Lung Cancer Detection via Nasal Swab cfDNA and mFAST-SeqS Analysis - A Proof-of-Concept Study

Introduction: Accurate and timely diagnosis is critical in lung cancer, with early detection being the key factor to improve patient outcomes. The nasal cavity is an easily accessible source of airway-derived biomolecules and may carry tumor-derived biomarkers from the lower respiratory tract, due to the anatomical connection to the lower airways [1]. Circulating tumor DNA (ctDNA), a fraction of cell-free DNA shed by tumor cells, can be detected in plasma but often with limited sensitivity [2]. We therefore hypothesized that nasal cfDNA may provide a more proximal source of ctDNA. To test this, we evaluated whether nasal swabs analyzed by modified Fast Aneuploidy Screening Test-Sequencing System (mFAST-SeqS), a genome-wide aneuploidy assay, can detect tumor-derived signal as a complementary diagnostic approach in lung cancer. Methods: We prospectively enrolled 10 female, never-smoker, treatment-naïve patients with pathologically confirmed non–small cell lung cancer (NSCLC) at Hospital Universitario Central de Asturias (HUCA) and three self-reported healthy controls. mFAST-SeqS was performed on nasal cfDNA by amplifying, sequencing, and mapping LINE-1 elements across chromosome arms. Sample-level aneuploidy z-scores were computed against a pool of healthy controls. As in prior plasma studies, z > 5 defined ctDNA-presence [3]. Results: Among samples collected from patients with lung cancer z-scores ranged 4.67–38.28 (median 5.80, IQR 5.17–6.83). Using the predefined threshold, 8/10 patients were ctDNA-positive (80%, 95% CI 44–97%). Two were borderline but below threshold (4.84, 4.67). By comparison, the three healthy controls showed uniformly low z-scores (2.07, 1.96, 1.49; median 1.96), and none met the ctDNA-positivity threshold. Consequently, every positive sample scored above every control, yielding complete separation between groups and supporting the biological validity of nasal cfDNA as a source of tumor-derived material. Conclusions: Despite the limited sample size, this study provides the first proof-of-concept that nasal swabs can capture tumor-derived genomic biomarkers, setting the stage for their use as a non-invasive, lung-proximal, and scalable liquid-biopsy modality. These findings provide a rationale for larger, controlled trials to define the clinical integration of nasal swabs in the diagnostic pathway of early lung cancer detection. [1] https://doi.org/10.1016/j.otc.2021.12.014 [2] https://doi.org/10.3390/arm93030017 [3] https://doi.org/10.1002/1878-0261.13196