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Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives

ABSTRACT:

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Management of gastrointestinal (GI) cancers t is a worldwide challenge and some new tools are needed to guide it. Circulating tumor DNA (ctDNA) is a fraction of tumor DNA that can be detected by a liquid biopsy through a simple blood sample. In this work, we tried to summarize in a clinical review to what extend the analysis of ctDNA can improve therapeutic support in digestive oncology and how this circulating biomarker appears as a very promising improvement in addition to classic diagnostic, prognostic and theranostic methods. Although the level of evaluation of this tool is still different between the different GI cancers locations, it is in dynamic evolution in all of them.

Abstract

Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.

SUBMITTER: Moati E

PROVIDER: S-EPMC8507552 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The promising aspect of circulating tumor DNA (ctDNA) is its rapid turnaround and non-invasive nature. According to the American Society of Clinical Oncology (ASCO) and College of American Pathologists joint ctDNA review published in March 2018, there is not sufficient evidence to support the use of ctDNA in practice for GI cancers. However, there were numerous studies presented at ASCO Annual Meeting supporting its value. We aimed to summarize on its role in the management of gastrointestinal cancers based on the studies presented recently, and future directions. Methods: We limited our search to keywords "ctDNA," "circulating tumor DNA," "cell-free DNA (cfDNA)" and/or "liquid biopsy," at the 2018 ASCO Annual Meeting library abstracts and presentations. Results: There were 35 studies that revolved around ctDNA as a diagnostic tool, prognostic marker and/or a measure of tumor heterogeneity in gastrointestinal cancers. Depending on the assay used, the results of several studies showed that ctDNA was able to identify relevant mutations or fusions including RAS, HER2/Neu, BRAF, MET, BRCA2, APC, TP53, ALK, ROS1, PTEN, and NF1. The prognosis in terms of tumor mutation burden, objective response rate, metastasis and survival were also estimated by various studies based on ctDNA. The findings showed that higher baseline ctDNA levels and/or increased number of mutations detected in ctDNA were associated with poor survival and multi-site metastasis. Right-sided colon cancer was associated with higher number of mutations in ctDNA than left-sided colon and rectal cancers. Similarly, tubular adenocarcinoma subtype of gastric cancer was more likely to have higher ctDNA levels than signet-ring cell subtype. The feasibility of assessing response to therapy and residual metastatic disease by using ctDNA which was otherwise not detected on imaging was also presented. Conclusions: The studies presented at ASCO 2018 report on the many ways ctDNA is of value in patients with gastrointestinal malignancies. Experts and discussants at the meeting argued that this may well indeed be ready for prime time for certain GI malignancies including colorectal cancers, especially in the metastatic setting. These findings alongside ongoing studies showing its feasibility into practice would likely lead to revision of the current guidelines for metastatic GI cancers.

Project description:Gastrointestinal cancers, including oesophageal, gastric and colorectal cancers (CRC) have high rates of disease recurrence despite curative resection. There are a number of recent studies that have investigated the use of circulating tumor DNA (ctDNA) for prognostic value in these cancers. We reviewed studies that had been published prior to March 2018 that assessed the prognostic values of ctDNA in patients with oesophageal and gastric cancers, gastrointestinal stromal tumors (GIST) and CRC. We identified 63 eligible clinical studies that focussed on recurrence and survival. Studies assessed investigated various ctDNA biomarkers in patients with different stages of cancer undergoing surgical resection, chemotherapy and no treatment. For oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, methylation of certain genes such as APC and DAPK have been highlighted as promising biomarkers for prognostication, but these studies are limited and more comprehensive research is needed. Studies focusing on gastric cancer patients showed that methylation of ctDNA in SOX17 and APC were independently associated with poor survival. Two studies demonstrated an association between ctDNA and recurrence and survival in GIST patients, but more studies are needed for this type of gastrointestinal cancer. A large proportion of the literature was on CRC which identified both somatic mutations and DNA methylation biomarkers to determine prognosis. ctDNA biomarkers that identified somatic mutations were more effective if they were personalized based on mutations found in the primary tumor tissue, but ctDNA methylation studies identified various biomarkers that predicted increased risk of recurrence, poor disease free survival and overall survival. While the use of non-invasive ctDNA biomarkers for prognosis is promising, larger studies are needed to validate the clinical utility for optimizing treatment and surveillance strategies to reduce mortality from gastrointestinal cancers.

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Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives

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