Detecting secondary C-KIT mutations in the peripheral blood of patients with imatinib-resistant gastrointestinal stromal tumor

Wada, Nobuhiro; Kurokawa, Yukinori; Takahashi, Tsuyoshi; Hamakawa, Takashi; Hirota, Seiichi; Serada, Satoshi; Naka, Takuji; Miyazaki, Yasuhiro; Makino, T; Yamasaki, M.; Nakajima, Kohei; Takiguchi, S.; Mori, Miki; Doki, Yuichiro

doi:10.1016/s0959-8049(16)32774-5

Cited by 11 publications

(17 citation statements)

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

Section: Discussionmentioning

confidence: 99%

“…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. Recently, Namlos et al showed that detection of ctDNA in plasma of GIST patients using NGS correlated with high tumor burden but at a relevantly low ctDNA detection rate (19 of 50 patients, i.e., 38%).…”

Section: Discussionmentioning

confidence: 99%

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

Jilg

Rassner

Maier

et al. 2019

Intl Journal of Cancer

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This prospective trial aimed to investigate whether tumor‐specific cKIT and PDGFRA mutations can be detected and quantified in circulating tumor (ct)DNA in patients with active GIST, and whether detection indicates disease activity. We included 25 patients with active disease and cKIT or PDGFRA mutations detected in tissue. Mutant ctDNA was detected in the peripheral blood plasma using allele‐specific ligation (L‐)PCR and droplet digital (d)PCR. CtDNA harboring tumor‐specific cKIT or PDGFRA mutations was detected at least once in 16 out of 25 patients using L‐PCR (64%) and in 20 out of 25 patients with dPCR (80%). Using dPCR, the absolute numbers of ctDNA fragments (DNA copies/ml) and the mutant allele frequency (MAF; in percent of wild‐type control) strongly correlated with tumor size expressed as RECIST1.1 sum of diameter (SOD) in mm (ρ = 0.3719 and 0.408, respectively, p < 0.0001) and response status (ρ = 0.3939 and 0.392, respectively, p < 0.0001 and p < 0.001). Specificity of dPCR for detection of progression was 79.2% with a sensitivity of 55.2% and dPCR discriminated CR from active disease with a specificity of 96% and s sensitivity of 44.7%. With L‐PCR, correlations of MAF with tumor size and response status were less prominent. Serial ctDNA measurement reflected individual disease courses over time. Targeted panel sequencing of four patients detected additional driver mutations in all cases and secondary resistance mutations in two cases. Thus, ctDNA indicates disease activity in patients with GIST and should be incorporated as companion biomarker in future prospective trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Jilg

Rassner

Maier

et al. 2019

Intl Journal of Cancer

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“…Detection of mutations in patients with GIST using liquid biopsy was reported previously [11][12][13][14][15]. These studies used sequencing as well as polymerase chain reactionbased techniques for detection of mutations in tumor and used the known tumor mutation for monitoring therapy in plasma.…”

Section: Brief Communicationsmentioning

confidence: 99%

Diagnosis and Treatment Monitoring of a Patient with Gastrointestinal Stromal Tumor by Next-Generation Sequencing and Droplet Digital Polymerase Chain Reaction Assay of a PDGFRA Mutation in Plasma-Derived Cell-Free Tumor DNA

et al. 2019

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In patients with a suspected malignancy, standard‐of care management currently includes histopathologic examination and analysis of tumor‐specific molecular abnormalities. Herein, we present a 77‐year‐old patient with an abdominal mass suspected to be a gastrointestinal stromal tumor (GIST) but without the possibility to collect a tumor biopsy. Cell‐free DNA extracted from a blood sample was analyzed for the presence of mutations in GIST‐specific genes using next generation sequencing. Furthermore, liquid biopsies were used to monitor the levels of mutant DNA copies during treatment with a tumor‐specific mutation droplet digital PCR assay that correlated with the clinical and radiological response. Blood‐based testing is a good alternative for biopsy‐based testing. However, it should only be applied when biopsies are not available or possible to obtain because overall, in only 50%–85% of the cell‐free plasma samples is the known tumor mutation detected.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Namløs

Boye

Mishkin³

et al. 2018

Molecular Cancer Therapeutics

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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 and 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 ( = 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. .

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Detecting secondary C-KIT mutations in the peripheral blood of patients with imatinib-resistant gastrointestinal stromal tumor

Cited by 11 publications

References 0 publications

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

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

Diagnosis and Treatment Monitoring of a Patient with Gastrointestinal Stromal Tumor by Next-Generation Sequencing and Droplet Digital Polymerase Chain Reaction Assay of a PDGFRA Mutation in Plasma-Derived Cell-Free Tumor DNA

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

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