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Analysis of Acquired Fusion Mutations in EGFR-TKIs-Resistant Patients with Advanced Lung Cancer
Yuan Yang1, Nana Zhang2, Liang Shi1
1Department of Oncology, Beijing Chest Hospital, Capital Medical University, and Beijing Tuberculosis and Thoracic Tumour Research Institute, Beijing, China.
Abstract:
To determine the characteristics of non-small cell lung cancer (NSCLC) patients with fusion genes emerging after resistance to EGFR-TKIs. This study retrospectively collected 2800 cases of NSCLC with EGFR-sensitive mutations who underwent tissue-based next- generation sequencing (NGS) testing at least once. Patients with acquired fusion mutations, including ALK, ROS1, RET, etc., were included in the study, and clinical data, gene mutation status, treatment strategies, and follow-up were collected. Given the small sample size and exploratory design of this case series (n = 9), the findings were reported descriptively. There were six cases of ALK fusion, two cases of RET fusion, and one case of ROS1 fusion. EGFR abundance decreased in five patients, while EGFR was detected as negative in the other four patients. When fusion mutations emerged, the use of ALK/RET/ROS1-TKIs or EGFR-TKIs combined with fusion-TKIs demonstrated efficacy. The progression-free survival ranged from 5 months to ≥39 months. One patient with acquired fusion gene mutations developed small-cell lung cancer transformation after ALK-TKIs resistance. Key Words: Lung cancer, ALK fusion, RET fusion, ROS1 fusion, EGFR-TKIs-resistance, Targeted therapy.
Insights
Acquired fusion genes like ALK, ROS1, and RET can emerge in non-small cell lung cancer (NSCLC) after EGFR-TKI resistance. Targeted therapies, including ALK/RET/ROS1-TKIs, show efficacy in these NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) treatment often involves Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs).
- Acquired resistance to EGFR-TKIs is a significant clinical challenge in NSCLC management.
- Emergence of gene fusions can be a mechanism of acquired resistance.
Purpose of the Study:
- To characterize non-small cell lung cancer (NSCLC) patients who develop fusion genes after resistance to EGFR-TKIs.
- To describe the clinical features, genetic landscape, and treatment outcomes in this patient cohort.
Main Methods:
- Retrospective collection of 2800 NSCLC cases with EGFR-sensitive mutations.
- Tissue-based Next-Generation Sequencing (NGS) for identifying acquired fusion mutations (ALK, ROS1, RET, etc.).
- Descriptive analysis of clinical data, mutation status, treatment strategies, and follow-up for a case series (n=9).
Main Results:
- Nine patients with acquired fusion mutations were identified: six ALK, two RET, and one ROS1.
- EGFR abundance decreased or became undetectable in most patients with fusion emergence.
- Treatment with ALK/RET/ROS1-TKIs or combination therapy showed efficacy, with progression-free survival ranging from 5 to ≥39 months.
- One patient experienced small-cell lung cancer transformation after ALK-TKI resistance.
Conclusions:
- Acquired gene fusions are a mechanism of EGFR-TKI resistance in NSCLC.
- Targeted therapies directed at these fusions, or combination strategies, are effective treatment options.
- Further research is needed to understand the clinical implications and management of fusion-driven NSCLC post-EGFR-TKI resistance.
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