Evaluation of liquid biopsy in lung cancer diagnostics: A pilot study

Abstract

Here is the paradox at the heart of modern lung cancer diagnostics: we possess extraordinarily sophisticated molecular profiling technologies capable of identifying actionable mutations in tumor tissue with over 94% sensitivity, yet 20 to 30% of patients with advanced non-small cell lung cancer never receive tissue-based molecular testing because obtaining adequate biopsy specimens proves technically impossible, medically contraindicated, or unacceptably delayed in the clinical workflow [1, 2]. Liquid biopsy the analysis of circulating tumor DNA, circulating tumor cells, and other tumor-derived analytes from a simple peripheral blood draw has been widely promoted as the definitive solution to this diagnostic access gap, but critical evaluation of its real-world diagnostic performance across the full spectrum of disease stages remains incomplete and often commercially influenced. This pilot research assessed the concordance, sensitivity, specificity, and clinical utility of liquid biopsy compared with standard tissue biopsy for comprehensive molecular profiling in newly diagnosed non-small cell lung cancer patients at two Swedish university hospitals. We enrolled 167 consecutive treatment-naive patients between February 2021 and October 2022, collecting paired liquid and tissue biopsy specimens at the time of initial diagnosis. Liquid biopsy achieved overall sensitivity of 72.6% and specificity of 92.1%, with substantial and clinically important stage dependence: sensitivity reached 91.7% in stage IV disease but dropped to just 48.3% in stage I, a finding that challenges the technology’s proposed role in early cancer detection. Mutation-specific concordance with tissue biopsy ranged from 87.4% for EGFR mutations down to 63.2% for MET amplifications, with gene fusions occupying an intermediate position. Serial ctDNA monitoring during first-line treatment discriminated responders from non-responders as early as three weeks after treatment initiation, with responders showing a mean 31.6% reduction in ctDNA levels versus a 5.3% increase in non-responders. These findings suggest that liquid biopsy serves as a valuable complement to but not yet a reliable replacement for tissue-based molecular diagnostics in lung cancer, with its greatest clinical utility concentrated in advanced disease, serial therapeutic monitoring, and cases where tissue acquisition is unobtainable.