• Lisa A Carey, Donald A Berry, Constance T Cirrincione, William T Barry, Brandelyn N Pitcher, Lyndsay N Harris, David W Ollila, Ian E Krop, Norah Lynn Henry, Douglas J Weckstein, Carey K Anders, Baljit Singh, Katherine A Hoadley, Michael Iglesia, Maggie Chon U Cheang, Charles M Perou, Eric P Winer, and Clifford A Hudis.
• Lisa A. Carey, David W. Ollila, Carey K. Anders, Katherine A. Hoadley, Michael Iglesia, and Charles M. Perou, University of North Carolina Chapel Hill, Chapel Hill; Constance T. Cirrincione and Brandelyn N. Pitcher, Alliance Statistics and Data Center, Duke University, Durham, NC; Donald A. Berry, Alliance Statistics and Data Center, MD Anderson, Houston, TX; William T. Barry, Alliance Statistics and Data Center, Dana-Farber Cancer Institute; Ian E. Krop and Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA; Lyndsay N. Harris, University Hospitals of Cleveland, Cleveland, OH; Norah Lynn Henry, University of Michigan, Ann Arbor, MI; Douglas J. Weckstein, New Hampshire Hematology-Oncology, Hooksett, NH; Baljit Singh, New York University; Clifford A. Hudis, Memorial Sloan-Kettering Cancer Center, New York, NY; and Maggie Chon U. Cheang, Clinical Trials and Statistics Unit, Institute of Cancer Research, Belmont, United Kingdom. lisa_carey@med.unc.edu.
• J. Clin. Oncol. 2016 Feb 20; 34 (6): 542-9.

PurposeDual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features.Patients And MethodsPatients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays.ResultsAmong 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%).ConclusionpCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.© 2015 by American Society of Clinical Oncology.

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