A107.