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Background: Neoadjuvant chemotherapy(NAC)and concomitant trastuzumab(T)have produced high pathologic complete response(pCR)rates in HER2+ breast cancers.Z1041 addresses the timing of initiation of T with NAC.Methods: Women with operable HER2+ invasive breast cancer were randomized 1:1 to: FEC → P+T(Arm 1)or P+T → FEC+T(Arm 2)where treatment was administered as 5-FU 500 mg/m2,epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4(FEC); paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11.Eligibility also included: tumor > 2 cm or a positive lymph node and left ventricular ejection fraction > 55%.The primary aim was to compare the pCR rates in the breast(pBCR)between the regimens.Secondary endpoints were pCR rate in the breast and lymph nodes(pBNCR)and safety profile.All pts who began study treatment were included in the analyses.With 128 pts per regimen,a two-sided alpha=0.05 test of proportions would have a 90%chance of detecting a difference of 20%or more in the pBCR rates,when the pBCR rate with the poorer regimen is ≤ 25%.Results: From September 15,2007 to December 15,2011,282 women(Arm 1: 140 pts)were enrolled.Two pts(Arm 1)withdrew without receiving treatment.The two arms were similar in age,stage,and hormone receptor(HR)status(HR neg: 40%).The severe(grade 3+)treatment-related toxicities included: neutropenia(Arm 1: 24.6%; Arm 2: 32.4%),fatigue(Arm 1: 4.3%; Arm 2: 8.5%),and neurosensory problems(Arm 1: 3.6%; Arm 2: 4.9%).The pBCR rate and pBNCR rates(Table)were not found to differ between the two regimens(Fishers exact p values: 0.905 and 0.811,respectively).Conclusions: High pCR rates can be achieved with trastuzumab in combination with anthracyclines and taxanes.The pBCR or pBNCR was not different between regimens based on the timing of initiation of trastuzumab.