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Updated: Oct 18, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Metastatic NSCLCs With Limited Tissues: How to Effectively Identify Driver Alterations to Guide Targeted Therapy in
1Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Introduction:
Molecular diagnostics of newly diagnosed patients with metastatic NSCLC (mNSCLC) with limited tissue samples often face several obstacles in routine practice using next-generation sequencing (NGS), mainly owing to insufficient tissue or DNA; thus, how to effectively identify the molecular profiling of these cases to accurately guide targeted therapy remains elusive. We evaluated whether an optimized workflow with the combined use of multiple technologies could be helpful.
Methods:
Tissue NGS was used as the frontline method. Amplification refractory mutation system polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, and plasma NGS were used as supplements.
Results:
Among 208 mNSCLC cases with limited tissue (cohort 1), molecular genotyping using single-tissue NGS failed in 42 (20.2%) and actionable alterations were identified in only 112 of 208 cases (53.8%). In comparison, the optimized workflow in 1184 additional mNSCLC cases with limited tissue (cohort 2) increased the discovery rate of actionable alterations from 59.7% detected by tissue NGS to 70.4%. It was because that driver alterations were identified using amplification refractory mutation system polymerase chain reaction plus immunohistochemistry or fluorescence in situ hybridization in 53 of 78 (67.9%) tissue NGS-failed cases, and using plasma NGS in 73 of 143 (51.0%) tissue NGS-failed cases, which led to matched targeted therapies in 57 cases with clinical response. Moreover, the median turnaround time of the optimized workflow was significantly shorter than that of repeated biopsy for tissue NGS (p < 0.001).
Conclusions:
The optimized workflow can improve mutation detection and may avoid repeated biopsy, thus allowing the timely initiation of targeted therapies for patients with newly diagnosed mNSCLC.
Insights
An optimized molecular profiling workflow improves actionable alteration detection in metastatic non-small cell lung cancer (mNSCLC) patients with limited tissue. This approach enhances targeted therapy initiation and may reduce the need for repeat biopsies.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Molecular diagnostics for metastatic non-small cell lung cancer (mNSCLC) using next-generation sequencing (NGS) face challenges with limited tissue samples.
- Insufficient tissue or DNA can hinder accurate molecular profiling for guiding targeted therapy.
Purpose of the Study:
- To evaluate an optimized workflow combining multiple technologies for molecular profiling in mNSCLC with limited tissue.
- To improve the identification of actionable alterations and facilitate timely targeted therapy.
Main Methods:
- Frontline tissue NGS was supplemented by amplification refractory mutation system polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, and plasma NGS.
- An optimized workflow was compared against standard tissue NGS in mNSCLC cohorts with limited tissue.
Main Results:
- The optimized workflow increased the discovery rate of actionable alterations from 59.7% to 70.4% in 1184 mNSCLC cases.
- It successfully identified driver alterations in tissue NGS-failed cases using supplementary methods, leading to targeted therapies in 57 patients.
- The optimized workflow demonstrated a significantly shorter turnaround time compared to repeated biopsy for tissue NGS.
Conclusions:
- An optimized workflow enhances mutation detection rates in mNSCLC patients with limited tissue.
- This approach can potentially avoid repeat biopsies, enabling prompt initiation of targeted therapies.
