Potential biomarkers of primary resistance to first- and second-generation EGFR-TKIs in non-small-cell lung cancer: a real-world study
Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the prognosis of EGFR-sensitive mutant non-small-cell lung cancer (NSCLC). However, the mechanisms underlying primary resistance to EGFR-TKIs remain unclear. Objective: This study aimed to explo...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2025-04-01
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| Series: | Therapeutic Advances in Medical Oncology |
| Online Access: | https://doi.org/10.1177/17588359251336632 |
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| Summary: | Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the prognosis of EGFR-sensitive mutant non-small-cell lung cancer (NSCLC). However, the mechanisms underlying primary resistance to EGFR-TKIs remain unclear. Objective: This study aimed to explore the biomarkers associated with primary resistance to first- and second-generation EGFR-TKIs. Primary resistance to EGFR-TKIs was defined as disease progression within 90 days (3 months) of treatment in patients with EGFR-sensitive mutant adenocarcinoma without any evidence of objective response. Design: Retrospective, single-center study. Methods: This study retrospectively screened patients with NSCLC who received EGFR-TKIs at Hunan Cancer Hospital from January 2018 to December 2022. According to pre-determined clinical outcomes, we divided the patients into primary resistance and sensitivity groups. Only patients with sufficient samples that passed quality control were included in this study. Tumor tissue and paired peripheral blood samples collected from patients before treatment were subjected to next-generation sequencing using an 825-gene panel. In addition, tumor tissue samples were analyzed for programmed cell death ligand 1 (PD-L1) expression. Results: A total of 70 patients were enrolled in this study, with 35 in each of the primary resistant and sensitive groups. Patients with exon 4 mutations in the TP53 gene had significantly shorter progression-free survival (PFS) and overall survival (OS) compared to those without the mutation. PTPRD and TACC3 mutation frequencies were substantially higher in the primary resistant group and were associated with shorter PFS and OS. Furthermore, patients in the primary resistant group exhibited substantially higher levels of PD-L1 expression. Conclusion: The potential mechanisms of primary resistance to EGFR-TKIs are highly heterogeneous. Combining some somatic variants affecting tumor function and high PD-L1 expression may contribute to this resistance. |
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| ISSN: | 1758-8359 |