Abstract 4603: Clinical application and potential usefulness of targeted next-generation sequencing on resected pancreatic ductal adenocarcinoma
Authors: Puleo Francesco , Nicolle Rémy , Blum Yuna , Cros Jérôme , Elarouci Nabila , Franchimont Denis , Devière Jacques , Reyniès Aurélien de , Laurent-Puig Pierre , Bachet Jean-Baptiste , Maréchal Raphaël , Laethem Jean-Luc Van 
Published: August 2018

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Virtually all PDA are characterized by mutation of four driver genes: KRAS, TP53, CDKN2A and SMAD4 and a long tail of rarely mutated genes. Application of targeted next-generation sequencing (NGS) has entered clinical routine for colon, lung and other cancers. Among patients with resected PDA, usefulness, applicability and prognostic significance of NGS results are still a matter of debate. Aims: To evaluate: 1) the alterations of the 4 main driver genes and patient outcomes after resection 2) the usefulness of targeted NGS in finding targetable alterations. Methods: We analyzed DNA alterations in FFPE tumors among 279 patients with curatively resected PDA who were treated at 4 Academic Hospitals (Franco-Belgian consortium). Sequencing libraries were prepared using a 50 genes panel (Ion AmpliSeqTM Cancer HotSpot Panel v2, Life Technologies). Sequencing was performed on an Ion ProtonTM System using an Ion PITM Sequencing 200 Kit and an Ion PITM Chip Kit v3 (Life Technologies). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjusted for age, sex, tumor characteristics and institution. Results: Of the 279 patients analyzed, 163 (58.4%) were men and 116 (41.6%) were women, with a median age of 64.59 (36.9-87.5) years. KRAS, TP53, CDKN2A and SMAD 4 were mutated in 246, 193, 45 and 44 patients respectively. Patients with KRAS mutant tumors did not have worse DFS (median [95% CI], 12.2 [11.35-14.6] months) and OS (23.9 [21.1-30.1] months) compared to patients with KRAS wild-type tumors (DFS, 14.3 [9.64-19.4] months; OS, 31.8 [19.4-53.5] months). The mutational status of TP53 or SMAD4 was not associated with DFS or OS as well. CDKN2A mutations were associated with a lower OS (mutation: 20.5 [14.6-33.0] versus wild-type 26.5 [21.9-33.3] months OS, log-rank &lt;1% HR 1.65 [1.124-2.436]) but not to a lower DFS. Patients had slightly worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 3 to 4 altered genes had worse DFS (HR, 1.377 [95% CI, 1-1.89; P=.05]) and OS (HR, 1.476 [95% CI, 1.04-2.09; P= .028]). For some patients (n=27, 9.68%), we found mutations that could be targeted (i.e PTEN, STK11, GNAS, PIK3CA, FLT3, BRAF, IDH1/2, RET, FGFR3, KIT, AKT1). Conclusions: Analysis of the four main driver gene alterations introduces weak prognostic information with little added clinical value. However, application of NGS in resected PDA is quite feasible and is able to find targetable mutations. KRAS and CDKN2A deserve future attention for targeting specific mutations
Citation Format: Francesco Puleo, Rémy Nicolle, Yuna Blum, Jérôme Cros, Nabila Elarouci, Denis Franchimont, Jacques Devière, Aurélien de Reyniès, Pierre Laurent-Puig, Jean-Baptiste Bachet, Raphaël Maréchal, Jean-Luc Van Laethem. Clinical application and potential usefulness of targeted next-generation sequencing on resected pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4603.