The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine

Oncologist. 2009 Apr;14(4):320-68. doi: 10.1634/theoncologist.2008-0230. Epub 2009 Apr 3.

Abstract

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.

Publication types

  • Review

MeSH terms

  • Anthracyclines / administration & dosage
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / chemistry*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Everolimus
  • Evidence-Based Medicine
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Lapatinib
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Practice Guidelines as Topic
  • Prognosis
  • Pyrazoles / administration & dosage
  • Pyrimidines / administration & dosage
  • Quinazolines / administration & dosage
  • RNA, Messenger / analysis
  • Receptor, ErbB-2 / analysis*
  • Receptor, ErbB-2 / drug effects*
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • Survival Analysis
  • Taxoids / administration & dosage
  • Trastuzumab
  • Treatment Outcome
  • Up-Regulation / drug effects

Substances

  • 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
  • Anthracyclines
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • Pyrazoles
  • Pyrimidines
  • Quinazolines
  • RNA, Messenger
  • Taxoids
  • Lapatinib
  • Bevacizumab
  • Everolimus
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • pertuzumab
  • ertumaxomab
  • Trastuzumab
  • Sirolimus