Circulating tumor cells and tumor-derived cell-free DNA in cancer management: Clinical evidence, limitations, and future directions

Liquid biopsy has emerged as a powerful approach for non-invasive cancer monitoring, with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) representing biologically distinct yet complementary analytes. Cell-free DNA (cfDNA) refers to fragmented DNA released into circulation from both normal and malignant cells, whereas ctDNA constitutes the tumor-derived fraction of cfDNA and carries cancer-specific genetic and epigenetic alterations. CTCs provide intact cellular material that enables phenotypic, transcriptomic, and functional characterization, offering unique insights into metastatic dissemination, tumor heterogeneity, and therapeutic resistance. In contrast, ctDNA enables sensitive detection of somatic mutations, copy number alterations, methylation patterns, and fragmentomic features that reflect tumor burden and clonal evolution. Clinically, ctDNA assays have achieved greater regulatory maturity, with several US Food and Drug Administration-approved tests for therapy selection, minimal residual disease (MRD) detection, and relapse monitoring, while most CTC-based platforms remain investigational or limited to specific clinical contexts. Importantly, combining CTC analysis with ctDNA profiling enhances biological resolution by integrating cellular behavior with molecular dynamics, overcoming limitations inherent to either analyte alone. Emerging advances in fragmentomics, methylation profiling, and ultra-deep sequencing are further expanding the sensitivity and clinical utility of ctDNA, particularly for early cancer detection and MRD assessment. This review critically evaluates the translational readiness, technical challenges, and clinical applications of CTCs and ctDNA, highlighting their synergistic potential in precision oncology.