Bile-Based Cell-Free DNA Analysis Is a Reliable Diagnostic Tool in Pancreatobiliary Cancer.

Caroline Driescher,Katharina Fuchs,Verena Keitel,Lena Haeberle,Wolfram Trudo Knoefel,Wolfgang Goering,Friederike V Opitz,Lisa Frohn,Dieter Haeussinger,Irene Esposito

doi:10.3390/cancers13010039

Caroline Driescher, Katharina Fuchs + Show 8 more

Open Access

https://doi.org/10.3390/cancers13010039

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Abstract

Simple SummaryTo elucidate and compare the value of plasma and bile as liquid biopsy source, cfDNA from 80 patients with pancreatobiliary cancers or non-malignant biliary obstructions was subjected to panel-based next generation sequencing (NGS). Results showed high correspondence in mutational profiles of bile-derived cfDNA and matched tissue samples, and the method proved superior to traditional plasma-based liquid biopsy techniques and with higher sensitivity than routine biomarkers such as CA19-9.Currently available serum biomarkers for pancreatobiliary cancers lack sensitivity and specificity and ultimate diagnosis still requires invasive procedures for histological confirmation. The detection of tumor-specific genetic aberrations with utilization of cell free DNA (cfDNA) is a less invasive approach than traditional tissue biopsies; however, it has not been implemented into clinical routine. In this study, we investigated bile as a liquid biopsy source in pancreatobiliary cancers and compared its potential as cell-free DNA source to plasma. Blood (n = 37) and bile (n = 21) samples were collected from patients affected by pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (CCA) or with non-malignant biliary obstructions (blood n = 16; bile n = 21). Panel-based next generation sequencing (NGS) and digital droplet PCR (ddPCR) were applied for tumor mutation profiling. NGS results from matched tumor tissues (n = 29) served as comparison. Sequencing of cfDNA from bile resulted in detection of 96.2% of the pathogenic tumor mutations found in matched tissue samples. On the other hand, only 31.6% of pathogenic tumor mutations found in tissue could be detected in plasma. In a direct comparison, only half of the mutations detected in bile cfDNA were concordantly detected in plasma from the same patients. Panel NGS and ddPCR displayed comparable sensitivity. In conclusion, bile is a suitable source of cfDNA for the diagnosis of pancreatobiliary cancer and performs more reliably than plasma. Although primary diagnosis still requires histologic confirmation, bile-derived cfDNA could offer an alternative if tissue sampling is not feasible and might allow less invasive disease monitoring.

Highlights

The outcome of patients with pancreatic and biliary cancers continues to be poor despite the strong efforts to improve diagnostic tools and treatment options
Tumor tissue remains a pre-requisite for initial diagnosis of pancreatic ductal adenocarcinoma (PDAC) or CCA and, to date, its availability is essential for genomic profiling for the purpose of targeted therapy [24,25,26]
We investigated bile as a source of cell free DNA (cfDNA) and elucidated its potential role as a novel liquid biopsy source in pancreatobiliary cancers

Summary

Introduction

The outcome of patients with pancreatic and biliary cancers continues to be poor despite the strong efforts to improve diagnostic tools and treatment options. Surgical resection is the only potentially curative treatment option, but only a fraction of patients are eligible for resection at the time of diagnosis, and local or distant recurrence rates continue to be high [3,4]. CA19-9 only provides suboptimal sensitivity and specificity, especially in asymptomatic patients [7,8]. It is not cancer-specific and is elevated in many other hepatobiliary and gastrointestinal tumors as well as in benign biliary obstructions [9,10,11]

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