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.
Highlights
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal malignancies of the gastrointestinal tract with an incidence of 10 cases per million people [1]
DdPCR was performed on a T100 Thermal Cycler (Bio-Rad, Hercules, CA, USA) and samples were transported to the QX200 Droplet Reader (Bio-Rad) for fluorescent measurement of FAM and HEX probes, data was analyzed with Quantasoft software version 1.6.6
Five of the fourteen papers describe data of progression free survival (PFS) or overall survival (OS) of patients with a PDGFRα mutated advanced GIST treated with imatinib (Table 1)
Summary
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal malignancies of the gastrointestinal tract with an incidence of 10 cases per million people [1]. A biopsy of a progressive nodule was performed and treatment with regorafenib (160mg daily for 3 out of 4 weeks) was started With this regimen stable disease during 5 months was obtained (Figure 1E). Treatment with imatinib 400 mg daily was initiated and after ten days she had clinical benefit She tolerated the treatment well and a partial response was seen on the CT-scan performed every 3 months (Figure 2C and 2D). Treatment was continued with increased dosage of imatinib 400 mg twice daily and the patient tolerated this dosage, yet no clinical and radiological response was seen (progressive lesions on CT-scan after 3 months treatment, Figure 2G and 2H). DdPCR was performed on a T100 Thermal Cycler (Bio-Rad, Hercules, CA, USA) and samples were transported to the QX200 Droplet Reader (Bio-Rad) for fluorescent measurement of FAM and HEX probes, data was analyzed with Quantasoft software version 1.6.6
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