(P048) Mutational Analysis by Next-Generation Sequencing in Patients With Pancreatic Adenocarcinoma

April 30, 2015

Novel mutations were identified in the majority of patients, including mutations within a number of genes that have the potential to influence KRAS-mediated signaling, as well as other prominent signaling pathways. These results could potentially serve to identify targets for novel chemotherapeutic agents and guide personalized, combinatorial therapy in appropriately selected patients.

Andrea L. Arnett, MD, PhD, Kenneth Chang, BS, Terence T. Sio, MD, MS, Robert C. Miller, MD, MS;Department of Radiation Oncology, Mayo Clinic, Rochester; Department of Radiation Oncology, Mayo Clinic, Jacksonville

BACKGROUND: Pancreatic adenocarcinoma carries a poor prognosis, and currently available systemic therapies have demonstrated only modest efficacy in advanced disease. In this retrospective study, next-generation exomic sequencing (NGS) was utilized in pancreatic adenocarcinoma samples to identify potential novel therapeutic targets that are not routinely assayed in the clinical setting.

MATERIALS AND METHODS: Eight patients with confirmed pancreatic adenocarcinoma were selected based on availability of tissues. These patients were treated at our institution from 2001 to 2013. A total of 236 somatic genes were surveyed in this review, including 3,230 exons and 47 introns at > 900x mapping coverage. NGS reports were generated from 2011 to 2013. Statistical analysis was performed using Kaplan-Meier survival analyses.

RESULTS: The most frequent genomic alterations were found within KRAS (88%) and TP53 (75%). Three patients were found to have mutations within the SMAD family of genes. All patients with SMAD alterations were also found to have concurrent KRAS mutations, which is consistent with the reported literature. KRAS mutations most commonly involved codon 12, while the locations of SMAD family mutations were heterogeneous. In addition, concurrent mutations were found within genes that have been shown to potentially modulate or interact with KRAS-mediated signaling pathways, including CCND3, CDKN2A/B, and RB1. Furthermore, 75% of patients had multiple, novel mutations that have not traditionally been associated with pancreatic adenocarcinoma. The average number of mutations was 8.1 (range: 0–17 mutations). The majority of patients had greater than six mutations identified, but there was substantial heterogeneity in the location and type of genomic alterations. Median survival and 5-year overall survival (OS) were 30.1 months and 41%, respectively. There was no significant correlation between the number of mutations and OS. Median age at diagnosis was 54 years (range: 35–82 yr). Overall, 88% of patients were found to have mutations associated with targeted therapies. One-third of patients possessed multiple concurrent molecular targets for which US Food and Drug Administration (FDA)-approved chemotherapeutic agents are currently available. 

CONCLUSION: Novel mutations were identified in the majority of patients, including mutations within a number of genes that have the potential to influence KRAS-mediated signaling, as well as other prominent signaling pathways. These results could potentially serve to identify targets for novel chemotherapeutic agents and guide personalized, combinatorial therapy in appropriately selected patients.

Proceedings of the 97th Annual Meeting of the American Radium Society- americanradiumsociety.org