Advances and challenges in circulating tumor DNA-based early detection of lung cancer

Lung cancer remains the leading cause of cancer-related mortality worldwide. The primary reason for this poor prognosis is late-stage diagnosis, as approximately 50% of lung cancer cases are detected at stage 4 when curative treatment is no longer an option, and the 5-year survival of this stage is approximately 15%. While low-dose computed tomography (LDCT) has significantly improved early detection, its high false-positive rate (60-70%) leads to unnecessary invasive procedures and patient anxiety. Therefore, a complementary, highly specific, and non-invasive biomarker is urgently needed. Liquid biopsy, particularly circulating tumor DNA (ctDNA) analysis, has emerged as a promising diagnostic tool for lung cancer screening. Unlike conventional tissue biopsies, ctDNA-based tests provide a minimally invasive means to detect cancer-specific genomic alterations, including somatic mutations, DNA methylation patterns, somatic copy number alterations (CNAs), and fragment size variations. While ctDNA analysis has demonstrated clinical utility in advanced lung cancer, its application in early-stage disease remains challenging due to the low abundance of ctDNA in circulation. Strategies such as whole-genome methylation profiling, CNA analysis, and fragmentomics have been explored to enhance sensitivity and specificity for early detection. This review summarizes recent advances and challenges in ctDNA-based lung cancer screening, focusing on the strengths and limitations of different approaches. We highlight the need for integrating ctDNA assays with current LDCT screening protocols to improve diagnostic accuracy. Future large-scale prospective studies are essential to validate the clinical utility of ctDNA-based liquid biopsy in early lung cancer detection. A multi-modal biomarker strategy that combines genetic, epigenetic, and structural features holds great promise for transforming lung cancer screening and improving clinical outcomes.