Nature Comm

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

Clark AS, Yau C, Wolf DM, Petricoin EF, Veer LJ van ‘t, Yee D, Moulder SL, Wallace AM, Chien AJ, Isaacs C, Boughey JC, Albain KS, Kemmer K, Haley BB, Han HS, Forero-Torres A, Elias A, Lang JE, Ellis ED, Yung R, Tripathy D, Nanda R, Wulfkuhle JD, Brown-Swigart L, Gallagher RI, Helsten T, Roesch E, Ewing CA, Alvarado M, Crane EP, Buxton M, Clennell JL, Paoloni M, Asare SM, Wilson A, Hirst GL, Singhrao R, Steeg K, Asare A, Matthews JB, Berry S, Sanil A, Melisko M, Perlmutter J, Rugo HS, Schwab RB, Symmans WF, Hylton NM, Berry DA, Esserman LJ, DeMichele AM

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.

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