Abstract A238: c-MET as a target for MET inhibitors in patients with poor prognostic pancreatic adenocarcinoma following completed surgical resection.

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Abstract Context: Pancreatic adenocarcinoma (PAC) displays a prominent desmoplastic stromal reaction, leading to tumor hypoxia and driving a selective pressure that selects cells exhibiting aggressive phenotypes. Activation of the HGF/c-MET pathway is involved in tumor-stroma interactions and promotes PAC 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 and hypoxia in PAC. Patients and Methods: Patients who underwent curative surgical resection for PAC 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 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) expressed high c-MET (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 PAC. High c-MET expression combined with tumor size and lymph node ratio (defined as the ratio of lymph nodes with tumor metastasis to the total lymph nodes dissected) predicted risk of early local or distant recurrence (RFS < 12 months) with an AUC = 0.836. Conclusion: c-MET appears to be a strong prognostic marker in completely resected PAC that may help to identify patients at high risk of early recurrence. Although the number of patients entered in this study was limited, this study suggests to explore the anti-metastatic potential of MET inhibitors in high c-MET expressing PAC following complete resection. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A238. Citation Format: Cindy Neuzillet, Jérôme Cros, Annemilaï Tijeras-Raballand, Julien Moroch, Louis de Mestier, Maryse Baia, Pierre Bedossa, Valérie Paradis, Alain Sauvanet, Jean-Baptiste Bachet, Eric Raymond, Pascal Hammel, Anne Couvelard. c-MET as a target for MET inhibitors in patients with poor prognostic pancreatic adenocarcinoma following completed surgical resection. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A238.

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