Background: Patients with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor before definitive surgery. Complete pathologic Response (pCR) predicts better long term outcome. Genomics assays that measure specific gene expression patterns in a patient's primary tumor have become important prognostic and predictive tools for early breast cancer. This study is designed to test the ability of molecular profiling, as well as traditional pathologic and clinical prognostic factors to predict responsiveness to neo-adjuvant chemotherapy in patients with LABC. Methods: Women ≥ 18 yrs with histologically-proven invasive breast cancer T2(≥3.5cm)-T4,N0M0 or T2-T4N1M0, with measurable disease, adequate bone marrow reserves and normal renal and hepatic function who signed informed consent are enrolled. Axillary lymph nodes will be staged according to protocol. MammaPrint risk profile, BluePrint molecular subtyping profile, TargetPrint ER, PR and HER2 single gene readout, and the 56-gene TheraPrint Research Gene Panel will be analysed using the whole genome expression array. Patients will receive neo-adjuvant chemotherapy treatment according to protocol. Response will be measured by centrally assessed Residual Cancer Burden (RCB). Objectives are: (1) To determine the predictive power of MammaPrint and BluePrint for sensitivity to neo-adjuvant chemotherapy as measured by pCR. (2) To identify and/or validate predictive gene expression profiles of clinical response or resistance to neo-adjuvant chemotherapy. (3) To compare TargetPrint ER, PR and HER2 with local and centralized IHC and/or CISH/FISH assessment. (4) To identify correlations between TheraPrint and response to neo-adjuvant chemotherapy. (5) To compare BluePrint molecular subtype with IHC-based subtype classification. To achieve a difference of 20% in chemotherapy sensitivity for patients stratified by MammaPrint, a total of 226 samples is needed (significance level 0.05 and power of 0.90). So far 45 patients have been enrolled from multiple institutions. Clinical trial information: NCT01501487.