What is the role of the HER2 (human epidermal growth factor receptor 2) gene in breast cancer?

The Role of HER2 Gene in Breast Cancer

The HER2 (human epidermal growth factor receptor 2) gene is amplified in approximately 15-20% of breast cancers, driving tumor proliferation, migration, and invasion, and is associated with worse prognosis but also presents an important therapeutic target for targeted treatments that significantly improve survival. 1

HER2 Biology and Function

• HER2 (also known as ERBB2 or neu) encodes a type I receptor tyrosine kinase that belongs to the epidermal growth factor receptor family 1
• The HER2 protein is a 185-kd glycoprotein with tyrosine kinase activity found in the cell membrane 1
• HER2 functions by forming homodimers or heterodimers with other HER family members, triggering downstream signaling cascades that control:
  • Cell proliferation
  • Cell survival
  • Apoptosis regulation 2

HER2 in Breast Cancer Pathophysiology

• Gene amplification is the primary mechanism of HER2 overexpression in breast cancer 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 1
• HER2 amplification creates a dichotomous separation between normal and pathologic expression levels, not a continuous spectrum 1
• HER2 overexpression drives:
  • Increased cell proliferation
  • Reduced apoptosis
  • Expression of mesenchymal markers associated with invasion
  • Greater metastatic potential 3

Clinical Significance of HER2 Status

• HER2 positivity is associated with:

  • More aggressive disease phenotype
  • Higher rates of recurrence and mortality when untreated
  • Relative resistance to certain endocrine therapies, particularly selective estrogen receptor modulators like tamoxifen 1
  • Potential increased sensitivity to anthracycline-based chemotherapy 1

• HER2 status is critical for therapeutic decision-making:

  • Identifies patients eligible for HER2-targeted therapies
  • Helps determine optimal chemotherapy regimens
  • Provides important prognostic information 1

HER2 Testing Methods

• Accurate determination of HER2 status is essential for optimizing treatment outcomes 1

• Two primary testing methods:

  1. Immunohistochemistry (IHC): Measures HER2 protein expression in cell membranes
  2. Fluorescence in situ hybridization (FISH): Assesses HER2 gene amplification 1

• Testing challenges:

  • IHC results can be affected by variability in tissue fixation methods and times
  • FISH is less dependent on tissue fixation methods, making it more reproducible between laboratories 1
  • Some experts recommend FISH as the primary testing modality due to its higher reproducibility and stronger correlation with treatment response 1

• The American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) developed guidelines for HER2 testing to reduce inaccuracy and standardize testing procedures 1

HER2-Targeted Therapies

• Several effective HER2-targeted therapies have been developed:

  • Trastuzumab (Herceptin): A humanized monoclonal antibody targeting the HER2 extracellular domain 1, 4
  • Pertuzumab: Works synergistically with trastuzumab 4
  • Trastuzumab emtansine (T-DM1): An antibody-drug conjugate 4
  • Lapatinib: A small molecule dual tyrosine kinase inhibitor of HER1/HER2 1, 5
  • Newer agents: Tucatinib, trastuzumab deruxtecan, neratinib, and margetuximab 4

• These targeted therapies have dramatically improved outcomes:

  • In metastatic disease: Improved response rates, time to progression, and survival 1, 4
  • In early-stage disease: Reduced risk of recurrence by approximately 50% and mortality by about 33% 1

Treatment Approaches for HER2-Positive Breast Cancer

• Standard approach for metastatic disease:

  • First-line: Taxane + trastuzumab + pertuzumab
  • Second-line: Trastuzumab emtansine (T-DM1)
  • Third-line and beyond: Newer targeted agents like tucatinib, trastuzumab deruxtecan, neratinib, or margetuximab 4

• For hormone receptor-positive, HER2-positive disease:

  • Chemo-free anti-HER2 strategies may be considered in selected patients 4

Clinical Pitfalls and Considerations

• Accurate HER2 testing is critical - false negatives may deny patients access to effective targeted therapies, while false positives expose patients to unnecessary toxicity and cost 1
• Testing should be performed in accredited laboratories that meet quality assurance standards 1
• HER2 status should be reassessed in metastatic lesions when possible, as discordance with the primary tumor can occur 4
• Brain metastases are common in HER2-positive disease and require special consideration in treatment planning 4
• Ongoing research is exploring biomarkers to better select patients for specific HER2-targeted therapies 4, 6