Abstract 4951: Dynamics of KIT exon 11 mutations in cell free plasma DNA of patients treated for advanced gastrointestinal stromal tumors: Results from the Dutch GIST bio-databank
Authors: Boonstra Pieter A. , Elst Arja ter , Tibbesma Marco , Mathijssen Ron H. , Atrafi Florence , Coevorden Frits van , Farag Sheima , Steeghs Neeltje , Desar Ingrid M. , Graaf Winette T. van der , Gelderblom Hans , Etten Boudewijn van , Overbosch Jelle , Suurmeijer Albert J. , Gietema Jourik A. , Schuuring Ed , Reyners Anna K. 
Published: July 2017

Introduction

Gastrointestinal stromal tumors (GISTs) are rare malignancies of the gastrointestinal tract. In the Netherlands, most patients with GIST are treated in five sarcoma expertise centers.

GIST is known to have driver mutations in the tyrosine kinase receptors KIT and PDGFRα in respectively 80% and 10% of the patients. Mutations (single nucleotide variations, insertions and deletions) are mostly found in KIT exon 9 and 11. GIST patients with a primary KIT exon 11 mutation respond generally well to tyrosine kinase inhibitors (TKIs).

The aim of this study was to evaluate treatment response by the detection of KIT exon 11 mutations in cell free DNA (cfDNA) of patients with GIST at multiple time points.

Materials and methods

Since Dec 2014, plasma samples of patients have been collected at every hospital visit and were put in a bio-databank for analysis of mutation detection in cfDNA. Eligibility criteria were histological diagnosis of GIST and treatment with a TKI. Patients with a known KIT exon 11 mutation, of which a baseline (before start of any TKI) sample or a recurrence/progression sample was available, were analyzed. A custom single-tube digital droplet PCR (ddPCR) drop-off assay, designed at the UMCG, was used. This assay detects 80% of the known KIT exon 11 mutations.

Results

Until Nov 2016, &gt;620 samples of 175 patients have been collected. From 43 patients with a KIT exon 11 mutations in the pretreatment tumor biopsy, a baseline/progression sample was available. Mutations in exon 11 were detected in cfDNA from baseline plasma of 22/43 patients, 20 with metastasized and 2 with localized disease. Of the 21 patients without detectable mutations, 11 had localized and 10 metastatic disease. Three of these patients with metastatic disease had mutations that could not be detected by our probe.

Two weeks after start of TKI, an increase in mutant allelic frequency was seen in 5 (of 9 available 2 week samples) patients, while 4 weeks later the mutant allelic frequency had decreased, in parallel

with decrease in tumor load on radiological imaging. Eight patients developed radiological disease recurrence (2 patients, after 4 and 20 months) or progression (6 patients, median 10 (6-24) months). This was paralleled by an increase in mutant allelic frequency in cfDNA in 6 of them (baseline median 0% (0-0.9%); at progression median 3.5% (0-30%); p= 0.028; related samples Wilcoxon signed rank test).

Summary and conclusion

KIT exon 11 mutations in cfDNA could be detected in 74% of the patients with metastatic disease. Disease progression or recurrence, coincides with a rise of mutant alleles detected in the plasma.

In conclusion, mutation detection in cfDNA of GIST patients with metastatic disease is feasible. Our study will be extended to include the monitoring of early progression based on cfDNA, which may guide early treatment adaptations.

Citation Format: Pieter A. Boonstra, Arja ter Elst, Marco Tibbesma, Ron H. Mathijssen, Florence Atrafi, Frits van Coevorden, Sheima Farag, Neeltje Steeghs, Ingrid M. Desar, Winette T. van der Graaf, Hans Gelderblom, Boudewijn van Etten, Jelle Overbosch, Albert J. Suurmeijer, Jourik A. Gietema, Ed Schuuring, Anna K. Reyners. Dynamics of KIT exon 11 mutations in cell free plasma DNA of patients treated for advanced gastrointestinal stromal tumors: Results from the Dutch GIST bio-databank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4951. doi:10.1158/1538-7445.AM2017-4951