Multi-Omics and Liquid Biopsy Integration for Precision Stratification of Breast Cancer

Breast cancer is a biologically heterogeneous disease that requires accurate diagnosis, risk stratification, treatment selection and longitudinal assessment. Conventional imaging and tissue biopsy remain the mainstays of clinical management. However, tissue sampling represents a specific anatomical site and time point, and may not reflect the molecular heterogeneity or evolution of disease. Liquid biopsy offers a minimally invasive complementary approach, analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and extracellular vesicles. Applications include molecular characterization, treatment-response assessment, resistance detection and minimal residual disease (MRD) evaluation, which are under investigation or in clinical use. Gene-expression profiles, mutational alterations and epigenetic marks can generate molecular signatures that offer further support for tumor classification and risk stratification, and have demonstrated clinical value in specific breast cancer populations. Advances in next-generation sequencing, digital PCR, proteomic analysis, and artificial intelligence have expanded the analytical capacity for detection and interpretation of circulating and tissue-derived biomarkers. However, biological heterogeneity, low abundance of circulating biomarkers, pre-analytical and analytical variability, standardization of assays and limited prospective evidence for some applications are still major barriers to clinical translation. In this review, we discuss the biological basis, detection technologies, clinical applications and limitations of liquid biopsies and molecular signatures in breast cancer, highlighting multi-omics integration and computational approaches. It distinguishes between promising analytical biomarkers and clinically validated applications and highlights the evidence and methodological needs for wider implementation in precision breast cancer care.