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Background: Recent trials in HER2-positive(HER2+)breast cancer(BrCa)demonstrate increased pathological complete response(pCR)using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease.CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel(T)and trastuzumab(H)alone or combined HER2-blockade of H with the small molecule lapatinib(L),and to identify biomarkers of sensitivity to these HER2-targeted agents.Methods: Eligible patients had newly diagnosed,noninflammatory stage Ⅱ-Ⅲ HER2+ BrCa and were randomized to receive T(80mg/m2/week Ⅳ)+ H(4mg/kg then 2mg/kg/week Ⅳ)alone(TH)or with the addition of L(750 mg/d PO)(THL)for 16 weeks preoperatively.A third arm,T + L(1500 mg/d)(TL),was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO.After surgery,4 cycles of adjuvant dose-dense AC and 1 year H was recommended.Tumors were biopsied for research before therapy; post-Rx samples of residual disease were requested.The primary endpoint was in-breast pCR rate; the study had 85%power to detect an increase from 30%(TH)to 50%(THL).Results: 305 patients were randomized(118 THL,120 TH,67 TL); 68%were clinical stage Ⅱ and 59%hormone receptor-positive.Grade 3+ toxicity was higher among L-containing arms,including neutropenia(12%TL,7%THL,2%TH),rash(15%TL,14%THL,2%TH),and diarrhea(20%TL,20%THL,2%TH).Breast pCR rates with 95%confidence limits were: 51%(42-60%)THL,40%(32-49%)TH,32%(22-44%)TL.pCR rate in the TH arm was higher than previous studies,and was not significantly different from THL(p=0.11).We will present molecular subtype,sequence and gene copy number abnormalities in primary tumors and residual disease.Conclusions: pCR rate was higher with combined THL compared with standard TH but did not reach statistical significance.These results are qualitatively similar to other neoadjuvant studies in HER2+ BrCa,and contribute to estimates of pCR rates after these agents.Tissue-based studies may illuminate which patients benefit from HER2-targeting using these agents.