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

Nat Commun. 2021 Nov 5;12(1):6428. doi: 10.1038/s41467-021-26019-y.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ado-Trastuzumab Emtansine / therapeutic use*
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Biomarkers, Tumor
  • Breast Neoplasms / drug therapy*
  • Humans
  • Maytansine / therapeutic use
  • Middle Aged
  • Neoadjuvant Therapy / methods*
  • Paclitaxel / therapeutic use
  • Receptor, ErbB-2 / therapeutic use
  • Trastuzumab / therapeutic use


  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • Maytansine
  • Receptor, ErbB-2
  • pertuzumab
  • Trastuzumab
  • Paclitaxel
  • Ado-Trastuzumab Emtansine