Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using "liquid biopsies" at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy.

Keywords: Circulating tumor DNA; Circulating tumor cells; Liquid biopsy; Pancreatic cancer.

Figure 1

Different ctDNA detection techniques and their sensitivity. Techniques are ranked according to their usual sensitivity towards minor allele detection. The optimal technique would allow the detection of a single mutated DNA molecule whatever the normal DNA background. Digital PCR (dPCR), and its variants, droplet‐dPCR and BEAMing (“Beads, Emulsion, Amplification, Magnetic”), can be considered as the current standard for hotspot mutation detection (typically, KRAS mutations) in ctDNA, with 0.01%–0.1% sensitivity. Pyrophosphorolysis‐activated polymerization (PAP)‐PCR and bidirectional‐PAP (biPAP)‐PCR techniques have similar theoretical 0.01%–0.1% sensitivity (although not tested on KRAS). Modified next generation sequencing procedures (CAPP‐Seq, Safe‐Seq, etc, called “E‐NGS” here) exhibited at least 0.1% sensitivity.

Figure 2

EMT and MET process in the development of PDAC metastasis. Cancer cells undergoing epithelial–mesenchymal transition (EMT) acquire extra motility, invasive features and are more resistant to apoptosis. These cells can intravasate, circulate in the blood (as CTC) and eventually extravasate in distant organs, leading to the later development of distant metastases. The reverse process (mesenchymal–epithelial transition, MET) is thought to happen during the invasion of the distant site, eventually induced by the new microenvironment of disseminated tumor cells.