The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.
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.
Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA. rossj@mail.amc.edu
Jeffrey S
JS
Ross
Elzbieta A
EA
Slodkowska
W Fraser
WF
Symmans
Lajos
L
Pusztai
Peter M
PM
Ravdin
Gabriel N
GN
Hortobagyi
D018943:Anthracyclines / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000068338:Everolimus; D019317:Evidence-Based Medicine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D000077341:Lapatinib; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D017410:Practice Guidelines as Topic; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D000068338:Everolimus; D000077341:Lapatinib; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D043823:Taxoids; D000068878:Trastuzumab; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C508053:ERBB2 protein, human; C485206:pertuzumab; C511895:ertumaxomab