State of the Art: ctDNA in Upper Gastrointestinal Malignancies

Abstract

Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive source to characterize genetic alterations related to the tumor. Upper gastrointestinal cancers, including gastroesophageal adenocarcinoma (GEC), biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PADC) are poor prognostic malignancies, usually diagnosed at advanced stages when no longer amenable to surgical resection and show a poor prognosis even for resected patients. In this sense, ctDNA has emerged as a promising non-invasive tool with different applications, from early diagnosis to molecular characterization and follow-up of tumor genomic evolution. In this manuscript, novel advances in the field of ctDNA analysis in upper gastrointestinal tumors are presented and discussed. Overall, ctDNA analyses can help in early diagnosis, outperforming current diagnostic approaches. Detection of ctDNA prior to surgery or active treatment is also a prognostic marker that associates with worse survival, while ctDNA detection after surgery is indicative of minimal residual disease, anticipating in some cases the imaging-based detection of progression. In the advanced setting, ctDNA analyses characterize the genetic landscape of the tumor and identify patients for targeted-therapy approaches, and studies show variable concordance levels with tissue-based genetic testing. In this line, several studies also show that ctDNA serves to follow responses to active therapy, especially in targeted approaches, where it can detect multiple resistance mechanisms. Unfortunately, current studies are still limited and observational. Future prospective multi-center and interventional studies, carefully designed to assess the value of ctDNA to help clinical decision-making, will shed light on the real applicability of ctDNA in upper gastrointestinal tumor management. This manuscript presents a review of the evidence available in this field up to date.

Keywords: cancer; ctDNA; gastrointestinal tumors; liquid biopsy; precision medicine.

Figure 1

Characteristics of genomic testing in tissue and ctDNA of liquid biopsy. Tissue analysis allows for histotyping and tumor microenvironment characterization. Genetic testing in tissue biopsy (left panel) needs an invasive procedure, thus preventing repetitive testing. It may also show high failure rates due to insufficient tumor material and may only represent part of the entire tissue architecture. On the other hand, high DNA quantities are usually extracted, which eases detection of genetic alteration including CNVs and genomic rearrangements. Genetic testing ctDNA (right panel) is minimally invasive, allowing repetitive testing, and can cover full tumor heterogeneity. Nevertheless, low DNA quantities require highly sensitive technologies, CNV and genomic rearrangement detection is still unsatisfactory, and CHIP may lead to false positives. Abbreviations: CNV: copy number variation; ctDNA: circulating tumoral DNA; CHIP: clonal hematopoiesis of indeterminate potential.