Background: The use of neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer (EBC) increases the opportunity for genomic testing which can help predict treatment response and optimize outcomes. MammaPrint (MP) classifies tumors as having a Low Risk (LR) or High Risk (HR) of distant recurrence. MP with BluePrint (BP), a molecular subtyping assay, categorize tumors as Luminal A (MP LR), Luminal B (MP HR), HER2, or Basal-Type. Our recent analysis comparing matched pre- and post-NAC tumors found 25% of pre-NAC Luminal B tumors changed to Luminal A post-NAC, which corresponded with improved 5-year outcomes compared with patients who remained Luminal B. Here, we report differential gene expression (DGE) and pathway analyses in these matched tumors that may distinguish the different responses. Methods: Among the patients with EBC who received NAC at Cedars Sinai Medical Center between 2007-2016, 38 with residual disease (RD) had paired pre- and post-NAC tissues. In patients with Luminal tumors, 8 were Luminal B pre- and post-NAC (HR/HR), and 7 were Luminal B pre-NAC but changed to Luminal A post-NAC (HR/LR). Limma R package was used for quantile normalization and DGE analyses. Differentially expressed genes (DEG) with < 0.05 false discovery rate and > 2-fold change were considered significant. Functional pathway enrichment was performed using Metascape. Results: Within HR/LR tumors, a DGE analysis identified 104 DEGs in post-NAC tissues relative to pre-NAC, with changes in cell cycle/proliferation pathways. Interestingly, there was a more robust transcriptional change in HR/HR tumors, with 956 DEGs between post- and pre-NAC samples, with enrichment of extracellular matrix organization, angiogenesis, and wound healing pathways. Notably, immune pathway enrichment was in both HR/LR and HR/HR groups, although the nature of enrichment differed. Immune deconvolution identified significant increases in activated myeloid dendritic cells (DC) and CD8+ T cells in HR/LR but not in HR/HR post-NAC tumors, suggestive of a host immune response. Conclusions: Although post-NAC RD correlates with poor prognosis, even in Luminal tumors, these data suggest gene expression profiling may distinguish a subset with good prognosis. Using matched samples, we assessed the transcriptional differences in tumors that changed MP risk (HR/LR) with tumors that stayed MP HR post-NAC (HR/HR). Overall, HR/HR tumors had a larger transcriptional response with metastatic-related pathway enrichment. Given these patients with HR/HR tumors displayed worse outcomes, pathway changes may indicate resistance and patients may need additional therapy. Differential changes in immune cells between HR/HR and HR/LR tumors were also observed. The activated immune response in HR/LR tumors may be a biomarker for therapy response and improved outcome and will be the focus of further evaluation.