It is known that chemokine receptors CXCR4 and CXCR7 in primary tumor cells are associated with tumor growth progression; however, the significance of their expression in circulating tumor cells (CTCs) remains insufficiently studied. The objective of this study was to investigate the expression of chemokine receptors CXCR4 and CXCR7 in subpopulations of CTCs with positive (EpCAM⁺) and negative (EpCAM⁻) EpCAM expression in breast cancer patients, as well as assessed their correlation with clinicopathological parameters and prognostic relevance.The study methods included protein expression analysis and transcriptome profiling of CTCs obtained from peripheral blood. This study comprehensively characterized CXCR4 and CXCR7 expression across EpCAM⁺ and EpCAM− CTC subsets and assessed their clinical relevance through protein-level detection, transcriptomic profiling, and long-term patient follow-up. CXCR4 and CXCR7 receptors were predominantly expressed in EpCAM+ CTCs, whereas EpCAM− cells were largely negative. Importantly, an increased number of EpCAM− CTCs, irrespective of CXCR4/7 status, was associated with disease progression over a six-year period (p = 0,0007). Prognostic significance was specifically attributed to EpCAM−CXCR4/7− CTCs, with counts exceeding 1.25 cells/ml predicting progression with high sensitivity and specificity. Distinct CTC subpopulations were further characterized by stemness and epithelial-mesenchymal transition (EMT) markers, underscoring the aggressive phenotype of EpCAM− cells exhibiting EMT traits. Transcriptomic analysis of EpCAM−CXCR4/7− CTCs revealed upregulation of genes involved in ferroptosis (p = 3.315 × 10⁻⁷) and androgen receptor signaling pathways (p = 8.0 × 10⁻⁵), alongside identification of progression-associated genes (HBB, IGLC2, and IGHM). Conversely, MALAT1 was overexpressed in patients without progression, indicating a potential metastasis-suppressive function (p = 1.52 × 10⁻²). These findings highlight the pathogenetic importance of EpCAM− CTCs in breast cancer progression and support a paradigm shift in CTC research towards this subpopulation. Further investigations are warranted to elucidate the functional roles of these cells and their utility as prognostic biomarkers.