WCLC 2025 - Posters & ePosters-P2.06.40 Integrated Molecular Analysis of Advanced NSCLC Depicts Molecular Signatures Associated With Tyrosine Kinase Inhibitors Efficacy

P2.06.40 Integrated Molecular Analysis of Advanced NSCLC Depicts Molecular Signatures Associated With Tyrosine Kinase Inhibitors Efficacy

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This retrospective study investigates molecular and epigenetic factors influencing the efficacy of first-line next-generation tyrosine kinase inhibitors (TKIs) — osimertinib or alectinib — in advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations or ALK rearrangements. The cohort included 44 EGFR-mutant and 16 ALK-rearranged advanced NSCLC patients. Genomic profiling was performed using the Oncomine Comprehensive Assay Plus, alongside miRNA profiling via PCR-based global miRNome assays. Clinical outcomes such as progression-free survival (PFS) and overall survival (OS) were analyzed relative to molecular features.<br /><br />Key findings highlight that in EGFR-mutant NSCLC, co-mutations in TP53, high copy number alteration index (CNAI), genomic instability (GI) index, and chromosomal gains—especially on chromosome arms 1, 4, 5p, and 7p—correlated with significantly shorter PFS and, in some cases, OS. Similarly, in ALK-rearranged cases, TP53 co-mutations predicted shorter PFS, and the presence of multiple co-mutations was linked to worse OS.<br /><br />MicroRNA analysis identified distinct miRNA expression clusters but found no correlation with treatment response clusters. However, comparison of short-term responders (STR) versus long-term responders (LTR) revealed deregulated microRNAs affecting key biological pathways in both cohorts. Notably, in EGFR-mutant patients, upregulation of miR-663b was associated with shorter PFS, while miR-874-3p, miR-671-3p, and miR-663b correlated with poorer OS. No significant miRNA-survival associations were observed in the ALK group.<br /><br />Overall, the study suggests that extended molecular profiling—including co-mutations, chromosomal alterations, and miRNA signatures—may improve prediction of response to next-generation TKIs in EGFR and ALK advanced NSCLC. The authors advocate for larger studies to validate these preliminary insights, potentially enhancing personalized treatment strategies in oncogene-driven NSCLC.

Asset Subtitle

Paolo Bironzo

Meta Tag

Speaker Paolo Bironzo

Topic Pathology and Biomarkers

Keywords

non-small cell lung cancer

NSCLC

EGFR mutations

ALK rearrangements

tyrosine kinase inhibitors

osimertinib

alectinib

TP53 co-mutations

copy number alteration index

microRNA profiling