Minimal residual disease (MRD) monitoring in breast cancer has largely relied on circulating tumor DNA (ctDNA)-based technologies, which are constrained by low tumor DNA shedding and potential confounding from clonal hematopoiesis and healthy tissues. To address these limitations, the OncoMRD BREAST assay, an 11-gene cell-free mRNA (cfmRNA)-based panel, has been developed to measure tumor biological activity rather than tumor-derived DNA fragments. To establish biological, clinical, and translational validity for broader, mutation-agnostic MRD monitoring in breast cancer, OncoMRD BREAST was evaluated across multiple independent validation frameworks, including six breast cancer cohorts comprising >5,600 patients, nine validated breast cancer gene signatures, four independent single-cell RNA sequencing datasets encompassing 595,514 cells and 110 annotated cell populations and 62 patient-derived xenograft (PDX) and three-dimensional (3D) organoid models. Retrospective studies demonstrated significant correlations with breast cancer clinical phenotypes and strong concordance with established commercial prognostic assays despite minimal gene overlap. Single-cell analyses revealed robust OncoMRD BREAST gene overexpression within malignant epithelial compartments, immune populations including neutrophils, T cells, and macrophages, and normal-adjacent tissues consistent with field cancerization biology. Across translational model systems, the OncoMRD BREAST gene signature demonstrated good reproducibility with strong performance in PDX and organoid platforms. The convergence of clinical, molecular, single-cell, spatial, and translational evidence establishes OncoMRD BREAST as a novel cfmRNA biomarker of breast tumor activity. By capturing tumor-, immune-, and microenvironment-associated transcriptional programs, OncoMRD BREAST offers a biologically relevant and potentially complementary approach to ctDNA-based MRD monitoring, supporting a new paradigm of functional residual disease assessment in breast cancer.