Background: Hormone receptor positive (HR+), HER2- early stage breast cancer (ESBC) is a heterogeneous disease that has shown lower response to neoadjuvant chemotherapy (NCT) compared with other clinicopathologic subtypes. Genomic profiling may help inform neoadjuvant treatment decisions for ESBC by predicting likelihood of pathological complete response (pCR) or chemosensitivity. The 70-gene MammaPrint (MP) test classifies ESBC patients as having a Low or High Risk of distant metastasis. In the ISPY2 trial, further stratification of MP High Risk into High 1 (H1) or High 2 (H2) improved prediction of chemosensitivity, with significantly higher pCR rates in H2 vs. H1 tumors, particularly in response to immune therapy. Here we evaluate the utility of H1/H2 risk as a biomarker for chemosensitivity and 5 year distant-metastasis free survival (DMFS) in NCT treated patients from the Neoadjuvant Breast Registry Symphony Trial (NBRST). Methods: NBRST (NCT01479101) is an observational prospective study that included 1069 patients with ESBC who received neoadjuvant therapy. Patients with HR+HER2-, MP High Risk tumors who received NCT were included in this analysis (n = 327). Patients were further stratified into H1 (score ≤ 0, > -0.57) or H2 (score ≤ -0.57) groups. Differences in pCR between MP High Risk subcategories were assessed by two-sided proportional z-test. Differences in DMFS was evaluated by Kaplan Meier analysis and log-rank test. Results: MP classified 198 (61%) patients with H1 tumors and 129 (39%) patients with H2 tumors. Age, tumor stage, and lymph node status were comparable between both groups. However, there was a higher proportion of Grade 3 tumors in the H2 group. A significantly higher percentage of pCR was achieved in H2 tumors (30/129; 23%) vs. H1 tumors (12/198; 6.1%) (p < 0.001). Median follow-up was 5.3 years. The 5-year DMFS (% [95% CI]) was significantly worse for patients with H2 tumors (64.8 [55.9 – 75.1]), with most events occurring early ( < 3 years), compared with H1 tumors (77.1 [70.4 – 84.3]; p = 0.012). Patients with H1 tumors that achieved pCR had improved 5-year DMFS (81.8 [61.9 – 100]) compared to H1 tumors that did not achieve pCR (76.8 (69.9 – 84.4; p = 0.009). Patients with H2 tumors that had a pCR demonstrated significantly better 5-year DMFS (80.7 [65.3 – 99.8]) than patients with residual disease (60.2 [50.1 – 72.4]; p = 0.009). Conclusions: These data suggest MammaPrint predicts pCR in HR+HER2- BC patients, with H2 risk tumors exhibiting higher chemosensitivity than H1 tumors. Patients with either H1 or H2 tumors that achieved pCR had similar outcomes, which were significantly improved compared to those with residual disease. Notably, the worst outcomes were observed among patients with H2 risk and residual disease; it should be investigated whether addition of immune therapy to standard NCT would enhance the pCR rates in this patient population. Clinical trial information: NCT01479101.