Clinical utility of molecular profiling using EUS-guided Biopsies in Pancreatic cancer: The PRECISION-Panc experience

Abstract

Introduction: Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in Pancreatic Cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy in PC. Methods: 95 patients underwent additional research biopsies at diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Matching resected specimens underwent genomic profiling for comparison. Whole genome (WGS) and RNA sequencing was performed in selected patients (Figure 1). Results: Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n = 54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n = 5) revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n = 53) segregated patients into clinically relevant molecular subtypes based on transcriptome; and reveals novel molecular differences between metastatic, locally advanced and resectable PC. Conclusion: We demonstrate integrated multi-omic analysis of all stages of PC using standard EUS guided biopsies. This offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC. Identifying gene signatures associated with pro-metastatic phenotype and poor prognosis pre-operatively may better select patients for neoadjuvant therapy rather than upfront resection.