Clinical Application of Circulating Tumor DNA in the Genetic Analysis of Patients with Advanced GIST

Abstract

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. Although, circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance, but the concordance was strong for patients with tumor size > 10 cm or Ki-67 > 5%. Tumor size, mitotic figure, Ki-67, and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type, were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients.

Circulating cKIT and PDGFRA DNA indicates disease activity in Gastrointestinal Stromal Tumor (GIST)

“…30 Similarly, Xu et al detected ctDNA in 56.3% of GIST patients when applying NGS, mainly investigating patients with larger tumors. 33 In line with these data, using targeted NGS, we detected the primary cKIT mutation only in two out of four patients, in which detection by dPCR was feasible. However, serial NGS analysis documented selection of additional cKIT mutations (cKIT V654A, D820Y) that are known to mediate imatinib resistance in two patients.…”

“…Similarly, Xu et al . detected ctDNA in 56.3% of GIST patients when applying NGS, mainly investigating patients with larger tumors . In line with these data, using targeted NGS, we detected the primary cKIT mutation only in two out of four patients, in which detection by dPCR was feasible.…”

“…Targeted NGS of ctDNA offers the advantage of covering hundreds to thousands of amplicons in one assay read in an unbiased fashion. 31,32 NGS was shown to successfully detect ctDNA in plasma, 30,[33][34][35][36] and in single cases to capture clonal heterogeneity in GIST patients. 30,34,35 However, GIST liquid biopsy studies that used NGS had either low patient numbers 34,35 or were limited to localized disease, 36 and data showing a long-term follow up of individual GIST patients are lacking.…”

Noninvasive Detection of ctDNA Reveals Intratumor Heterogeneity and Is Associated with Tumor Burden in Gastrointestinal Stromal Tumor

“…Thus, the greatest potential use of liquid biopsies seems to be for the more advanced cases where the clinical benefit of mutational monitoring may be most readily seen. Two previous studies in GIST have also shown higher levels of ctDNA in larger tumors (14,15). Maier and colleagues found that patients with measurable disease more often had detectable ctDNA, but a blood sample prior to start of treatment was only available for 9 of the 38 included patients (14).…”

“…Such blood plasma biopsies have a potential application in diagnosis, prognosis, monitoring of disease progression, and evolution and prediction of therapy response (13). Only a few studies of ctDNA in GIST have been reported; mutant ctDNA has been detected in plasma from patients with GIST, and the amount was correlated with the disease course (14) and tumor size (15). Secondary KIT mutations that confer treatment resistance have also been identified from liquid biopsies (16).…”