Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme implicated in cancer cell metabolic reprogramming. This is underscored by the detection of functional, somatic IDH1 mutations frequently found in secondary glioblastoma. To our knowledge, there has never been a reported, validated case of an IDH1 mutation in a pancreatic ductal adenocarcinoma (PDA). Herein, we present a case of a patient with metastatic PDA that harbored a potentially actionable, albeit rare, IDH1 mutation. As part of the Know Your Tumor project (Pancreatic Cancer Action Network), a 48-year-old female was diagnosed with metastatic PDA and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. This mutation was confirmed by an independent sequencing reaction from the tumor sample, and by immunohistochemistry using an antibody specific for the IDH1 R132H mutation. The patient subsequently received a mutant IDH1 inhibitor (AG-120, Agios Pharmaceuticals, Cambridge, MA), but with no response. IDH1 mutations are common in certain cancer types, but have not been reported in PDA. We report the first case of an IDH1 mutation in this tumor type, perhaps providing a rare opportunity for a targeted therapy as a treatment option for PDA.

Background: There is a lack of precision medicine in pancreatic ductal adenocarcinoma (PDA) and related cancers, and outcomes for patients with this diagnosis remain poor despite decades of research investigating this disease. Therefore, it is necessary to explore novel therapeutic options for these patients who may benefit from personalized therapies. Objective: Molecular profiling of hepatopancreaticobiliary malignancies at our institution, including but not limited to PDA, was initiated to assess the feasibility of incorporating molecular profiling results into patient oncological therapy planning. Methods: All eligible patients from Thomas Jefferson University (TJU) with hepatopancreaticobiliary tumors including PDA, who agreed to molecular testing profiling, were prospectively enrolled in a registry study from December 2014 to September 2017 and their tumor samples were tested to identify molecular markers that can be used to guide therapy options in the future. Next generation sequencing (NGS) and protein expression in tumor samples were tested at CLIA-certified laboratories. Prospective clinicopathologic data were extracted from medical records and compiled in a de-identified fashion. Results: Seventy eight (78) patients were enrolled in the study, which included 65/78 patients with PDA (local and metastatic) and out of that subset, 52/65 patients had surgically resected PDA. Therapy recommendations were generated based on molecular and clinicopathologic data for all enrolled patients. NGS uncovered actionable alterations in 25/52 surgically resected PDAs (48%) which could be used to guide therapy options in the future. High expression of three proteins, TS (p ¼ 0.005), ERCC1 (p = 0.001), and PD-1 (p = 0.04), was associated with reduced recurrence-free survival (RFS), while TP53 mutations were correlated with longer RFS (p = 0.01). Conclusions: The goal of this study was to implement a stepwise strategy to identify and profile resected PDAs at our institution. Consistent with previous studies, approximately half of patients with resected PDA harbor actionable mutations with possible targeted therapeutic implications. Ongoing studies will determine the clinical value of identifying these mutations in patients with resected PDA.

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211 Background: We correlated genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identified novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management through multi-omic profiling. Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. PanNETs having undergone molecular profiling for precision matched therapeutic purposes were screened. We performed correlative analyses by pairwise comparisons between pathogenic alterations or altered molecular pathways and clinicopathologic variables. Hierarchical clustering was used to visualize associations. The Kaplan-Meier method was used to estimate overall survival (OS) and survival differences across variables were analyzed by the log-rank test. Results: We included 33 patients with predominantly locally advanced and metastatic PanNETs from 12/2014-1/2018. Chromatin remodeling pathway and MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs, while MEN1 alterations were also less associated with metastatic disease at diagnosis (all Fisher’s exact two-tailed p ≤ 0.05). Several molecular pathway or pathogenic alterations correlated with worse OS: DNA repair pathway (log-rank p = 0.0022), RB1 alterations by NGS (p = 0.018), and TP53 alterations by NGS (p = 0.01). There were several significant co-occurring alterations (Fisher’s exact p ≤ 0.05): ERCC1 expression by immunohistochemistry (IHC) and DAXX (NGS), RB1 (NGS) and DNA repair pathway (NGS), and TS (IHC) and cyclin-dependent kinase pathway (NGS). Having an altered chromatin remodeling pathway was less associated with having an altered receptor tyrosine kinase (RTK) signaling pathway (Fisher’s exact p ≤ 0.05). Conclusions: We identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs.