Katarina Krstajić1*, Djordje Stojanovic1, Djordje Pavlovic1, Natasa Tosic1, Filip Markovic2, Bojan Ristivojevic1, Ivana Grubisa1, Irena Marjanovic1, Teodora Karan Djurasevic1, Milica Kontic Jovanovic2 and Branka Zukic1
1Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
2Clinic for Pulmonology, University Clinical Centre,11000 Belgrade, Serbia
katarina.krstajic [at] imgge.bg.ac.rs
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide and in Serbia. Despite advances in diagnostics and therapy, the disease is diagnosed in most patients at an advanced or metastatic stage, resulting in extremely low five-year survival rates. Non-small Cell Lung Cancer is characterized by pronounced molecular heterogeneity and the presence of genomic alterations that may serve as therapeutic targets. This study aimed to characterize the genomic profile of advanced NSCLC and identify therapeutically relevant genomic alterations using comprehensive genomic profiling. Genomic profiling of formalin-fixed paraffin-embedded tumor tissue samples from 72 patients with advanced NSCLC was performed using the AVENIO Tumor Tissue comprehensive genomic profiling kit based on next-generation sequencing technology. Data analysis and interpretation were conducted using the NAVIFY® Mutation Profiler software based on the FoundationOne® platform. Only variants with clear or potential clinical significance and a minimum variant allele frequency of 3% were included in the analysis. The most frequent genomic alterations were detected in the genes TP53 (67%), KRAS (40%), STK11 (32%), KMT2D (26%), and KEAP1 (24%). Additional genomic alterations included single nucleotide variants, insertions/deletions, and copy number variations. Concurrent alterations affecting key tumorigenic signaling pathways, including the RAS/MAPK and PI3K/AKT pathways, indicated substantial molecular heterogeneity. Clinically relevant genomic alterations were identified in a significant proportion of patients, most commonly involving KRAS G12C (13.9%), EGFR alterations, including exon 19 deletions, L858R, G719C, S768I, and L861Q mutations, and ALK rearrangements (6.9%). Less frequent alterations were detected in MET and ERBB2, including amplifications and exon 20 insertions, representing potential targets for existing or investigational targeted therapies. These findings contribute to a better understanding of the molecular landscape of advanced NSCLC in Serbia and support the implementation of personalized therapeutic approaches in routine clinical practice. Furthermore, the study highlights the importance of integrating comprehensive genomic profiling into clinical workflows for the identification of predictive biomarkers and novel therapeutic opportunities.
Keywords: NSCLC, CGP, NGS, biomarkers, oncology