Mark William Linder1, Michael E Egger2, Tracy Van Meter3, Shesh N Rai4,5, Roland Valdes6,7, Melissa Barousse Hall8,9, Xiaoyong Wu4, Norah Alghamdi6, Jason A Chesney8,10,11. 1. Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, 511 S. Floyd Street, Louisville, KY, 40202, USA. mwlind01@louisville.edu. 2. Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA. 3. Department of Radiology, University of Louisville School of Medicine, Louisville, KY, USA. 4. Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. 5. Department of Bioinformatics and Biostatistics, University of Louisville School of Medicine, Louisville, KY, USA. 6. Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, 511 S. Floyd Street, Louisville, KY, 40202, USA. 7. Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY, USA. 8. James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. 9. Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA. 10. Departments of Medicine, Biochemistry/Molecular Biology, University of Louisville School of Medicine, Louisville, KY, USA. 11. Department of Pharmacology/Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
Abstract
BACKGROUND: Circulating tumor DNA (ctDNA) may complement radiography for interim assessment of patients with cancer. OBJECTIVE: Our objective was to explore the relationship between changes in plasma ctDNA versus radiographic imaging among patients with metastatic melanoma. METHODS: Using the Idylla system, we measured B-Raf proto-oncogene (BRAF) V600 ctDNA in plasma from 15 patients with BRAF V600E/K-positive primary tumors undergoing standard-of-care monitoring, including cross-sectional computed tomography (CT) imaging. BRAF V600 mutant allele frequency (%MAF) was calculated from the Idylla Cq values and directly measured using droplet digital polymerase chain reaction (ddPCR). RESULTS: The Idylla ctDNA assay demonstrated 91% sensitivity, 96% specificity, 91% positive predictive value, and 96% negative predictive value for the presence of > 93 mm metastatic disease. Qualitative ctDNA results corresponded to changes in RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 status determined by CT imaging in 11 of 15 subjects (73%). Calculated %MAF results correlated with ddPCR (R2 = 0.94) and provided evidence of progressive disease 55 and 97 days in advance of CT imaging for two subjects with persistently positive qualitative results. CONCLUSIONS: Overall, interim ctDNA results provided evidence of partial response or progressive disease an average of 82 days before radiography. This pilot study supports the feasibility of using the Idylla plasma BRAF V600 ctDNA assay as a complement to CT scanning for routine monitoring of therapeutic response. Somatic mutation quantification based on Cq values shows promise for identifying disease progression and warrants further validation.
BACKGROUND: Circulating tumor DNA (ctDNA) may complement radiography for interim assessment of patients with cancer. OBJECTIVE: Our objective was to explore the relationship between changes in plasma ctDNA versus radiographic imaging among patients with metastatic melanoma. METHODS: Using the Idylla system, we measured B-Raf proto-oncogene (BRAF) V600 ctDNA in plasma from 15 patients with BRAF V600E/K-positive primary tumors undergoing standard-of-care monitoring, including cross-sectional computed tomography (CT) imaging. BRAF V600 mutant allele frequency (%MAF) was calculated from the Idylla Cq values and directly measured using droplet digital polymerase chain reaction (ddPCR). RESULTS: The Idylla ctDNA assay demonstrated 91% sensitivity, 96% specificity, 91% positive predictive value, and 96% negative predictive value for the presence of > 93 mm metastatic disease. Qualitative ctDNA results corresponded to changes in RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 status determined by CT imaging in 11 of 15 subjects (73%). Calculated %MAF results correlated with ddPCR (R2 = 0.94) and provided evidence of progressive disease 55 and 97 days in advance of CT imaging for two subjects with persistently positive qualitative results. CONCLUSIONS: Overall, interim ctDNA results provided evidence of partial response or progressive disease an average of 82 days before radiography. This pilot study supports the feasibility of using the Idylla plasma BRAF V600 ctDNA assay as a complement to CT scanning for routine monitoring of therapeutic response. Somatic mutation quantification based on Cq values shows promise for identifying disease progression and warrants further validation.
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