Background: ctDNA-based NGS MRD testing in breast cancer faces a critical but overlooked limitation: low-frequency somatic mutations from normal aging non-malignant tissues—beyond clonal hematopoiesis—contaminate plasma ctDNA at levels indistinguishable from true MRD signals, creating a specificity ceiling that increased sequencing depth cannot resolve. The OncoMRD BREAST panel, an 11-gene transcriptomic index, offers an orthogonal liquid biopsy approach measuring tumor gene hyperactivity rather than mutant DNA, addressing limitations of ctDNA NGS. This study performed the first comprehensive multi-dataset retrospective clinical validation of the OncoMRD BREAST gene signature. Methods: OncoMRD BREAST gene overexpression index (GOI) was computed as the mean z-score composite of 11 genes across six public datasets (n>5,600). Correlations were assessed against: validated ctDNA MRD from I-SPY2 (n=253); genomic proxy-simulated MRD (FGA/TMB) from TCGA-BRCA (n=1,218); tumor activity metrics (MKI67, ER, HER2, survival) from METABRIC (n=2,114); RECIST responses across four neoadjuvant cohorts (n=727); and nine validated breast cancer transcriptomic assays including Oncotype DX and MammaPrint panels in TCGA-BREAST (n=1,018). Statistical methods included Spearman/Pearson correlation with bootstrap CIs, Wilcoxon, Kruskal-Wallis, Cox, Kaplan-Meier, and FDR correction. Results: In TCGA-BRCA, GOI correlated significantly with FGA and composite simulated MRD score. In I-SPY2, subtype-stratified analysis revealed significant GOI-ctDNA MRD correlation in TNBC patients with strengthening associations at post-NAC timepoints. In METABRIC, GOI significantly correlated with MKI67, ER status, HER2 status, and overall survival. RECIST response analyses yielded significant correlations in the GSE20194 neoadjuvant cohort. External benchmark concordance analyses demonstrated significant Pearson correlations with all nine validated transcriptomic panels: 17-gene CTC MRD signature (R=0.76), 26-gene FDG-PET metabolic signature (R=0.73), 3q metastasis signature (R=0.52), MammaPrint (R=0.52), 6-gene chemotherapy persistence signature (R=0.44), Oncotype DX 21-gene (R=0.46), Prosigna/PAM50 (R=0.36), EndoPredict (R=0.29), Breast Cancer Index (R=0.19); all p<2.2×10⁻⁸. Conclusions: The comprehensive mega-dataset retrospective validation presented here provides the most rigorous pre-prospective evidence base yet assembled for a novel breast cancer liquid biopsy MRD panel, strongly supporting immediate advancement of OncoMRD BREAST to prospective interventional clinical validation in breast cancer MRD monitoring trials.