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.
| Original language | English |
|---|---|
| Journal | International Journal of Cancer |
| Volume | 145 |
| Issue number | 8 |
| Pages (from-to) | 2292-2303 |
| Number of pages | 12 |
| ISSN | 0020-7136 |
| DOIs | |
| Publication status | Published - 15.10.2019 |
Funding
diagnostic imaging, response to therapy (surgery and/or therapy with a TKI) or relapse or progression of the disease as assessed by diagnostic imaging. Furthermore, the sensitivity of L-PCR and dPCR for specific cKIT or PGDFRA mutations was analyzed. The study was approved by the responsible Institutional Review Board (Technical University of Munich, 5108/11). This trial was registered under Eudra-CTNo. 2011-002544-27 and ClinicalTrials.gov NCT01462994. This trial received financial support by Novartis Pharma (Study Code: CSTI571BDE78T). The authors would also like to acknowledge the support of the Munich Study Center, the University of Freiburg Medical Faculty, the Comprehensive Cancer Center Freiburg (CCCF), the German Cancer Consortium (DKTK; grant no. L665 to NvB), the Bundesministerium für Bildung und Forschung (BMBF; grant no. 13GW0198E to NvB) and Novartis Germany for research support (study no. CSTI5781BDE78T to NvB). We thank Fol-ker Schneller for patient management, Sandra Eckert and Monika Mathew for administrative support, and Amanda Kalman for critical advice. In addition, the authors want to thank Laura-Jane Behl as well as the whole “Genomics and Proteomics Core Facility of the DKFZ Heidelberg (Germany)” for providing excellent sequencing service. The authors would also like to acknowledge the support of the Munich Study Center, the University of Freiburg Medical Faculty, the Comprehensive Cancer Center Freiburg (CCCF), the German Cancer Consortium (DKTK; grant no. L665 to NvB), the Bundesministerium f?r Bildung und Forschung (BMBF; grant no. 13GW0198E to NvB) and Novartis Germany for research support (study no. CSTI5781BDE78T to NvB). We thank Folker Schneller for patient management, Sandra Eckert and Monika Mathew for administrative support, and Amanda Kalman for critical advice. In addition, the authors want to thank Laura-Jane Behl as well as the whole ?Genomics and Proteomics Core Facility of the DKFZ Heidelberg (Germany)? for providing excellent sequencing service.
