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.

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma

“…The utility of ctDNA analysis is sustained on the tumor dynamics. [13,24] ctDNA is released in peripheral blood from tumor cells undergoing apoptosis, necrosis or even due to metabolic secretion. Advances in genome sequencing including targeted methods such as NGS have made analysis of ctDNA feasible for clinical use.…”

“…Although advances have been done in lung, breast and colon cancer, evidence is less advanced in PDAC and needs further translation to the clinics. [13,14,24] More than 90% of PDAC present KRAS variants, the most frequently mutated oncogene in cancer. [27]Although not targetable for many years, novel approaches have been developed for mutant KRAS tumors in the last decade, thus making some mutated variants of this gene druggable.…”

“…In line with this, the potential information derived from the analysis of circulating tumor DNA (ctDNA) raises as a promising non-invasive tool to monitor disease evolution while obtaining real-time real-time genetic information of the tumor during treatment. [12,13] The usefulness of ctDNA is mostly stablished in lung, breast, prostate and colon cancer, where clinical trials have assessed its potential value for early diagnosis, detection of minimal residual disease, selection of patients for targeted therapies and monitoring of tumor evolution [14]. In the case of PDAC, several studies have revealed the valuable role of ctDNA in different time-points along tumor evolution.…”

“…Nevertheless, real clinical application of ctDNA for PDAC is still far from clear and needs further validation. [13,24] We present the results of a prospective ctDNA analysis in a cohort of patients with resectable and borderline PDAC diagnosed and treated in the Hospital Universitario de Navarra (HUN), Spain. This study is part of two consecutive research projects for the development of precision medicine in cancer, granted by the Government of Navarra (DIANA (ref: 0011-1411-2017-000033) and AGATA (ref: 0011-1411-2020-000013)).…”

Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

“…Despite advancements in early detection and treatments such as surgery, radiation, and chemotherapy, the prognosis remains poor for many, especially those diagnosed at advanced stages. [ 2 , 3 ] In recent times, immunotherapy has risen to the forefront of cancer treatments, offering hope for numerous cancer types, including GI cancers. [ 4 ] Immunotherapy harnesses the body immune system to detect and eliminate malignant cells.…”