Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

Circulating Tumor DNA as a Sensitive Marker in Patients Undergoing Irreversible Electroporation for Pancreatic Cancer

“…This result suggested that ctDNA diffused into the systemic circulation in some cases. Indeed, ctDNA+ patients may be related to micrometastasis which cannot be found by imaging, as described by other researchers [35].Therefore, ctDNA+ patients should be considered for other options before IRE, such as moderate chemotherapy.…”

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer

“…However, while the proportion of cfDNA that is tumor-derived (the ctDNA fraction) is largely unknown in metastatic bladder cancer, it is often greater than 1% in advanced solid malignancies studied to date (24,37,38). In data from The Cancer Genome Atlas (TCGA), 98% of primary muscle-invasive bladder cancer had a nonsynonymous somatic mutation in at least one of 50 bladder cancer genes in our panel (13).…”

Circulating tumour DNA: a minimally invasive biomarker for tumour detection and stratification

“…Subsequently, several proof of concept studies showed various tumour specific aberrations in the circulation such as mutation in oncogene and tumour suppressor gene (Sorenson et al 1994;Silva et al 1999b), microsatellite instability (Chen et al 1996) and aberrant DNA methylation (Silva et al 1999a). In recent years, studies are directed towards evaluating the clinical utility of ctDNA in the management of cancer (Takai et al 2015).…”