Abstract
Simple SummaryWe compared the UltraSEEK™ Lung Panel on the MassARRAY® System (Agena Bioscience) with the FDA-approved Cobas® EGFR Mutation Test v2 for the detection of EGFR mutations in liquid biopsies of NSCLC patients, accompanied with preanalytical sample assessment using the novel Liquid IQ® Panel. For the detection of relevant predictive mutations using the UltraSEEK™ Lung Panel, an input of over 10 ng showed 100% concordance with Cobas® EGFR Mutation Test v2 and detection of all tissue confirmed mutations. In case of lower ccfDNA input, the risk of missing clinically relevant mutations should be considered. The use of a preanalytical ccfDNA quality control assay such as the Liquid IQ® Panel is recommended to confidently interpret results, avoiding bias induced by non-specific genomic DNA and low input of specific tumoral ccfDNA fragments.Plasma-based tumor mutational profiling is arising as a reliable approach to detect primary and therapy-induced resistance mutations required for accurate treatment decision making. Here, we compared the FDA-approved Cobas® EGFR Mutation Test v2 with the UltraSEEK™ Lung Panel on the MassARRAY® System on detection of EGFR mutations, accompanied with preanalytical sample assessment using the novel Liquid IQ® Panel. 137 cancer patient-derived cell-free plasma samples were analyzed with the Cobas® and UltraSEEK™ tests. Liquid IQ® analysis was initially validated (n = 84) and used to determine ccfDNA input for all samples. Subsequently, Liquid IQ® results were applied to harmonize ccfDNA input for the Cobas® and UltraSEEK™ tests for 63 NSCLC patients. The overall concordance between the Cobas® and UltraSEEK™ tests was 86%. The Cobas® test detected more EGFR exon19 deletions and L858R mutations, while the UltraSEEK™ test detected more T790M mutations. A 100% concordance in both the clinical (n = 137) and harmonized (n = 63) cohorts was observed when >10 ng of ccfDNA was used as determined by the Liquid IQ® Panel. The Cobas® and UltraSEEK™ tests showed similar sensitivity in EGFR mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making.
Highlights
Mutations and gene-fusions underlie key molecular mechanisms that drive cancer development and progression
In 2015, osimertinib was approved for treatment of EGFR T790M-positive patients who have progressed on first- or second- generation EGFR-tyrosine kinase inhibitors (TKIs) [6]
Plasma-derived circulating cell-free DNA (ccfDNA) of 137 patients was tested for mutation-harboring circulating tumor DNA (ctDNA) using the Plasma-derived ccfDNA
Summary
Mutations and gene-fusions underlie key molecular mechanisms that drive cancer development and progression. Treatment strategies that target specific molecules related to gene mutations or gene-fusions have been developed. In non-small cell lung cancer (NSCLC), activating mutations of EGFR in exons 18–21 are well established as predictive biomarkers for treatment of patients with. Despite the high response rates to various first- and second-generation EGFR-TKIs, eventually all patients with metastasized NSCLC with an EGFR mutation will develop disease progression due to acquired resistance, mostly attributable to the EGFR. Osimertinib was introduced as a third-generation EGFR-TKI that selectively and irreversibly targets the EGFR T790M mutation [5]. In 2015, osimertinib was approved for treatment of EGFR T790M-positive patients who have progressed on first- or second- generation EGFR-TKIs [6]
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