Circulating tumor DNA analysis in lung cancer: from molecular origins to analytical boundaries

Circulating tumor DNA (ctDNA) has revolutionized lung cancer management, yet its clinical sensitivity remains fundamentally limited by biological factors governing ctDNA release, clearance, and abundance. This review examines how these biological realities constrain each stage of ctDNA analysis, from pre-analytical variables to bioinformatic processing, with additional complexity from clonal hematopoiesis. Given these layered constraints, we argue that further incremental technical improvements face diminishing returns. The future lies in AI-driven methodologies that aggregate weak, heterogeneous molecular signals across multiple dimensions and learn directly from raw sequencing data, enabling ultrasensitive detection even in ultra-low-burden settings.