Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA
By G. Oxnard, C. Paweletz, Y. Kuang, Stacy L. Mach, Allison O'Connell, M. Messineo, J. Luke, M. Butaney, P. Kirschmeier, D. Jackman and 1 more. Clinical Cancer Research, 2014
747 citations recorded by the source corpus.
Purpose: Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false-positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype. Experimental Design: ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with nonoverlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in patients with EGFR-mutant lung cancer on a prospective trial of erlotinib. Results: We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic curve analysis of four assays demonstrated an area under the curve in the range of 0.80 to 0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging before objective progression. Conclusions: Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks before radiographic progression. Clin Cancer Res; 20(6); 1698–705. ©2014 AACR.
Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/562a2b6eaa71bc43ad67d7d83cc9f79bdab0cbe8
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In Pulmonary and Respiratory Medicine
Citations in the corpus
- Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology (2018, background): “This recommendation is evidence based and supported by 6 studies, comprising 2 MAs,(243,247) 2 PCSs,(235,242) and 2 PRCSs.(232,234) The identified studies used various EGFR”
- The Digital MIQE Guidelines Update: Minimum Information for Publication of Quantitative Digital PCR Experiments for 2020. (2020, methodology): “Other applications that exploit the unique partitioning of dPCR include cis-trans linkage relationships between two targets (29–31) and ‘dropoff’ assays for identifying the frequency of a mutation of unknown sequence (32), and evaluation of gene editing efficiency when using approaches like CRISPRCa”