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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
The correlation between crizotinib efficacy and molecular heterogeneity by next-generation sequencing in non-small
Tangfeng Lv1,2, Qian Zou1, Zhengbo Song3,4
1Department of Respiratory Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
Background:
Non-small cell lung cancer (NSCLC) patients with EML4-ALK fusion exhibited various durations of response to crizotinib. Molecular heterogeneity is also one of the factors associated with resistance to crizotinib. This study investigated the relevance of molecular heterogeneity to the clinical efficacy of crizotinib using next-generation sequencing (NGS).
Methods:
A total of 52 ALK-positive advanced NSCLC patients were enrolled. The genetic variation was revealed by NGS. We identified different ALK fusion types, allelic fraction (AF) and additional coexisting mutations (ACMs) and evaluated the correlation between the above three factors and clinical response to crizotinib.
Results:
Among the group that was detected with ALK+ fusion by immunohistochemistry (IHC), patients detected as ALK- fusion by the NGS method were associated with a shorter progression-free survival (PFS) compared with ALK+ patients by NGS. Moreover, for different ALK fusion types, the median PFS of variant 1/2/3 and other uncommon variants were 305, 557, 242 and 370 days, respectively. Although there was no statistically significant difference (P=0.201), patients with ALK variant 2 appeared to display a longer PFS than other types of variants in this study. There was no significant difference in the relationship between ALK fusion AF and PFS (P=0.639). Additionally, there was no correlation between ACMs and PFS in the three groups (IHC+, IHC+/NGS-, and IHC+/NGS+, P=0.738, 0.801 and 0.550). We analysed the relationship between TP53/FAT3 and PFS in the IHC+/NGS+ group, and there was no statistically significant difference (P=0.712/0.631).
Conclusions:
It is necessary to use multiple methods together to detect ALK fusion, and we can continue to carry out the study of the correlation between the different contents of heterogeneity of gene mutations and TKI effects using the NGS method.
Insights
Next-generation sequencing (NGS) is crucial for detecting EML4-ALK fusion in non-small cell lung cancer (NSCLC). Molecular heterogeneity impacts crizotinib efficacy, with specific ALK fusion variants influencing progression-free survival (PFS).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) patients with EML4-ALK fusion show varied responses to crizotinib.
- Molecular heterogeneity is a known factor contributing to crizotinib resistance.
- Understanding this heterogeneity is key to optimizing treatment strategies.
Purpose of the Study:
- To investigate the role of molecular heterogeneity in the clinical efficacy of crizotinib in ALK-positive NSCLC patients.
- To evaluate the correlation between ALK fusion types, allelic fraction (AF), and additional coexisting mutations (ACMs) with crizotinib response using NGS.
- To compare NGS-based ALK detection with immunohistochemistry (IHC) for predicting treatment outcomes.
Main Methods:
- Enrolled 52 ALK-positive advanced NSCLC patients.
- Utilized next-generation sequencing (NGS) to identify genetic variations, including ALK fusion types, AF, and ACMs.
- Correlated these genetic factors with clinical response to crizotinib, specifically progression-free survival (PFS).
Main Results:
- Patients negative for ALK fusion by NGS but positive by IHC had significantly shorter PFS.
- Different ALK fusion variants showed varying median PFS (e.g., variant 2: 557 days).
- No significant correlation was found between ALK fusion AF, ACMs, or specific mutations (TP53/FAT3) and PFS.
Conclusions:
- Employing multiple methods, including NGS, is essential for accurate ALK fusion detection in NSCLC.
- Further research into the correlation between gene mutation heterogeneity and tyrosine kinase inhibitor (TKI) efficacy using NGS is warranted.
- NGS provides valuable insights into molecular heterogeneity influencing treatment response.
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