Abstract
Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing tumor-specific aberrations through noninvasive sampling. In gastrointestinal stromal tumor (GIST), analysis of KIT and PDGFRA mutations is important for therapeutic decisions, but the invasiveness of traditional biopsies limits the possibilities for repeated sampling. Using targeted next-generation sequencing, we have analyzed circulating cell-free DNA from 50 GIST patients. Tumor-specific mutations were detected in 16 of 44 plasma samples (36%) from treatment-naïve patients and in three of six (50%) patients treated with tyrosine kinase inhibitors. A significant association between detection of ctDNA and the modified National Institutes of Health risk classification was found. All patients with metastatic disease had detectable ctDNA, and tumor burden was the most important detection determinant. Median tumor size was 13.4 cm for patients with detectable mutation in plasma compared with 4.4 cm in patients without detectable mutation (P = 0.006). ctDNA analysis of a patient with disease progression on imatinib revealed that multiple resistance mutations were synchronously present, and detailed analysis of tumor tissue showed that these were spatially distributed in the primary tumor. Plasma samples taken throughout the course of treatment demonstrated that clonal evolution can be monitored over time. In conclusion, we have shown that detection of GIST-specific mutations in plasma is particularly feasible for patients with high tumor burden. In such cases, we have demonstrated that mutational analysis by use of liquid biopsies can capture the molecular heterogeneity of the whole tumor, and may guide treatment decisions during progression. Mol Cancer Ther; 17(11); 2473-80. ©2018 AACR.
Highlights
Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal tumor in the gastrointestinal tract
next-generation sequencing (NGS) panel designed for analysis of circulating tumor DNA (ctDNA), we have demonstrated that detection of gastrointestinal stromal tumor (GIST) disease-causing mutations in plasma is significantly associated with the classification of tumors into risk groups. ctDNA was detected in all patients with metastatic disease
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]
Summary
Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal tumor in the gastrointestinal tract. The key molecular drivers of GIST are mutations in KIT (80%) or PDGFRA 1), and the majority of GISTs with such mutations are sensitive to tyrosine kinase inhibitors Imatinib is the preferred first-line treatment for most patients with inoperable or metastatic disease [3]. The likelihood of tumor response depends on the mutational profile, with exon 11 mutated KIT being the most. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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