Somatic Copy-Number Alterations in Plasma Circulating Tumor DNA from Advanced EGFR-Mutated Lung Adenocarcinoma Patients
Anna Buder,
Ellen Heitzer,
Julie Waldispühl-Geigl,
Sabrina Weber,
Tina Moser,
Maximilian J. Hochmair,
Klaus Hackner,
Peter Errhalt,
Ulrike Setinek,
Martin Filipits
Affiliations
Anna Buder
Comprehensive Cancer Center, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
Ellen Heitzer
Diagnostic and Research Center for Molecular BioMedicine, Institute of Human Genetics, Medical University of Graz, 8036 Graz, Austria
Julie Waldispühl-Geigl
Diagnostic and Research Center for Molecular BioMedicine, Institute of Human Genetics, Medical University of Graz, 8036 Graz, Austria
Sabrina Weber
Diagnostic and Research Center for Molecular BioMedicine, Institute of Human Genetics, Medical University of Graz, 8036 Graz, Austria
Tina Moser
Diagnostic and Research Center for Molecular BioMedicine, Institute of Human Genetics, Medical University of Graz, 8036 Graz, Austria
Maximilian J. Hochmair
Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Department of Respiratory and Critical Care Medicine, Hospital North, 1210 Vienna, Austria
Klaus Hackner
Department of Pneumology, University Hospital Krems, Karl Landsteiner University of Health Sciences, 3500 Krems, Austria
Peter Errhalt
Department of Pneumology, University Hospital Krems, Karl Landsteiner University of Health Sciences, 3500 Krems, Austria
Ulrike Setinek
Department of Pathology and Bacteriology, Otto Wagner Hospital, 1140 Vienna, Austria
Martin Filipits
Comprehensive Cancer Center, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
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.
