Background: P binds to HER2 and has complementary mechanisms of action with H. A clinical study of P+H showed meaningful activity in patients (pts) with metastatic HER2-positive breast cancer whose disease progressed on prior H therapy (Baselga et al. JCO 2010). NeoSphere is a Phase II randomized trial of preoperative systemic therapy comparing H and docetaxel (TH), THP, HP and TP to rank antitumor activity and tolerability. Methods: 417 pts with centrally-confirmed HER2-positive (IHC 3+ or FISH positive) breast cancer (stage II or III including locally advanced) were randomized to receive 4 cycles of TH (n=107), THP (n=107), HP (n=107), or TP (n=96) before surgery. Cycles were given intravenously q3w: P, 840 mg loading dose and 420 mg maintenance; H 8 mg/kg loading dose and 6 mg/kg maintenance; T, 75 mg/m2 with escalation to 100 mg/m2 if the starting dose was well tolerated. After surgery all pts received H to 1 year and 3 cycles of FEC; in case of neoadjuvant HP they also received T before FEC. The primary endpoint was rate of pathological complete response (pCR) in the breast. For all patients, a tissue sample at baseline, as well as at surgery following 4 cycles of neoadjuvant therapy, was collected for biomarker analyses. Results: Baseline characteristics were well balanced. About 40% of patients had locally advanced/inflammatory breast cancer. In the intent-to-treat analysis the rates of pCR and clinical objective response in the breast were: pCR for THP was significantly higher (p=0.014) than TH which was significantly higher than HP (p=0.031). Clinical disease progression was reported in 1 patient on TH and 2 patients on HP. Feasibility was good for all T-containing arms. Adverse events of grade ≥3 were rare (<7%) with HP in sharp contrast with the >50% incidence in T-containing arms. One pt developed congestive heart failure with HP. Five more patients had asymptomatic decreased LVEF with TH (1), THP (3) and TP (1) that resolved at the subsequent assessment. Biomarker analysis is ongoing. Conclusions: These data show the superior antitumor activity of THP and very favorable therapeutic ratio for HP that justify continuing study of the two monoclonals with and without docetaxel in women with HER2- positive early or metastatic breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-2.