Background: The EGFR pathways are important therapeutic targets in HER2/neu+ BC. Lapatinib (L) a dual, inhibitor of EGFR and HER2/neu tyrosine kinase activity improves overall survival (OS) in patients with metastatic BC when added to paclitaxel (SABCS 2010:P3-1424).The relative efficacy of L + taxane compared to trastuzumab (T) + taxane in the metastatic setting is unknown. Further research using standardized methodology is required to define prognostic and predictive molecular markers. Methods: NCIC CTG led, international randomized, open label phase III trial comparing: L 1250 mg po daily + taxane therapy* x 24 weeks followed by L 1500 mg po daily vs T (standard dose) + taxane therapy* x 24 weeks followed by T *docetaxel 75 mg/m2 q 3 wk or paclitaxel 80 mg/m2 q wkly 3/4). Eligibility criteria: HER2/neu+ (local or central lab) metastatic BC and no CNS metastases. No prior chemotherapy for metastatic BC. Prior taxane or anti-HER2/nue therapy in (neo)adjuvant setting only. Adequate organ function and PS Endpoints: Primary: progression free survival (PFS). Secondary: OS, incidence and time to CNS metastases, RR, adverse events, QOL, economic evaluation (health utilities and healthcare utilization). Correlative studies will include: Central lab confirmation of HER2/neu, ER/PR, EGFR, Ki67 and CK5/6; PTEN, IGFR, phosphorylated EGFR pathway biomarkers, DNA analysis for genetic mutations (e.g. TP53, P13KCA, HEr1-4, PTEN) predictive of response to therapy; pharmacogenetic analysis for predictors of outcome and toxicity. A substudy will examine tumor molecular changes at progression. Statistical Methods: Planned accrual is 536 patients with HER2/neu+ (central lab) BC over 2 years with 1 more year of follow-up. The primary test is non inferiority (L+taxane)/ T+taxane using a target hazard ratio 1.25 (1 sided alpha 2.5%). If noninferiority is demonstrated, superiority will be tested. An interim analysis is planned. Conduct to Date: Study activation: July 2008. Current accrual: 440. In Nov 2010 the DSMC review supported trial continuation. Supported by GlaxoSmithKline ClinicalTrials.gov: NCT00667251.