Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies

Cancer Cell. 2022 Jun 13;40(6):609-623.e6. doi: 10.1016/j.ccell.2022.05.005. Epub 2022 May 26.


Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.

Keywords: DNA repair; Immune; Luminal; breast cancer; clinical trial; immunotherapy; multiple arms; platinum; response prediction; subtyping.

Publication types

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

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Female
  • Humans
  • Neoadjuvant Therapy
  • Receptor, ErbB-2 / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism


  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Receptor, ErbB-2

Associated data