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Concordance Analysis of ALK Gene Fusion Detection Methods in Patients with Non-Small-Cell Lung Cancer from Chile,
Gonzalo Sepúlveda-Hermosilla1, Matías Freire2, Alejandro Blanco1
1Center of Excellence in Precision Medicine, Pfizer Chile, Santiago, Chile; Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
Abstract:
About 4% to 7% of the non-small-cell lung cancer patients have anaplastic lymphoma kinase (ALK) rearrangements, and specific targeted therapies improve patients' outcomes significantly. ALK gene fusions are detected by immunohistochemistry or fluorescent in situ hybridization as gold standards in South America. Next-generation sequencing-based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4240 non-small-cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru, where ALK rearrangements were determined as part of their standard of care (SofC) using either immunohistochemistry or fluorescent in situ hybridization. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a real-time quantitative PCR echinoderm microtubule-associated protein-like 4-ALK fusion detection kit. ALK fusion prevalence is similar for Chile (3.67%; N = 2142), Brazil (4.05%; N = 1013), and Peru (4.59%; N = 675). Although a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements.
Insights
Anaplastic lymphoma kinase (ALK) rearrangements occur in 4-7% of non-small-cell lung cancer patients. Next-generation sequencing offers higher specificity for detecting ALK fusions compared to standard methods.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- Anaplastic lymphoma kinase (ALK) rearrangements are key biomarkers in non-small-cell lung cancer (NSCLC).
- Targeted therapies for ALK-positive NSCLC significantly improve patient outcomes.
- Current gold standard diagnostic methods include immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH).
Purpose of the Study:
- To evaluate the performance of next-generation sequencing (NGS) using the Oncomine Focus Assay (OFA) for detecting ALK rearrangements in NSCLC patients across South America.
- To compare the concordance, sensitivity, and specificity of OFA against standard-of-care (SofC) IHC/FISH methods.
- To assess the prevalence of ALK rearrangements in NSCLC patients in Chile, Brazil, and Peru.
Main Methods:
- Analysis of 4240 NSCLC samples from 37 hospitals in Chile, Brazil, and Peru.
- ALK rearrangements were initially determined by standard-of-care (SofC) IHC or FISH.
- A subset of 1450 samples underwent NGS using the Oncomine Focus Assay (OFA).
- Orthogonal validation was performed using real-time quantitative PCR for echinoderm microtubule-associated protein-like 4-ALK fusion detection.
Main Results:
- ALK rearrangement prevalence was consistent across countries: Chile (3.67%), Brazil (4.05%), and Peru (4.59%).
- Comparison between OFA and SofC assays demonstrated similar sensitivity.
- OFA exhibited significantly higher specificity and positive predictive value compared to SofC methods.
Conclusions:
- Next-generation sequencing (NGS) with the Oncomine Focus Assay (OFA) provides a reliable and highly specific method for detecting ALK gene rearrangements in NSCLC.
- NGS offers a valuable alternative for ALK fusion detection, potentially improving diagnostic accuracy.
- The findings support the broader implementation of NGS-based assays for precision oncology in South America.
