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Updated: Jun 24, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Successive next-generation sequencing strategy for optimal fusion gene detection in non-small-cell lung cancer in
Simon Garinet1, Audrey Lupo2, Thomas Denize3
1Department of Biochemistry and Molecular Oncology, Hopital Européen Georges Pompidou, APHP Centre, Paris, France; Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, INSERM, Team Personalized Medicine, Pharmacogenomics and Therapeutic Optimization (MEPPOT), Paris, France.
Abstract:
Metastatic non-small-cell lung cancer (NSCLC) displays various molecular alterations in the RAS-MAPK pathway. In particular, NSCLCs show high rates of targetable gene fusion in ALK, RET, ROS1, NRG1 and NTRK, or MET exon 14 skipping. Rapid and accurate detection of gene fusion in EGFR/KRAS/BRAF mutations is important for treatment selection especially for first-line indications. RNA-based next-generation sequencing (NGS) panels appear to be the most appropriate as all targets are multiplexed in a single run. While comprehensive NGS panels remain costly for daily practice, optimal sequencing strategies using targeted DNA/RNA panel approaches need to be validated. Here, we describe our lung cancer screening strategy using DNA and RNA targeted approaches in a real-life cohort of 589 NSCLC patients assessed for molecular testing. Gene fusions were analysed in 174 patients negative for oncogene driver mutations or ALK immunohistochemistry in a two-step strategy. Targetable alterations were identified in 28% of contributive samples. Non-smokers had a 63.7% probability to have a targetable alteration as compared to 21.5% for smokers. Overall survival was significantly higher (p=0.03) for patients who received a molecularly matched therapy. Our study shows the feasibility in routine testing of NSCLC DNA/RNA molecular screening for all samples in a cost- and time-controlled manner. The significant high fusion detection rate in patients with wild-type RAS-MAPK tumours highlights the importance of amending testing strategies in NSCLC.
Insights
This study validates a cost-effective DNA/RNA sequencing strategy for detecting targetable gene fusions in non-small cell lung cancer (NSCLC). A significant 28% of patients had actionable alterations, particularly non-smokers, improving treatment selection.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Metastatic non-small-cell lung cancer (NSCLC) exhibits diverse molecular alterations, including targetable gene fusions and mutations within the RAS-MAPK pathway.
- Accurate and rapid detection of these alterations is crucial for guiding first-line treatment selection in NSCLC patients.
- While RNA-based next-generation sequencing (NGS) panels offer comprehensive multiplexed analysis, their cost can be prohibitive for routine practice.
Purpose of the Study:
- To validate an optimized DNA/RNA targeted sequencing strategy for molecular screening in a real-world NSCLC cohort.
- To assess the feasibility, cost-effectiveness, and detection rate of targetable genomic alterations using a two-step approach.
- To evaluate the impact of molecularly matched therapy on overall survival in NSCLC patients.
Main Methods:
- A cohort of 589 NSCLC patients underwent molecular testing using a combination of DNA and RNA targeted approaches.
- Gene fusions were specifically analyzed in 174 patients negative for common oncogene driver mutations or ALK expression via immunohistochemistry.
- A two-step strategy combining DNA and RNA targeted panels was employed for comprehensive molecular profiling.
Main Results:
- Targetable molecular alterations were identified in 28% of evaluable NSCLC samples.
- Non-smokers demonstrated a significantly higher probability (63.7%) of harboring targetable alterations compared to smokers (21.5%).
- Patients receiving molecularly matched therapy exhibited significantly improved overall survival (p=0.03).
Conclusions:
- The implemented DNA/RNA targeted screening strategy is feasible for routine NSCLC molecular testing in a cost- and time-controlled manner.
- A high rate of targetable gene fusions was detected, especially in patients with wild-type RAS-MAPK tumors, underscoring the need for updated testing strategies.
- Molecularly guided therapy significantly improves outcomes, highlighting the clinical utility of comprehensive genomic profiling in NSCLC.
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