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

What is HER2 (Human Epidermal Growth Factor Receptor 2)?

HER2 is a transmembrane receptor tyrosine kinase protein encoded by the ERBB2 gene that, when amplified and overexpressed in approximately 15-20% of breast cancers, drives aggressive tumor behavior and serves as a critical therapeutic target for improving survival. 1

Molecular Structure and Biology

HER2 (also known as ERBB2, c-erbB-2, or neu) is a 185-kDa glycoprotein with tyrosine kinase activity that belongs to the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. 1, 2

• The protein functions by forming homodimers or heterodimers with other HER family members (HER1/EGFR, HER3, HER4), triggering downstream signaling cascades that control cell proliferation, survival, and migration 2, 3
• Unlike other EGFR family members, HER2 is considered a ligand orphan receptor—it has no known direct ligand but is activated through heterodimerization with ligand-bound family members 4
• The intracellular signaling involves multiple pathways including RAS-MAPK, PI3K-AKT, and phospholipase C-gamma pathways 4, 5

Gene Amplification Mechanism

Gene amplification is the primary mechanism driving HER2 overexpression in breast cancer, creating a dramatic dichotomous separation between normal and pathologic expression levels. 1, 3

• Normal breast cells express 25,000-185,000 HER2 receptors per cell 3
• When amplified, expression increases to 500,000-2,000 receptors per cell—a 10-20 fold increase 3
• This creates abnormally high levels of the glycoprotein with constitutive tyrosine kinase activity 1
• The amplification occurs in approximately 18-20% of breast cancers 1

Clinical Significance and Prognostic Impact

HER2 positivity is associated with significantly worse prognosis, including higher rates of recurrence and mortality in untreated patients, but also identifies patients who will benefit dramatically from HER2-targeted therapies. 1, 2

Prognostic Value

• HER2-positive tumors demonstrate more aggressive clinical behavior with enhanced metastatic potential 6, 7
• Without treatment, HER2 positivity predicts shorter time to relapse and shorter overall survival 5
• HER2 status should be incorporated into clinical decisions regarding adjuvant systemic therapy alongside other prognostic factors 1

Predictive Value for Therapy

• HER2 positivity predicts relative (but not absolute) resistance to selective estrogen receptor modulators like tamoxifen, though this may not apply to aromatase inhibitors 1
• HER2 status may predict relative lower benefit from non-anthracycline, non-taxane chemotherapy regimens (like CMF) 1
• HER2 positivity appears to predict enhanced response to anthracycline-based chemotherapy, possibly due to co-amplification with topoisomerase II 1
• Most critically, HER2 positivity identifies patients who will benefit from HER2-targeted therapies like trastuzumab, which dramatically improve response rates, time to progression, and overall survival 1, 2

HER2 Testing Methods and Criteria

Two primary testing methods are used: immunohistochemistry (IHC) detects protein overexpression, while fluorescent in situ hybridization (FISH) detects gene amplification. 1, 2, 3

Positive HER2 Result Criteria

• IHC 3+: uniform, intense membrane staining of ≥30% of invasive tumor cells 1
• FISH: >6 HER2 gene copies per nucleus OR HER2/chromosome 17 ratio >2.2 1

Negative HER2 Result Criteria

• IHC 0 or 1+ 1
• FISH: <4.0 HER2 gene copies per nucleus OR HER2/chromosome 17 ratio <1.8 1

Equivocal Results

• Results falling between positive and negative thresholds require additional testing for final determination 1

Testing Standards and Quality Requirements

HER2 testing must be performed in CAP-accredited laboratories or laboratories meeting equivalent accreditation standards, with laboratories demonstrating 95% concordance with validated tests. 1, 2

• Testing should be performed on every primary invasive breast cancer at diagnosis or recurrence 1
• FISH is considered the primary testing modality due to higher test accuracy, reproducibility, and predictive value 2
• Laboratories must use standardized operating procedures and comply with stringent proficiency testing and competency assessment 1

Therapeutic Implications

HER2-targeted therapies have revolutionized outcomes for HER2-positive breast cancer, transforming what was once the most aggressive subtype into one with excellent treatment options. 1, 2, 3

• Trastuzumab (Herceptin) is a humanized monoclonal antibody targeting the HER2 extracellular domain, approved for both metastatic and adjuvant treatment 1, 8
• Pertuzumab targets a different epitope (subdomain II) and blocks ligand-dependent heterodimerization, working synergistically with trastuzumab 9
• These agents mediate antibody-dependent cellular cytotoxicity (ADCC) preferentially against HER2-overexpressing cells 8, 9
• In elderly patients with ER+/HER2+ disease and significant comorbidities, endocrine therapy combined with trastuzumab (with or without pertuzumab) provides effective disease control with lower toxicity than chemotherapy-containing regimens 10

Common Pitfalls to Avoid

• Do not assume all HER2-positive patients require chemotherapy: In selected elderly or frail patients with ER+/HER2+ disease, endocrine therapy plus trastuzumab without chemotherapy is a valid option 10
• Do not rely on testing from non-accredited laboratories: Inaccurate HER2 testing can lead to inappropriate treatment decisions with significant mortality implications 1, 2
• Do not ignore equivocal results: These require reflex testing or alternative methodology for definitive determination 1
• Remember that HER2 testing accuracy directly impacts survival: Only patients with truly HER2-positive disease benefit from HER2-targeted therapies, while false positives expose patients to unnecessary cardiac toxicity 1, 8