Beyond Circulating Tumor Cell (CTC) Enumeration: Clinical Significance of EMT- and Cancer Stem Cell-like CTCs in Castration-Resistant Prostate Cancer—A Systematic Review

Circulating tumor cells (CTCs) are established prognostic biomarkers in metastatic castration-resistant prostate cancer (mCRPC); however, conventional epithelial marker-based detection platforms may miss biologically aggressive CTC subpopulations with epithelial–mesenchymal transition (EMT) or cancer stem cell (CSC)-like features. This systematic review evaluated the clinical significance of EMT- and CSC-associated CTC phenotypes in mCRPC. Following PRISMA 2020 guidelines and prospective PROSPERO registration (CRD420261308460), PubMed, Embase, and Web of Science were searched for studies published from March 2016 to March 2026. Twelve studies involving 661 patients met inclusion criteria. Because of substantial heterogeneity in CTC enrichment methods, biomarker definitions, and outcomes, findings were synthesized qualitatively. EMT-associated phenotypes, including vimentin-positive CTCs, N-cadherin-positive CTCs, EMT-transitioning CTCs, and platelet-coated CTCs, were generally associated with greater metastatic burden, treatment resistance, and shorter progression-free or overall survival (OS). CSC-associated markers, including OCT4, CD44, and ALDH1, were similarly linked to adverse outcomes and treatment resistance. Across five studies reporting OS hazard ratios, EMT- or CSC-positive CTC phenotypes generally trended toward poorer survival, although associations varied in magnitude and statistical significance. Overall, EMT- and CSC-like CTCs are associated with aggressive mCRPC biology, supporting their potential prognostic value beyond conventional CTC enumeration.