Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) expression guide the use of neoadjuvant chemotherapy (NACT) in patients with early breast cancer. We evaluate the independent predictive value of adding a multigene profile (CIT256 and PAM50) to immunohistochemical (IHC) profile regarding pathological complete response (pCR) and conversion of positive to negative axillary lymph node status. The cohort includes 458 patients who had genomic profiling performed as standard of care. Using logistic regression, higher pCR and node conversion rates among patients with Non-luminal subtypes are shown, and importantly the predictive value is independent of IHC profile. In patients with ER-positive and HER2-negative breast cancer an odds ratio of 9.78 (95% CI 2.60;36.8), P < 0.001 is found for pCR among CIT256 Non-luminal vs. Luminal subtypes. The results suggest a role for integrated use of up-front multigene subtyping for selection of a neoadjuvant approach in ER-positive HER2-negative breast cancer.