HER2-positive advanced breast cancer: Optimizing patient outcomes and opportunities for drug development Review uri icon


MeSH Major

  • Antineoplastic Agents
  • Breast Neoplasms
  • Drug Design
  • Molecular Targeted Therapy
  • Receptor, ErbB-2


  • Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2-targeted therapies. In this article, we review the optimal sequence of HER2-targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development.

publication date

  • January 2014



  • Review



  • eng

PubMed Central ID

  • PMC4229628

Digital Object Identifier (DOI)

  • 10.1038/bjc.2014.388

PubMed ID

  • 25025958

Additional Document Info

start page

  • 1888

end page

  • 98


  • 111


  • 10