What Is HER2? What Does Positivity Mean in Cancer? Overexpression, Amplification and Mutation

Why Is HER2 Important?

As molecular biology has advanced in cancer diagnosis and treatment, certain genes and proteins have become key determinants of disease course. One of these is HER2 (Human Epidermal Growth Factor Receptor 2) , a gene.

Particularly in breast cancer and stomach (gastric) cancer , as well as certain other tumors, HER2 positivitymay indicate a more aggressive disease course, while also opening up targeted treatment options. This article examines what HER2 is, which changes indicate positivity and how they affect treatment decisions.

What Is HER2?

HER2 is a member of the human epidermal growth factor receptor family and is a transmembrane tyrosine kinase receptor. Located on the cell membrane, it transmits signals for growth, proliferation and survival into the cell.

This receptor, the product of the HER2 gene, may be overproduced or structurally altered in some cancers, leading to uncontrolled cell growth.

What Does HER2-Positive Mean?

HER2 positivitymeans that the HER2 protein in tumor cells is overproduced (overexpression) or that the HER2 gene has an increased copy number (amplification) . These two conditions often occur together and may cause more aggressive cancer cell behavior.

In HER2-positive tumors:

• Cells proliferate more rapidly.

• Treatment resistance may occur more frequently.

• However, there is also a high likelihood of responding to HER2-specific targeted treatments.

How Is HER2 Positivity Detected?

1. Immunohistochemistry (IHK/IHC):

• Measures the amount of HER2 protein on the cell surface
• Scoring: 0, 1+, 2+, 3+
  • 3+: HER2-positive (overexpression)
  • 2+: Equivocal; confirmed with FISH testing
  • 0–1+: Negative

2. FISH (Fluorescence In Situ Hybridization):

• Measures HER2 gene copy number at the DNA level (amplification)
• FISH positivity generally indicates excess HER2 protein as well

3. NGS (Next-Generation Sequencing):

• Can detect changes in the HER2 gene such as point mutations or rare structural alterations
• Particularly in cancers outside the breast (e.g., lung and colon cancer), HER2 mutations are becoming targetable

Differences Between Overexpression, Amplification and Mutation

In Which Cancers Is HER2 Found?

Breast Cancer

• Of all breast cancers, approximately 15-20% are HER2-positive
• HER2-positive tumors are generally more aggressive
• Trastuzumab (Herceptin), Pertuzumab (Perjeta), T-DM1, T-DXd can produce good responses

Gastric and Gastroesophageal Junction Cancer

• The HER2 positivity rate is approximately 10-20%
• Trastuzumabmay be added to standard first-line treatment for advanced gastric cancer

Other Cancer Types

• Lung adenocarcinoma (particularly EGFR-negative cases)
• In endometrial, bladder, colon and biliary tract cancers, HER2 mutations or amplification may occur
• For these situations, off-label or clinical-trial-based targeted therapy options may be considered

HER2-Targeted Treatments

Targeted treatments developed for HER2-positive patients have fundamentally changed the course of the disease:

Looking Ahead: HER2-Low Positivity and New Treatment Approaches

Recent years have shown that, even in some tumors considered HER2-negative, patients with low HER2 expression (e.g., IHC 1+ or 2+/FISH-negative) also respond to ADCs such as T-DXd.

DESTINY-Breast04 and similar studies are opening new treatment opportunities for these patients. This means HER2 positivity must now be viewed not simply as present or absent, but as a spectrum .

Conclusion: Understanding HER2 Means Understanding Cancer

HER2 is more than a biomarker: it is a powerful molecular compass determining cancer biology and treatment response. Identifying different alterations, such as overexpression, amplification and mutation, can help provide patients with the most appropriate treatment paths.

The more we know about HER2, the further we can advance, particularly in early diagnosis and targeted treatment strategies.