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Updated: Jan 12, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Actionable Gene Alterations in Resected Non-Small Cell Lung Cancer: Primary Results From the AGA-R Study
Ilaria Attili1, Gloria Pellizzari2, Luca Bertolaccini3
1Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Introduction:
In resected non-small cell lung cancer (NSCLC), molecular testing is currently limited to EGFR mutations and ALK rearrangements, as these guide approved adjuvant therapies. The role of next-generation sequencing (NGS), routinely used in metastatic NSCLC, remains unclear in earlier stages. The prevalence of other driver mutations and their impact on outcomes is not well established.
Methods:
We retrospectively analyzed clinical, molecular, and survival data from patients (pts) with stage IA-IIIB NSCLC (AJCC 8th) who underwent surgery and NGS at our Institute from January 2020 to December 2023. The primary endpoint was the prevalence of driver alterations. Exploratory analyses assessed recurrence, disease-free survival (DFS), overall survival (OS), and correlation with mutation status.
Results:
Of 221 pts, 216 were eligible. Oncogenic alterations were found in 71% (73% in stage I), most commonly KRAS (30%) and EGFR (26%), followed by MET exon 14 skipping (6%), BRAF (4%), HER2 exon 20 mutations (3%), and ALK and RET rearrangements (1%). Alteration distribution differed by sex and smoking status. With a median follow-up of 20 months, 36% of pts experienced recurrence, including 10 stage I cases. Median time to recurrence was 14 months. Recurrence rates were higher in pts with driver mutant NSCLC (39.6%) versus wild-type (29.6%). Highest recurrence was seen in pts with oncogenic fusion positive NSCLC and EGFR exon 20 insertions.
Conclusions:
Driver mutations were detected in 70% of resected NSCLC, including stage I. The recurrence patterns observed support integrating NGS into early-stage management and exploring tailored adjuvant therapies, even for stage I tumors.
Insights
Next-generation sequencing (NGS) finds driver mutations in 70% of early-stage non-small cell lung cancer (NSCLC), including KRAS and EGFR. These findings support routine NGS for guiding tailored adjuvant therapies in resected NSCLC.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Current molecular testing for resected non-small cell lung cancer (NSCLC) is limited to EGFR mutations and ALK rearrangements.
- The utility of next-generation sequencing (NGS) in early-stage NSCLC is not well-defined.
- The prevalence and impact of other driver mutations in early-stage NSCLC remain largely unknown.
Purpose of the Study:
- To determine the prevalence of driver alterations in resected NSCLC using NGS.
- To explore the association between driver mutations and recurrence patterns, disease-free survival (DFS), and overall survival (OS).
- To evaluate the potential of integrating NGS into the management of early-stage NSCLC.
Main Methods:
- Retrospective analysis of clinical, molecular, and survival data from 216 patients with stage IA-IIIB NSCLC who underwent surgery and NGS.
- Primary endpoint: prevalence of driver alterations.
- Exploratory analyses: recurrence rates, DFS, OS, and correlation with mutation status.
Main Results:
- Oncogenic alterations were identified in 71% of patients, with KRAS (30%) and EGFR (26%) being the most common.
- Recurrence occurred in 36% of patients, with higher rates in those with driver mutant NSCLC (39.6%) compared to wild-type (29.6%).
- Elevated recurrence rates were observed in patients with oncogenic fusion-positive NSCLC and EGFR exon 20 insertions.
Conclusions:
- Driver mutations are prevalent in approximately 70% of resected NSCLC, including stage I.
- Recurrence patterns suggest that NGS should be integrated into early-stage NSCLC management.
- Tailored adjuvant therapies, guided by NGS, may benefit even patients with stage I NSCLC.
