Background: Combinations of two different anti-HER2 therapies without chemotherapy have generated great expectations. However, it is unclear which group of patients benefits the most from this strategy. Within HER2-positive breast cancer, the PAM50 assay identifies a HER2-Enriched HER2-E intrinsic subtype characterized by high activation of the EGFR/HER2 pathway. Trial Design: This non-randomized, open label multi-centre translational research study will evaluate the ability of the HER2-E subtype to predict pathological complete response (pCR) to dual HER2 blockade with lapatinib and trastuzumab for a total of 18 weeks. Patients with hormone receptor (HR)-positive disease will also receive endocrine therapy. Eligibility Criteria: Operable primary Stage I-IIIa HER2+ breast cancer. Specific Aims: The primary objective is to evaluate the ability of the PAM50 assay to predict pCR in the breast at the time of surgery.Secondary objectives are to (1) assess the correlation of HER2-E with pCR in the breast and axilla, (2) assess the correlation of HER2-E with Residual Cancer Burden (RCB) (3) evaluate the gene expression changes from Day 0 to Day 14 and the correlations with Ki67-IHC at Day 14, (4), identify additional gene expression signatures predictive of pCR, and (5) evaluate safety and tolerability. Methods: The statistical plan is based on the assumption that breast pCR rate will be 35.0% for HER2-E tumors and 8.0% for non-HER2E. The study will have a 95% power with a significance level of 5% (two-sided) and an assumed drop-out rate of 15%. Biomarker Analyses: Baseline, 14-day treated and post-treatment (surgical) formalin–fixed, paraffin–embedded tissues will be obtained. The expression of 547 genes will be explored with the nCounter platform. Subtype will be identified using the PAM50 predictor (Parker et al. J Clin Oncol 2009). Ki-67-IHC will also be evaluated on pre-treatment and Day-14 samples. Target Accrual: 150 patients with a maximum of 75 HR-positive patients across Spain and Portugal. Patient enrollment will begin in May 2013.