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Mol Cancer Ther. 2018 Nov;17(11):2473-2480. doi: 10.1158/1535-7163.MCT-18-0174. Epub 2018 Aug 10.

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

Author information

1
Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
2
Department of Oncology, Oslo University Hospital, Oslo, Norway.
3
Archer DX Inc., Boulder, Colorado.
4
Genomics Core Facility, Department of Core Facilities, Oslo University Hospital, Oslo, Norway.
5
Department of Pathology, Oslo University Hospital, Oslo, Norway.
6
Department of Clinical Science, University of Bergen, Bergen, Norway.
7
Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Leonardo.Meza-Zepeda@rr-research.no.
#
Contributed equally

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.

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