Somatic Copy-Number Alterations in Plasma Circulating Tumor DNA from Advanced EGFR-Mutated Lung Adenocarcinoma Patients

Abstract

Background: To assess the clinical relevance of genome-wide somatic copy-number alterations (SCNAs) in plasma circulating tumor DNA (ctDNA) from advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients. Methods: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR. Results: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 31 (32%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before the initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 81%, p = 0.08) and was an independent predictor for shorter progression-free survival (adjusted HR 3.33, 95% CI 1.37–8.10, p = 0.008) and overall survival (adjusted HR 2.54, 95% CI 1.09–5.92, p = 0.03). Conclusions: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach enables the comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.

Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations

“…In contrast, T790M cases did not show correlation with the duration of drug response, suggesting that the changes in hypo-methylation and CNA in those cases could be passenger events that might not have a functional role during the response to 1G or 2G TKIs. Our finding was consistent with a recent study showing that genome-wide CNA was detected in patients carrying T790M at the time of resistance to gefitinib and that the presence of CNA was associated with poor response to subsequent treatment with 3G TKI, osimertinib 47 . MET and HER2 amplification did not show noticeable changes in both global methylation and CNA, suggesting that the acquisition of genome instability during the response to TKI drugs might be unique to the EGFR dependent resistance mechanisms.…”

Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring

“…A previous study evaluated the feasibility of using ctDNA in blood samples as a substitute for tumor biopsy to determine EGFR mutation status and further linked EGFR mutation in ctDNA to prognosis [ 29 ]. Univariate analysis of patients with an EGFR mutation in ctDNA showed that the L858R mutation in tumor tissue or ctDNA was a marker of shorter OS and PFS.…”