Distinct CTC Specific RNA Profile Enables NSCLC Early Detection and Dynamic Monitoring of Advanced NSCLC

Abstract Circulating tumor cells (CTCs) hold significant potential as biomarkers for the diagnosis and management of non‐small cell lung cancer (NSCLC). However, their clinical utility is limited by the heterogeneity of CTC subtypes and the need for robust, quantitative assays. In this study, a quantitative CTC RNA assay incorporating multi‐antibody‐based CTC isolation and specific mRNA quantification by RT‐ddPCR is developed. Two distinct models are established: NSCLC CTC Score ^D for detecting early NSCLC (stages I‐II), and NSCLC CTC Score ^M for monitoring advanced NSCLC (stages III‐IV), based on distinct cohort criteria. NSCLC CTC Score ^D demonstrates high diagnostic performance for early‐stage NSCLC, achieving an area under the receiver operating characteristic curve (AUC) of 0.93, significantly outperforming serum CEA (AUC = 0.70). Compared to NSCLC CTC Score ^D , NSCLC CTC Score ^M captures a key gene feature of KRT19 , whose fragment protein, serum CYFRA 21‐1, is used as a prognostic biomarker for advanced NSCLC. Notably, CTC Scores ^M exhibits a more accurate early warning of patient responses to different therapies than serum CYFRA21‐1 levels, which may provide a potential blood test‐based biomarker for improved treatment assessment in advanced NSCLC.