Genetic Alterations Predict Long-Term Survival in Ductal Adenocarcinoma of the Pancreatic Head

SIMPLE SUMMARY: Pancreatic cancer is notorious for its poor prognosis. However, rare long-term survivors of pancreatic cancer exist. The aim of this study was to characterize the molecular profile of pancreatic cancer long-term survivors, to improve the stratification and management of pancreatic cancer patients in the future. Thirty-nine pancreatic cancer patients including short-term and long-term survivors were evaluated thoroughly. Their molecular profile was analyzed using panel next generation sequencing. As a result, patients with mutations commonly found in pancreatic cancer (KRAS G12D mutations and/or TP53 nonsense and splice site mutations) showed significantly worse survival. In contrast, long-term survivors of pancreatic cancer did not show the above-mentioned mutations but did show rare mutations of KRAS (Q61H/D57N). In conclusion, long-term survivors of pancreatic cancer do have a distinct molecular profile. Further studies using larger patient cohorts are warranted to confirm these results and possibly unravel rare potential targets for targeted therapy in pancreatic cancer. ABSTRACT: Background: Survival of patients with adenocarcinoma of the pancreas (PDAC) is poor and has remained almost unchanged over the past decades. The genomic landscape of PDAC has been characterized in recent years. The aim of this study was to identify a genetic profile as a possible predictor of prolonged survival in order to tailor therapy for PDAC patients. Methods: Panel next generation sequencing (NGS) and immunohistochemistry (IHC) were performed on paraffin-embedded tumor tissues from curatively treated PDAC patients. Tumor slides were re-evaluated with a focus on the histomorphology. Patients were subgrouped according to short and long overall (<4 years/>4 years) and disease-free (<2 years/>2 years) survival. Results: Thirty-nine patients were included in the study. Clinicopathological staging variables as well as the histomorphological subgroups were homogenously distributed between short- and long-term overall and disease-free survivors. In survival analysis, patients with the KRAS G12D mutation and patients with TP53 nonsense and splice-site mutations had a significantly worse overall survival (OS) and disease-free survival (DFS). Patients with long-term OS and DFS showed no KRAS G12D, no TP53 nonsense or splice-site mutations. Rare Q61H/D57N KRAS mutations were only found in long-term survivors. The allele frequency rate of KRAS and TP53 mutations in tumor cells was significantly higher in short-term disease-free survivors and overall survivors, respectively. Conclusions: NGS of PDAC revealed significant differences in survival outcome in a patient collective with homogenously distributed clinicopathological variables. Further multi-institutional studies are warranted to identify more long-term survivors to detect genetic differences suitable for targeted therapy.