Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial

Amy S. Clark*, Christina Yau, Denise M. Wolf, Emanuel F. Petricoin, Laura J. van ‘t Veer, Douglas Yee, Stacy L. Moulder, Anne M. Wallace, A. Jo Chien, Claudine Isaacs, Judy C. Boughey, Kathy S. Albain, Kathleen Kemmer, Barbara B. Haley, Hyo S. Han, Andres Forero-Torres, Anthony Elias, Julie E. Lang, Erin D. Ellis, Rachel YungDebu Tripathy, Rita Nanda, Julia D. Wulfkuhle, Lamorna Brown-Swigart, Rosa I. Gallagher, Teresa Helsten, Erin Roesch, Cheryl A. Ewing, Michael Alvarado, Erin P. Crane, Meredith Buxton, Julia L. Clennell, Melissa Paoloni, Smita M. Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Katherine Steeg, Adam Asare, Jeffrey B. Matthews, Scott Berry, Ashish Sanil, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, Richard B. Schwab, W. Fraser Symmans, Nola M. Hylton, Donald A. Berry, Laura J. Esserman, Angela M. DeMichele

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Original languageEnglish
Article number6428
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2021
Externally publishedYes


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