What is HER2/neu (Human Epidermal growth factor Receptor 2)?

HER2/neu: A Critical Oncogene in Breast Cancer

HER2/neu is a proto-oncogene that encodes a 185-kDa transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor family, which is amplified in approximately 15-20% of breast cancers and serves as both a prognostic marker for aggressive disease and a therapeutic target for targeted treatments that significantly improve survival. 1

Biological Structure and Function

• HER2 (also known as ERBB2 or neu) functions by forming homodimers or heterodimers with other HER family members, triggering downstream signaling cascades that control cell proliferation, survival, and migration 1
• When amplified, HER2 expression levels increase dramatically from normal levels of 25,000-185,000 receptors per cell to pathologic levels of 500,000-2,000 receptors per cell, creating a dichotomous separation between normal and pathologic expression 1
• The HER2 protein has tyrosine kinase activity that, when overexpressed, leads to constitutive activation of growth-promoting signaling pathways 2

Clinical Significance in Breast Cancer

• HER2 amplification and overexpression are recognized as important markers for aggressive disease and are associated with higher rates of recurrence and mortality when untreated 2
• HER2 status is critical for therapeutic decision-making as it identifies patients eligible for HER2-targeted therapies and helps determine optimal chemotherapy regimens 1
• HER2 overexpression appears to be associated with relative, but not absolute, resistance to endocrine therapies in general, particularly selective estrogen receptor modulators like tamoxifen 2
• HER2 positivity may be associated with response to anthracycline therapy, though this effect may be secondary to coamplification with topoisomerase II 2

Detection Methods

• Two primary testing methods are used to determine HER2 status: 1
  • Immunohistochemistry (IHC): Detects protein overexpression
  • Fluorescent in situ hybridization (FISH): Detects gene amplification
• According to ASCO-CAP guidelines, a positive HER2 result is defined as: 2
  • IHC staining of 3+ (uniform, intense membrane staining of ≥30% of invasive tumor cells)
  • FISH result of more than six HER2 gene copies per nucleus
  • FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2
• FISH is considered more reproducible than IHC as it is less dependent on tissue fixation methods, making it more reliable between central and peripheral laboratories 2

HER2-Targeted Therapies

• Trastuzumab (Herceptin) is a humanized monoclonal antibody targeting the HER2 extracellular domain that has been shown to inhibit the proliferation of tumor cells that overexpress HER2 3
• Trastuzumab works through multiple mechanisms: 3
  • Inhibition of HER2 signaling pathways
  • Mediation of antibody-dependent cellular cytotoxicity (ADCC)
• Pertuzumab targets a different epitope of the HER2 extracellular domain (Subdomain II) and blocks ligand-dependent heterodimerization of HER2 with other HER family members 4
• The combination of pertuzumab and trastuzumab augments anti-tumor activity in HER2-overexpressing models 4
• These targeted therapies have dramatically improved outcomes for patients with HER2-positive breast cancer 1

HER2 in Other Cancers

• While most extensively studied in breast cancer, HER2 overexpression has been identified in other cancer types: 2
  • Esophageal adenocarcinomas (15-30%)
  • Esophagogastric junction cancers (higher rates than gastric cancers)
  • Squamous cell carcinoma of the esophagus (5-13%)

Clinical Testing Considerations

• The ASCO-CAP guidelines recommend that HER2 testing be performed in CAP-accredited laboratories or laboratories that meet specific accreditation and proficiency testing requirements 2
• Laboratories performing HER2 testing should demonstrate 95% concordance with another validated test for positive and negative assay values 2
• Equivocal results require additional testing for final determination of HER2 status 2
• FISH is suggested as the primary HER2 testing modality for women with breast cancer who are candidates for HER2-targeted therapies due to its higher test accuracy, reproducibility, and predictive value 2

HER2/neu testing has revolutionized breast cancer treatment by identifying patients who can benefit from targeted therapies, significantly improving outcomes for a subset of patients with historically aggressive disease.