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

Anna Buder,Maximilian J Hochmair,Sabrina Weber,Klaus Hackner,Ellen Heitzer,Martin Filipits,Julie Waldispühl-Geigl,Tina Moser,Peter Errhalt,Ulrike Setinek

doi:10.3390/biom11050618

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.

Highlights

T790M-positive based on plasma genotyping by ddPCR prior to the initiation of second-line treatment with osimertinib
It has previously been shown that amplifications of wildtype or mutant epidermal growth factor receptor (EGFR) [36,37,38], ERBB2 amplifications [39], MET amplifications [40], and rrSCNAs of CDKN2A or CDK4/6 [21,40] are associated with rapid progression to osimertinib and acquired drug resistance
The findings of our present study suggest that rrSCNAs in plasma circulating tumor DNA (ctDNA) detected before second-line therapy with osimertinib are clinically relevant in patients with advanced EGFR-mutated lung adenocarcinoma

Summary

Introduction

Osimertinib is the standard treatment of advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients and EGFR T790M-mediated resistance [1,2,3,4]. Patients will develop resistance to osimertinib therapy and clinically progress. Resistance mechanisms in osimertinib-treated patients appear to be complex and are currently not fully understood. Both EGFR-dependent and EGFR-independent mechanisms of resistance may be important [5]

Methods

Results

Discussion

Conclusion