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Updated: Sep 8, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Up-front cell-free DNA next generation sequencing improves target identification in UK first line advanced non-small
Wanyuan Cui1, Charlotte Milner-Watts1, Hazel O'Sullivan1
1Lung Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.
Background:
Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC.
Methods:
cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results.
Results:
Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001).
Conclusions:
cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC.
Insights
Upfront cell-free DNA next-generation sequencing (cfDNA-NGS) in advanced non-small cell lung cancer (aNSCLC) significantly increases treatment-related variant detection and reduces time to therapy. This plasma-based approach offers a faster, more effective alternative to traditional tissue testing for aNSCLC patients.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Genomic sequencing is crucial for guiding first-line treatment in advanced non-small cell lung cancer (aNSCLC).
- Tissue-based next-generation sequencing (NGS) is the current standard but faces challenges with sample quantity, quality, and turnaround time.
- Cell-free DNA (cfDNA) NGS presents a potential alternative to overcome these limitations.
Purpose of the Study:
- To compare the clinical utility of upfront cfDNA-NGS with routine tissue testing for treatment decisions in aNSCLC patients.
- To evaluate the differences in variant detection rates and turnaround times between cfDNA-NGS and tissue-based NGS.
Main Methods:
- Consecutive aNSCLC patients underwent both cfDNA-NGS and tissue genotyping from December 2019 to October 2021.
- Variants were interpreted using AMP/ASCO/CAP guidelines, with tier-1 variants as the primary endpoint.
- Results from cfDNA-NGS were directly compared to those from tissue tests.
Main Results:
- 91% of cfDNA-NGS tests were informative, identifying tier-1 variants in 38% of patients.
- Tissue tests were informative in 50% of cases, with tier-1 variants found in 35%.
- cfDNA-NGS detected 46% more tier-1 variants than tissue alone, with a median reporting time of 8 days versus 22 days for tissue. Treatment initiation was also significantly faster with cfDNA-NGS.
Conclusions:
- cfDNA-NGS significantly enhances tier-1 variant detection in aNSCLC compared to tissue testing, with high concordance.
- This approach substantially reduces the time to treatment initiation, improving patient management.
- 'Plasma-first' cfDNA-NGS should be routinely considered for upfront testing in aNSCLC.
