Non-Invasive Diagnosis of Early Breast Cancer: Current and Emerging Liquid Biopsy Biomarkers

Background/Objectives: Breast cancer (BC) remains the most frequently diagnosed malignancy among women worldwide, and patient outcome is strongly influenced by disease stage at diagnosis. Although imaging-based screening has improved early detection, its performance may be reduced in dense breast tissue and is associated with false-positive findings. In addition, tissue biopsy is invasive and unsuitable for longitudinal disease monitoring. Liquid biopsy (LB) has emerged as a minimally invasive approach for detecting tumor-derived material in peripheral blood. However, early-stage tumors typically exhibit low tumor burden and limited biomarker shedding, generating weak systemic signals that challenge reliable detection. This review examines current and emerging LB biomarkers for early BC detection. Methods: A comprehensive review of recent literature was conducted focusing on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNAs, proteins, and other blood-based biomarkers associated with early BC. Studies addressing biomarker biology, detection technologies, clinical applications, and methodological limitations were critically evaluated. Results: ctDNA, CTCs, EVs, circulating RNAs, proteins, and additional blood-based biomarkers capture distinct aspects of tumor biology and disease evolution. ctDNA enables the analysis of tumor-specific mutations, methylation patterns, and fragmentation profiles, whereas CTCs provide direct cellular and phenotypic information despite their rarity and marked epithelial-mesenchymal plasticity. EVs offer increased molecular stability and actively participate in tumor progression, immune modulation, and metastatic niche formation. Nevertheless, low biomarker abundance, biological heterogeneity, technical variability, and background biological noise continue to limit analytical performance, particularly in early-stage disease. Current evidence further suggests that no single biomarker consistently provides sufficient sensitivity and specificity for reliable early BC detection. Conclusions: LB represents a promising strategy for non-invasive early BC detection. Future clinical implementation will likely depend on integrated multi-analyte approaches that combine complementary genomic, transcriptomic, proteomic, and cellular information, supported by multi-omics technologies and artificial intelligence-based analytical frameworks.