Background: The heterogeneity of TNBC results in varied responses to NAST: 30-40% of patients (pts) have pathologic complete response (pCR) with excellent prognosis. Those with residual disease, have a much higher risk of recurrence. Longitudinal profiling assesses biologic response to NAST and mechanisms of resistance. Methods: Pts with stage I-III TNBC began a planned 4 cycles of Adriamycin-based chemo (AC). Biopsies were performed pre (mandatory) and post (optional) AC. Volumetric change by ultrasound (VUS) at completion of AC (or progression) was calculated. Pts with sensitive disease received subsequent taxane-based (T) therapy. Pts with insensitive disease were offered phase II trials. Pathologic response was assessed at surgical resection in 47 pts. Matched samples, pre and post AC (N = 48 pts) underwent transcriptomic and genomic profiling. Samples were classified into six previously identified ARTEMIS subtypes of TNBC (ART-Type). Immune deconvolution and estimation was performed using RNA-Seq profiles. Differential pathway-level analysis was performed comparing pre and post AC samples. Results: There was heterogeneity in response to AC with 4 predominate patterns of biologic response (Table). In 48% of cases the ART-Type of the tumor switched after AC, with androgen receptor like (LAR) and immune modulatory (IM) showing greatest stability. Tumors with enrichment in EMT or those with no significant dysregulation after AC (Groups C + D) were associated with less immune modulation and lower rates of pCR compared to those with depleted EMT (A and B) (8.7% vs 45.8%, p = 0.0078). Conclusions: Molecular profiling of longitudinal TNBC samples reveals distinct response patterns in tumors and their micro-environments upon treatment with AC. These patterns were indicative of pathologic response in this cohort; however, they require validation in a separate cohort. Clinical trial information: NCT02276443