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Circulating cKIT and PDGFRA DNA indicates disease activity in Gastrointestinal Stromal Tumor (GIST) |
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| Authors: | Stefanie Jilg Michael Rassner Jacqueline Maier Silvia Waldeck Victoria Kehl Marie Follo Ulrike Philipp Andreas Sauter Katja Specht Jan Mitschke Thoralf Lange Sebastian Bauer Philipp J. Jost Christian Peschel Justus Duyster Timo Gaiser Peter Hohenberger Nikolas von Bubnoff |
| Affiliation: | 1. Center for Internal Medicine, Department of Hematology/Oncology and Hemostaseology, University of Leipzig, Leipzig, Germany;2. Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany German Cancer Consortium (DKTK) partner site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany;3. Institute for Medical Informatics, Statistics, and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;4. Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany;5. Department of Diagnostic and Interventional Radiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;6. Institute of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;7. Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany German Cancer Consortium (DKTK) partner site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany;8. Asklepios Klinik Weißenfels, Weißenfels, Germany;9. Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany;10. III Medical Department for Hematology and Oncology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;11. Institute of Pathology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany;12. Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany |
| Abstract: | 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. |
| Keywords: | liquid biopsy circulating tumor DNA GIST cancer biomarker |