What is the importance of Human Epidermal growth factor Receptor 2 (HER2)/neu in breast cancer?

HER2/neu in Breast Cancer: Clinical Importance

HER2/neu testing is essential in every primary invasive breast cancer because it identifies patients who will benefit from life-saving targeted therapies like trastuzumab, which reduces recurrence risk by 50% and mortality by 33% in the adjuvant setting. 1

Prognostic Significance

HER2 as a Poor Prognostic Marker:

• HER2 is overexpressed or amplified in 15-30% of breast cancers and marks aggressive disease with higher recurrence and mortality rates when untreated 1, 2
• The gene amplification drives tumor proliferation, migration, and invasion through constitutive activation of growth-promoting signaling pathways 2, 3
• When amplified, HER2 expression increases dramatically from normal levels (25,000-185,000 receptors/cell) to pathologic levels (500,000-2,000 receptors/cell), creating a clear dichotomous separation rather than a continuous spectrum 2, 3

Predictive Value for Treatment Selection

Primary Indication - Anti-HER2 Therapy:

• High levels of HER2 expression (IHC 3+) or gene amplification (FISH positive) must be used to identify patients for trastuzumab therapy in both adjuvant and metastatic settings 1
• Trastuzumab improves response rates, time to progression, and overall survival when combined with chemotherapy compared to chemotherapy alone in metastatic disease 1, 4
• In the adjuvant setting, trastuzumab reduces disease recurrence by approximately 50% and mortality by 33% based on large randomized trials 4
• Only patients with IHC 3+ or FISH-positive tumors benefit from trastuzumab; those with HER2-negative status should not receive it 5, 4

Chemotherapy Selection:

• HER2 positivity predicts relative resistance to CMF-like regimens (cyclophosphamide, methotrexate, fluorouracil) 1
• HER2 amplification may predict benefit from anthracycline-based chemotherapy, though this effect may be secondary to co-amplification with topoisomerase II 1
• Preliminary data suggest HER2 positivity predicts response to paclitaxel in metastatic and adjuvant settings 1

Endocrine Therapy Considerations:

• HER2 positivity is associated with relative (not absolute) resistance to endocrine therapies, particularly tamoxifen 1, 2
• The resistance may be specific to selective estrogen receptor modulators and potentially not to aromatase inhibitors, though this remains controversial 1
• In ER-positive/HER2-positive tumors, the relative benefit from antiestrogens is lower than in HER2-negative cancers 1

Testing Requirements and Standards

Mandatory Testing Protocol:

• HER2 expression and/or amplification should be evaluated in every primary invasive breast cancer at diagnosis or recurrence 1
• Testing must be performed in CAP-accredited laboratories meeting specific accreditation and proficiency testing requirements 2
• Laboratories must demonstrate 95% concordance with validated tests for positive and negative results 2

Testing Methods:

• Two primary methods are used: Immunohistochemistry (IHC) detects protein overexpression, and Fluorescence in situ hybridization (FISH) detects gene amplification 2, 3
• FISH is the primary testing modality due to higher test accuracy, reproducibility, and predictive value 2
• A positive HER2 result is defined as IHC 3+ or FISH showing more than six HER2 gene copies per nucleus 2

Critical Testing Pitfall:

• Standardization of HER2 testing is essential to minimize false-negative results that would exclude patients from potentially life-saving therapy 1
• Only 24% of IHC 2+ tumors show gene amplification by FISH, emphasizing the need for confirmatory testing in equivocal cases 1

Serum HER2 Testing

Not Recommended for Clinical Use:

• Measuring circulating extracellular domain of HER2 is not currently recommended in any clinical setting 1
• While elevated serum HER2 correlates with tissue overexpression in roughly 25% of patients, it is confounded by tumor burden and lacks sufficient predictive value 1
• Serum HER2 does not provide actionable information that would change treatment decisions 1

Available HER2-Targeted Therapies

FDA-Approved Agents:

• Trastuzumab: humanized monoclonal antibody binding the HER2 extracellular domain, inducing responses in 15-25% as monotherapy 1, 5, 4
• Pertuzumab: binds a different HER2 epitope with complementary mechanisms to trastuzumab 5
• Lapatinib: dual HER1/HER2 tyrosine kinase inhibitor showing benefit when added to capecitabine in advanced disease 1, 3
• Trastuzumab emtansine (T-DM1): antibody-drug conjugate for metastatic disease 6
• Tucatinib: approved for HER2-positive metastatic breast cancer in combination with trastuzumab and capecitabine, particularly effective in patients with brain metastases 6

Mechanism of Trastuzumab:

• Binds with high affinity to HER2 extracellular domain, blocking HER2-HER4 signaling and downstream pathways 5
• Mediates antibody-dependent cellular cytotoxicity (ADCC), preferentially targeting HER2-overexpressing cancer cells 5
• Unlike anthracyclines, trastuzumab-induced cardiotoxicity is reversible and does not cause permanent myocyte loss 5