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Potential biomarkers of primary resistance to first- and second-generation EGFR-TKIs in non-small-cell lung cancer: a
Jingyi Wang1,2,3, Bolin Chen1, Xingxiang Pu1
1The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China.
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.
Insights
Primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer is linked to TP53 mutations and elevated PD-L1 expression. These factors, along with PTPRD and TACC3 mutations, contribute to shorter progression-free and overall survival.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improve outcomes for EGFR-sensitive mutant non-small-cell lung cancer (NSCLC).
- Mechanisms of primary resistance to EGFR-TKIs are not fully understood.
Purpose of the Study:
- To identify biomarkers associated with primary resistance to first- and second-generation EGFR-TKIs in NSCLC.
- Define primary resistance as disease progression within 90 days of treatment in EGFR-mutant NSCLC patients without objective response.
Main Methods:
- Retrospective analysis of 70 NSCLC patients treated with EGFR-TKIs.
- Next-generation sequencing of tumor tissue and peripheral blood using an 825-gene panel.
- Analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissues.
Main Results:
- TP53 exon 4 mutations correlated with significantly shorter progression-free survival (PFS) and overall survival (OS).
- Increased mutation frequencies of PTPRD and TACC3 were observed in the primary resistant group, associated with poorer PFS and OS.
- Higher PD-L1 expression levels were found in patients with primary resistance.
Conclusions:
- Primary resistance to EGFR-TKIs is heterogeneous.
- Somatic variants (e.g., TP53, PTPRD, TACC3) and high PD-L1 expression may contribute to primary resistance in NSCLC.
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