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Updated: Sep 4, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Identification and therapeutic evaluation of ALK rearrangements in non-small-cell lung cancer
Ruiying Zhao1, Lianying Guo1, Bo Zhang2
1Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, PR China.
Abstract:
This study aimed to present a comprehensive assessment of anaplastic lymphoma kinase (ALK) rearrangements evaluated by DNA/RNA-based next-generation sequencing (NGS) and Ventana immunohistochemistry (IHC) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the therapeutic outcomes of ALK tyrosine kinase inhibitor (TKI) treatment. We investigated ALK gene fusions in 14,894 patients with NSCLC using Ventana IHC and NGS, including 12,533 cases detected via DNA-based NGS and 2,361 cases using RNA-based NGS. The overall percentage agreement (OPA), positive percentage agreement (PPA), and negative percentage agreement (NPA) were calculated when comparing the results between NGS and IHC. The therapeutic responses to ALK-TKIs were also evaluated. In total, 3.50% (439/12,533) of specimens were NGS ALK-positive (NGS-p) in the DNA-based NGS cohort and 3.63% (455/12,533) were IHC ALK-positive (IHC-p). The OPA of NGS was 99.60%, whereas its PPA and NPA were 92.75 and 99.86%, respectively. In the adenocarcinoma (ADC) subcohort, the PPA was 95.69%. In the RNA-based NGS cohort, 2.20% (52/2,361) of specimens were NGS-p and 2.63% (62/2,361) were IHC-p. The OPA of NGS was 99.49%; its PPA and NPA were 82.26 and 99.96%, respectively. Thirteen patients with discordant results received ALK-TKI treatment. In the seven NGS-p/IHC-negative (IHC-n) patients, the overall response rate (ORR) was 85.4% (6/7) and the disease control rate (DCR) was 100%. In the six NGS-negative/IHC-p patients, the ORR was 66.7% (4/6) and the DCR was 100%. In summary, a high concordance of ALK gene fusion detected via NGS and IHC was observed in this study. DNA-based NGS had a higher OPA, PPA, and PPA in the ADC subcohort, whereas RNA-based NGS had a higher NPA. Overall, the results suggest that the combination of NGS and IHC can improve the accuracy of ALK fusion detection; hence, a result determination algorithm for clinical detection of ALK gene fusion was also proposed.
Insights
Next-generation sequencing (NGS) and immunohistochemistry (IHC) show high concordance for detecting anaplastic lymphoma kinase (ALK) rearrangements in non-small-cell lung cancer (NSCLC). Combining these methods improves ALK fusion detection accuracy, guiding ALK tyrosine kinase inhibitor (TKI) therapy.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Anaplastic lymphoma kinase (ALK) rearrangements are key drivers in a subset of non-small-cell lung cancer (NSCLC).
- Accurate detection of ALK rearrangements is crucial for guiding targeted therapy with ALK tyrosine kinase inhibitors (TKIs).
- Evaluating diagnostic methods like next-generation sequencing (NGS) and immunohistochemistry (IHC) is essential for clinical practice.
Purpose of the Study:
- To comprehensively assess ALK rearrangements using DNA/RNA-based NGS and Ventana IHC in NSCLC patients.
- To evaluate the therapeutic outcomes of ALK-TKI treatment in patients with ALK rearrangements.
- To compare the concordance between NGS and IHC for ALK fusion detection and propose an algorithm for clinical use.
Main Methods:
- Investigated ALK gene fusions in 14,894 NSCLC patients using Ventana IHC and NGS (12,533 DNA-based, 2,361 RNA-based).
- Calculated overall percentage agreement (OPA), positive percentage agreement (PPA), and negative percentage agreement (NPA) between NGS and IHC.
- Evaluated therapeutic responses to ALK-TKIs in patients with discordant results.
Main Results:
- High concordance observed between NGS and IHC for ALK fusion detection (e.g., DNA-NGS OPA: 99.60%, PPA: 92.75%).
- DNA-based NGS showed higher PPA in the adenocarcinoma subcohort (95.69%).
- Patients with discordant results receiving ALK-TKIs showed high overall response rates (ORR) and disease control rates (DCR).
Conclusions:
- NGS and IHC demonstrate high concordance in detecting ALK gene fusions in NSCLC.
- Combining NGS and IHC can enhance the accuracy of ALK fusion detection.
- A result determination algorithm for clinical ALK gene fusion detection was proposed based on these findings.
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