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Abstract
Analysis of circulating cell-free tumor DNA (cftDNA) has emerged as a specific and sensitive blood-based approach to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. Still, there is some debate on what should be the preferential clinical method for plasma-derived cftDNA analysis. We tested 31 NSCLC patients treated with anti-EGFR tyrosine kinase inhibitors (TKIs), at baseline and serially during therapy, by comparing three methodologies in detecting EGFR mutations (L858R, exon 19 deletion, and T790M) from plasma: scorpions-amplification refractory mutation system (ARMS) methodology by using EGFR Plasma RGQ PCR Kit-QIAGEN, peptide nucleic acid (PNA) clamp and PANA RealTyper integration by using PNAClamp EGFR-PANAGENE, and digital real time PCR by using QuantStudio 3D Digital PCR System-Thermo Fisher Scientific. Specificity was 100% for all three mutations, independently from the platform used. The sensitivity for L858R (42.86%) and T790M (100%) did not change based on the method, while the sensitivity for Del 19 differed markedly (Scorpion-ARMS 45%, PNAClamp 75%, and Digital PCR 85%). The detection rate was also higher (94.23%) as measured by Digital PCR, and when we monitored the evolution of EGFR mutations over time, it evidenced the extreme inter-patient heterogeneity in terms of levels of circulating mutated copies. In our study, Digital PCR showed the best correlation with tissue biopsy and the highest sensitivity to attain the potential clinical utility of monitoring plasma levels of EGFR mutations.
Highlights
The identification of activating epidermal growth factor receptor (EGFR) mutations plays an important role in determining the treatment response to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, afatinib and, more recently, osimertinib in advanced non-small cell lung cancer (NSCLC) patients
We reported a performance comparison between three technologies (Scorpion-amplification refractory mutation system (ARMS) EGFR Plasma RGQ PCR Kit-QIAGEN, QuantStudio 3D Digital PCR System-Thermo Fisher Scientific and PNAClamp EGFR-PANAGENE) in detecting clinically-relevant EGFR mutations in tumor tissue and plasma collected from NSCLC patients
We found a total of 104 EGFR mutations in the cell-free tumor DNA (cftDNA) of 31 NSCLC patients considering the three platforms together
Summary
The identification of activating epidermal growth factor receptor (EGFR) mutations plays an important role in determining the treatment response to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, afatinib and, more recently, osimertinib in advanced non-small cell lung cancer (NSCLC) patients. DNA from normal cells is always present in plasma together with tumor-released cell free DNA, which often represents only a small fraction of the total circulating DNA, so it is important to use high sensitive technologies to detect tumor-specific somatic mutations. Among several methodologies, such as amplification refractory mutation system (ARMS), Digital PCR and next-generation sequencing (NGS) [27,28,29], there is not a widely accepted and approved method for EGFR mutation analysis from cftDNA. We monitored EGFR mutations in plasma samples at baseline and serially during treatment with EGFR-TKIs to predict early development of resistance to treatment
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