Tyrosine kinase inhibitor sensitive PDGFRΑ mutations in GIST: Two cases and review of the literature

Abstract

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal malignancies of the gastrointestinal tract. Most GISTs harbor a c-KIT (80%) or a PDGFRα (10%) mutation that leads to constitutive activation of the tyrosine kinase receptor. Response to treatment with tyrosine kinase inhibitors (TKIs) is dependent on mutational status of the tumor. The most common mutation in PDGFRα, D842V, is known to be imatinib resistant. Almost all other PDGFRα mutations are imatinib sensitive. We describe two patients with a PDGFRα exon 18 mutated GIST responding to treatment with TKIs. One of these patients has a p.M844_S847 deletion, not previously described in relation with TKI treatment response. Mutations in circulating tumor DNA were detectable with digital droplet PCR in serial plasma samples taken during treatment and correlated with treatment response of both patients. Computer 3D-modeling of the PDGFRα kinase domain of these two variants revealed no direct interference in imatinib or sunitinib binding and no effect in its activity in contrast to the reported structure of the imatinib resistant D842V mutation.An overview is given of the literature regarding the evidence of patients with different PDGFRα mutated GISTs on response to TKIs. The findings emphasize the use of mutational analysis in GIST to provide patients personalized treatment. Detection of mutations in plasma is feasible and can provide real-time information concerning treatment response. We suggest to register GIST patients with these uncommon mutations in a prospective international database to understand the tumor biology and obtain more evidence of such mutations to predict treatment response.

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors

“…The main limitation from our study is the cohort size: despite exhaustive inter-platform analysis and crossvalidations, these low numbers cannot capture the biological complexity of this disease from paucisymptomatic localized tumors to TKI-refractory disease. This limitation, also affecting prior publications in GIST and sarcomas [35,36,38,39,42,43,[45][46][47], would benefit from international consortiums delving deeper the clinical utility of ctDNA in malignant mesenchymal neoplasms. Likewise, the role of other circulating markers [48] or epigenetic biomarkers [49] with potential role in tumor diagnosis, monitoring and response evaluation is yet to be defined in GIST.…”

In search of definitions: Cancer‐associated fibroblasts and their markers

“…Crenolanib, a receptor tyrosine kinase inhibitor for PDGFRα and PDGFRβ, is currently undergoing phase III trials in advanced or metastatic gastrointestinal stromal tumor (GIST) patients . While this is largely driven by the common nature of PDGFRα mutations in GIST patients, which is mutated in approximately 10% of all patients, the heightened activity of the PDGFR pathways in CAFs make them an attractive target for potential therapeutics. Furthermore, other PDGFR inhibitors such as Dasatinib and Imatinib, have been shown to be capable of reducing the pro‐proliferative effect of CAF conditioned media and changing the microarray gene expression signature of primary cancer‐associated fibroblasts into one more closely resembling normal non‐tumorigenic fibroblasts …”

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

“…The patient gave permission to participate in a study to perform mutation analysis on cell‐free DNA extracted from plasma of patients with advanced GIST (KWF research grant RUG 2013‐6355, http://clinicaltrials.gov NCT02331914). cfDNA was extracted and sequenced using NGS as reported previously . The analysis revealed a mutation in PDGFRα (NM_006206.5: c.2524_2532del; p.D842_M844del), with a variant allelic frequency (VAF) of 4%.…”

“…C, D). Procedures for DNA extraction and ddPCR analysis were reported previously . Upon request, details on primers and probes could be provided.…”