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Updated: Sep 6, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
A Real-World Systematic Analysis of Driver Mutations' Prevalence in Early- and Advanced-Stage NSCLC: Implications for
Irene Terrenato1, Cristiana Ercolani2, Anna Di Benedetto2
1UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.
Abstract:
The approval of osimertinib for adjuvant treatment of stage I-II-III EGFR-mutated NSCLC (early stage) represents a paradigm shift, raising the question of whether other genotype-matched therapeutics approved for advanced-stage NSCLC can also provide clinical benefit in the adjuvant setting. However, there is a paucity of real-world data on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC. We used next-generation sequencing, complemented by immunohistochemistry and fluorescence in situ hybridization, to screen our single-institution cohort of 1961 NSCLC consecutive cases for actionable molecular targets. The prevalence of actionable GAs was comparable in early versus advanced-stage NSCLC, the only exception being KRAS mutations (more frequent in early-stage cases). Consistent with advanced-stage tumors being more aggressive, co-occurrence of TP53 and EGFR GAs as well as copy number gains were less frequent in early-stage tumors. EGFR mutations and high expression of PD-L1 were inversely associated, whereas KRAS mutations and high PD-L1 reactivity showed positive association. Recapitulating advanced-stage tumors, early-stage NSCLC had the highest share of EGFR mutations in lepidic and acinar subtypes. Resected lepidic tumors contained the highest proportion of the KRAS G12C actionable variant. These results, obtained with routine diagnostic technologies in an unselected clinical setting, provide a significant addition of real-world data in early-stage NSCLC.
Insights
The prevalence of actionable genomic alterations in early-stage non-small cell lung cancer (NSCLC) mirrors that of advanced stages. This study provides crucial real-world data on these alterations in early-stage NSCLC.
Area of Science:
- Oncology
- Genomics
- Thoracic Surgery
Background:
- Osimertinib's approval for adjuvant treatment in EGFR-mutated non-small cell lung cancer (NSCLC) prompts investigation into other advanced-stage therapies for early-stage use.
- Limited real-world data exists on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC.
Purpose of the Study:
- To determine the prevalence of actionable GAs in early-stage NSCLC.
- To compare GA prevalence between early and advanced-stage NSCLC.
- To explore associations between GAs, tumor subtypes, and PD-L1 expression in early-stage NSCLC.
Main Methods:
- Utilized next-generation sequencing, immunohistochemistry, and fluorescence in situ hybridization.
- Screened a cohort of 1961 consecutive NSCLC cases from a single institution.
- Analyzed GAs, tumor histology, and PD-L1 expression.
Main Results:
- Actionable GA prevalence was similar in early and advanced-stage NSCLC, except for KRAS mutations (more frequent in early-stage).
- TP53 and EGFR co-mutations and copy number gains were less frequent in early-stage tumors.
- EGFR mutations inversely correlated with PD-L1 expression, while KRAS mutations showed a positive association. Lepidic and acinar subtypes had the highest EGFR mutation rates; lepidic tumors showed the most KRAS G12C variants.
Conclusions:
- Real-world data on actionable GAs in early-stage NSCLC is now available.
- Findings support the investigation of genotype-matched therapies in the adjuvant setting for NSCLC.
- Routine diagnostic technologies can effectively identify actionable targets in unselected early-stage NSCLC patients.
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