What does a HER2 (Human Epidermal growth factor Receptor 2) +3 result mean?

HER2 +3 Interpretation

A HER2 +3 result means the breast cancer is HER2-positive, defined as uniform intense membrane staining of more than 30% of invasive tumor cells, and this patient is a candidate for HER2-targeted therapies such as trastuzumab. 1

What HER2 +3 Represents

HER2 +3 is the highest immunohistochemistry (IHC) score and indicates HER2 protein overexpression on the tumor cell surface. 1

• The +3 designation specifically requires uniform intense complete membrane staining in more than 30% of invasive tumor cells 1
• This result reflects underlying HER2 gene amplification, where receptor levels increase from normal (25,000-185,000 receptors per cell) to pathologic levels (500,000-2,000 receptors per cell) 2
• The amplification drives constitutive activation of growth-promoting signaling pathways that control cell proliferation, survival, and migration 3, 4

Clinical Significance for Treatment

Patients with HER2 +3 breast cancer should receive HER2-targeted therapy, as this dramatically improves survival outcomes. 1, 3

• HER2 +3 status makes patients eligible for trastuzumab (Herceptin), a monoclonal antibody that has proven remarkably effective in both metastatic and adjuvant settings 1, 4
• Additional HER2-targeted options include lapatinib (a dual tyrosine kinase inhibitor) and other agents under investigation 4, 5
• Without HER2-targeted therapy, HER2-positive disease is associated with higher rates of recurrence and mortality 1, 2

Prognostic Implications

HER2 +3 tumors represent a more aggressive breast cancer phenotype when untreated, but targeted therapies have transformed outcomes. 2, 6

• HER2 overexpression historically correlated with worse prognosis, including higher recurrence rates and mortality in untreated patients 1, 2
• The aggressive nature relates to HER2-driven proliferation, vessel formation, and invasiveness 6
• HER2 positivity may be associated with relative resistance to selective estrogen receptor modulators (like tamoxifen) but not necessarily to aromatase inhibitors 1

Testing Considerations

No confirmatory FISH testing is required for HER2 +3 results, as this IHC score alone defines HER2-positive disease. 1

• The testing must be performed on the invasive component of the breast cancer, not in situ disease, as HER2 is frequently increased in in situ cancer with uncertain clinical implications 1
• Laboratories performing HER2 testing should demonstrate 95% concordance with validated assays and meet CAP accreditation standards 1, 3
• In contrast, IHC 2+ results are equivocal and require FISH confirmation, while IHC 0 or 1+ are negative 1

Common Pitfalls to Avoid

• Do not confuse HER2 +3 with HER2 2+: Only 2+ is equivocal and requires additional FISH testing; +3 is definitively positive 1
• Ensure testing was performed on invasive tumor: In situ components may show HER2 overexpression that doesn't guide systemic therapy decisions 1
• Verify laboratory quality: Testing should only be performed in CAP-accredited laboratories or those meeting equivalent standards 1, 3