Liquid Biopsy May Have Prognostic, Theranostic Benefits in PDAC

Despite being the most common pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat, while new research shows treatment and diagnosis could benefit from minimally invasive liquid-based biopsy.

In contrast with tissue-based biopsy, which has been associated with potential risk underestimation, liquid biopsy may produce a more complete picture of disease development in pancreatic ductal adenocarcinoma (PDAC), according to a new review in Frontiers in Medicine.

“Tissue biopsy with fragments of primary/metastatic tumors has been traditionally used for the histological classification of disease and, more recently, for the genetic mutational profiling of cancer,” the authors wrote. “However, evolving techniques for the analysis of histological samples have highlighted the limitations associated with such assessment.”

In particular, liquid biopsy “can capture all the genetic material released from all tumor sites, thereby enabling us to portray whole tumor heterogeneity.” This can be especially beneficial in PDAC, which has high mortality rates because it is often diagnosed at a late stage and is resistant to many treatments.

With success seen using carbohydrate antigen (CA) 19-9 and prostate-specific antigen in pancreatic cancer and prostate cancer, respectively, investigating the use of circulating tumor cells (CTCs) in PDAC could lead to a similar biomarker test for the cancer, authors explained. The micromaterials they investigated were cell-free DNA (cfDNA), cell-free RNA (cfRNA), and extracellular vesicles (EVs).

While acknowledging that there are obstacles to using CTCs in PDCA—such as their presence not always indicating the degree of malignancy and that there can be low levels in peripheral circulation—the investigators also noted that their immunobiology can capture the whole-body burden of a tumor. That is, the tumor’s heterogeneity and evolution. CTCs can also be developed in an ex-vivo culture to mirror a PDAC tumor so that clinicians can identify, test, and individualize treatment, perhaps even new immunotherapies.

The exosomes and nucleosomes of ctDNA and ctRNA, in addition, can act as potential therapeutic targets and biomarkers for diagnosis and disease progression of PDAC. Nucleosomes facilitate access to ctDNA through the 150 to 160 base pairs associated with them, which help to detect ctDNA. Their controlling of exposed noncoding regions of RNA and DNA “have a direct impact on the epigenetics of PDAC,” the authors wrote.

“In the evolving epigenetic landscapes of pancreatic cancer, the ability to access the DNA of PDAC tumors is imperative to orchestrate a personalized precision therapeutic regime,” they added.

ctRNA is also important as a biomarker in liquid biopsy for PDAC due to several of its subclassifications: tumor-educated platelets (TEPs), microRNA, and metabolites. For TEPs, RNA biomarker signatures are mutated in the presence of cancer, and they have been shown to differentially express certain genes in patients with cancer. MicroRNA, in addition, has several molecular signatures that previous studies have implicated as important at detecting and surveilling PDAC early in its course due to their high diagnostic sensitivity and specificity. These include miR- 17-5p, miR-21, miR-155, miR-196a, miR-17-5p, and miR-21.

For EVs, the genetically significant proteins they hold, the authors noted, allow for easier mapping and interpretation of a tumor’s genetic and metabolic makeup. They also have a longer half-life than ctDNA, ctRNA, or microRNA, and their numbers are regularly high in peripheral blood circulation, “due to their consistent production from PDAC tumors.” Ascites, blood, and saliva are just a few of the sources in which they can be found.

“Exosomes, EVs CTC, ctRNA, and ctDNA have been investigated to provide a matching analysis of PDAC tumor genomic profiles confirming heterogeneity,” the authors concluded. “This finding is essential in highlighting potential therapeutic targets against PDAC variants personalizing precision medicine for each patient afflicted by PDAC.”

Further large-scale, prospective studies are needed, however, to ensure liquid biopsies can be safely used in a clinical environment for disease management among patients with PDAC.

Reference

Osei-Bordom DC, Sachdeva G, and Christou N. Liquid biopsy as a prognostic and theranostic tool for the management of pancreatic ductal adenocarcinoma. Front Med (Lausamme). Published online January 14, 2022. doi:10.3389/fmed.202