From Molecular Resolution to Clinical Decision in Triple-Negative Breast Cancer: A Time-Aware Framework for Multi-Omic Precision Oncology

Triple-negative breast cancer (TNBC) is a receptor-defined diagnosis encompassing genomic, transcriptional, epigenetic, proteomic, metabolic, cellular and spatial heterogeneity. Although transcriptomic classifications established biologically interpretable TNBC subtypes, multi-omic, single-cell and spatial studies show that tumour states may coexist within the same lesion and evolve under treatment pressure. The central translational question is therefore not simply how to generate higher-resolution molecular maps, but which biological layer should be measured, at what clinical time point, and whether that information can change patient-level decisions. This narrative review proposes a time-aware resolution-to-decision framework for TNBC precision oncology. We examine how genomics defines molecular potential; transcriptomics and epigenomics capture active and plastic cellular programmes; proteomics and metabolomics provide functional pathway readouts; and single-cell and spatial approaches resolve cellular and anatomical context. We then evaluate circulating tumour DNA as a longitudinal biomarker for molecular residual disease and tumour evolution, distinguishing strong prognostic evidence from still-unproven treatment-intervention utility. Using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) as a reference for genomic actionability, we distinguish established biomarkers from context-dependent markers and investigational multi-omic signatures, while noting that several recent therapeutic advances required little or no molecular selection. Molecular profiling should be judged by biological resolution, disease time point and evidence maturity rather than by technological complexity alone.