Abstract
Molecular analysis of tumor material is standard in metastatic non-squamous non-small cell lung cancer (NSCLC), but it is not always feasible, limiting targeted treatment options. We investigated the clinical value of cell-free DNA (cfDNA) next-generation sequencing (NGS) in patients with clinically and radiologically suspected metastatic NSCLC. Within the comprehensive cancer network Southwest (The Netherlands), Erasmus MC launched the Lung Cancer Diagnosis (LCD) – cfDNA project. For patients with suspected metastatic lung cancer where tissue analysis was not feasible, thoracic oncologists submitted plasma samples for cfDNA NGS. Results were discussed by the Thoracic Oncology Molecular Tumor board. Between January 1st, 2019, and January 1st, 2023, 108 plasma samples were submitted and analyzed. In 6 patients (5.6%), an activating EGFR mutation was identified as a potential target for treatment. Additional actionable genomic alterations (AGA) include a BRAF p.V600E mutation (n = 1) and KRAS p.G12C mutations (n = 6). In 42 patients, other non-AGA (KRAS other than p.G12C, NRAS, BRAF p.G466V, PIK3CA, TP53) were detected that did not affect the choice of systemic therapy. In a real-world clinical practice setting, our study showed that NGS can detect AGAs in plasma when tumor tissue analysis is not feasible in suspected metastatic NSCLC. However, plasma diagnostics cannot replace histological diagnosis.
Data availability
Raw sequencing data and unfiltered variant call files cannot be publicly shared due to restrictions imposed by the institutional review board. However, all variants assessed as (potentially) clinically relevant are presented in this paper and its supporting files. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
Part of these data were presented at WCLC 2021 (abstract #286). Steendam C, Atmodimedjo P, Van Der Leest C, Van Loenhout K, Van’T Westeinde S, Dumoulin D, et al. P24.08 Lung Cancer Diagnosis in Absence of Adequate Tissue Molecular Analysis in Metastatic Disease by NGS Analysis of Plasma cfDNA. Journal of Thoracic Oncology. 2021;16(10): S1034.
Funding
This work was partly funded by AstraZeneca (grant number 2604937054, unrestricted grant). The funding source had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
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CS: conceptualization, methodology, formal analysis, investigation, data curation, writing - original draft, visualization; RM: formal analysis, investigation, data curation, writing—original draft, visualization, PA: validation, formal analysis, investigation, data curation, writing—review & editing; CL: investigation, writing—review & editing; LvD: formal analysis, data curation, writing—review & editing; KL: investigation, writing—review & editing; SW: investigation, writing—review & editing; DD: investigation, writing—review & editing; WH: investigation, writing—review & editing; MP: investigation, writing—review & editing; EJ: investigation, writing—review & editing; RS: resources, writing—review & editing; JT: writing—review & editing; JA: conceptualization, resources, writing—review & editing, supervision; AD: conceptualization, methodology, resources, writing—review & editing, supervision, project administration; HD: conceptualization, methodology, resources, writing—review & editing, supervision, project administration, funding acquisition.
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CS: no conflict of interestRM: no conflict of interestPA: no conflict of interestLvD: no conflict of interestCL: no conflict of interestKL: no conflict of interestSW: no conflict of interestDD: Honoraria and advisory boards for MSD, Amgen, AstraZeneca, BMS, Roche, Pharmamar. (personel and institution)WH: no conflict of interestMP: received consulting Advisory Boards: Amgen, Eli Lilly, Janssen, Merck, Pfizer all paid to insituteEJ: no conflict of interestRS: no conflict of interestJT: no conflict of interestJA: A received institutional research grants from AstraZeneca, Danone, Genmab and consulting fees from AstraZeneca, MSD, Danone, CureVac and speakers fees from BMS, MSD, Eli-Lilly and has issued patents for allogenic tumor cell lysate, combination immune-oncology drug, biomarker for immunotherapy and unpaid leadership role as Treasurer of IASLC and board member of IMIG and stock options in AmpheraAD: has received institutional consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi, Johnson&Johnson, Pfizer, Roche, Abbvie, Mirati and received institutional speaker fees from Amgen, Eli Lilly, Johnson&Johnson and institutional fees for IDMC from Roche, Takeda and institutional fees for steering committee participation from Roche, Eli Lilly, Amgen and unpaid leadership as chair EORTC lung cancer groupHD: received institutional grants from AstraZeneca, MSD and personal speaker fees from AstraZeneca, MSD, GSK, BMS, Johnson&Johnson, Roche, Illumina and institutional support for attending a meeting from OncoDNA and personal fees for Advisory boards from Astellas, Abbvie, AstraZeneca, Janssen, MSD and institutional equipment/materials from Illumina, OncoDNA, HederaDx.
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The Medical ethical committee of the Erasmus MC approved this study but waived the need for informed consent. However, patients provided local consent for use of their (anonymized) data.
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Steendam, C.M.J., Meijers, R.W.J., Atmodimedjo, P. et al. Prospective clinical evaluation of cell-free DNA next generation sequencing in patients with suspected metastatic lung cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47197-z
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DOI: https://doi.org/10.1038/s41598-026-47197-z
