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Updated: Jan 11, 2026
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Beyond ALK fusion positivity: structural complexity as a prognostic indicator in first-line ALK-TKI therapy
Dujiang Liu1,2, Kaibo Ding3, Linjing Zhou1
1Department of Medical Thoracic Oncology, Institute of Basic Medicine and Cancer (IBMC), Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No.1 East Banshan Road, Hangzhou, 310022, Zhejiang, China.
Background:
Although tyrosine kinase inhibitors (TKIs) have significantly improved survival outcomes in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), the efficacy of current TKIs for emerging ALK rearrangement subtypes warrants further investigation, particularly with the advancements in genomic sequencing technologies.
Methods:
We retrospectively analyzed 118 NSCLC patients with ALK rearrangements identified by next-generation sequencing (NGS) from January 2015 to April 2024. Among these, 89 patients who received first-line ALK-TKIs were assessed to determine therapeutic outcomes based on ALK rearrangement subtypes.
Results:
Among 118 NSCLC patients, 36 (30.5%) harbored nonreciprocal/reciprocal translocations, 73 (61.9%) carried solitary EML4-ALK fusion, and 9 (7.6%) had solitary non-EML4-ALK fusions. Of the 89 patients treated with first-line TKIs, 60 (67.4%) had solitary 3'-ALK fusions, whereas 29 (32.6%) exhibited nonreciprocal/reciprocal ALK translocations. Compared with patients harboring solitary 3'-ALK fusions, those with nonreciprocal/reciprocal translocations experienced significantly shorter median progression-free survival (mPFS) (15.6 vs. 31.1 months; HR = 1.805; P = 0.048), although no significant difference in median overall survival (mOS) was observed (66.6 vs. 75.7 months; HR = 1.162; P = 0.714). Additionally, TP53 mutations were the most common co-occurring alterations in both groups, with no significant difference in frequency (P = 0.650).
Conclusions:
Nonreciprocal/reciprocal ALK translocations represent an independent adverse prognostic factor for ALK-positive NSCLC patients compared with solitary 3'-ALK fusions. However, their poorer prognosis does not appear to be directly associated with TP53 co-mutations.
Insights
Anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer (NSCLC) indicate a poorer prognosis compared to solitary ALK fusions. This finding is independent of TP53 co-mutations, highlighting new therapeutic considerations for ALK-positive NSCLC.
Area of Science:
- Oncology
- Genomics
- Thoracic Surgery
Background:
- Tyrosine kinase inhibitors (TKIs) have improved outcomes for anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC).
- Emerging ALK rearrangement subtypes require further investigation regarding TKI efficacy.
- Genomic sequencing advancements facilitate detailed analysis of ALK rearrangements.
Purpose of the Study:
- To investigate the therapeutic outcomes of first-line ALK-TKIs in NSCLC patients based on ALK rearrangement subtypes.
- To identify prognostic factors associated with different ALK rearrangement patterns in NSCLC.
Main Methods:
- Retrospective analysis of 118 NSCLC patients with ALK rearrangements identified by next-generation sequencing (NGS).
- Assessment of therapeutic outcomes in 89 patients receiving first-line ALK-TKIs, stratified by ALK rearrangement subtypes.
- Comparison of progression-free survival (PFS) and overall survival (OS) between patients with nonreciprocal/reciprocal ALK translocations and solitary 3'-ALK fusions.
Main Results:
- Nonreciprocal/reciprocal ALK translocations were identified in 30.5% of patients, solitary EML4-ALK fusions in 61.9%, and solitary non-EML4-ALK fusions in 7.6%.
- Patients with nonreciprocal/reciprocal translocations (32.6%) had significantly shorter median PFS (15.6 months) compared to those with solitary 3'-ALK fusions (67.4%, 31.1 months).
- No significant difference in median overall survival was observed between the groups; TP53 mutations were common co-occurring alterations without significant frequency differences.
Conclusions:
- Nonreciprocal/reciprocal ALK translocations are an independent adverse prognostic factor in ALK-positive NSCLC.
- The poorer prognosis associated with these translocations is not directly linked to TP53 co-mutations.
- These findings underscore the importance of characterizing ALK rearrangement subtypes for personalized NSCLC treatment strategies.
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