Handbook of Targeted Cancer Therapy and Immunotherapy

102 deescalate therapy based on risk stratification are clinically warranted. Other applica tions for ctDNA in pancreatic cancer include monitoring response to therapy and sur veillance of disease with the potential for early detection of recurrences. In addition to ctDNA analytes for liquid biopsies, circulating tumor cells and extracellular vesicles and exosomes detectable in the circulation are also being studied in pancreatic cancer with sim ilar clinical applications (21,24). Gastric Cancer Similar to the other cancer types, increased levels of cfDNA have been significantly associated with gastric cancer compared to benign or healthy controls in multiple studies. Levels were found to correlate with advanced stage and tumor size > 5 cm. cfDNA has also been shown to be more sensitive at disease detection in comparison to conventional markers such as carcinoembryonic antigen and CA19.9 (25). In a large-scale analysis of 1,005 patients with stage I–III disease of eight common cancer types, including gastric and esophageal, a combination of eight known protein markers with use of a 61-amplicon panel querying 16 genes that included TP53 , KRAS , PIK3CA , APC (CancerSEEK panel) was used to study early detection when compared to 812 healthy con trols. With application of rigorous statistical analyses, this panel had shown median 70% sensi tivity at specificity of > 99% for detection of all eight cancer types; however, sensitivity for this assay had been limited to 40% for early-stage disease partly limited by the abundance of analytes in circulation in early-stage disease (26). Methylation patterns of ctDNA-detected genes have also been evaluated and hypermethylation of several genes including RunX3, RPRM, and RASSF1A has been associated with early-stage gastric cancer, though no clinically validated tests currently are in routine use (27). Copy number variants of cMYC and HER2 have also been detected via ctDNA analysis. Though its utility in gastric cancer detection is limited by its overall low prevalence in this patient population, a recent study demonstrated its utility in monitoring response to therapy in HER2-amplified gastric cancer and identifying new alterations that emerged with development of resistance to therapy, which can help to inform subsequent line therapies for these patients (28). Incorporation of ctDNA into prospective clinical trials in this setting is warranted with standard ization of ctDNA amplification criteria and interpretation.

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