HER2, or Human Epidermal Growth Factor Receptor 2, is a protein found on the surface of all cells, playing a role in regulating their growth, division, and repair. In the context of cancer, particularly breast and gastric cancers, understanding HER2 status is a significant diagnostic step. This process, known as HER2 scoring, helps guide specific treatment decisions, providing insights into which therapies are most likely to be effective.
What is HER2 and Its Role in Cancer
HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family, which helps control cell proliferation and differentiation. It acts like a receiver on the cell’s surface, picking up signals that tell the cell to grow and divide.
In some cancers, there can be too many copies of the HER2 gene or an overabundance of the HER2 protein on the surface of cancer cells. This overexpression can lead to uncontrolled cell growth and division, often resulting in more aggressive disease. Identifying this overexpression is an important step for oncologists because it indicates that the cancer may respond to specific targeted therapies.
How HER2 Status is Determined
Determining HER2 status involves testing tissue samples obtained from a biopsy or surgery. Two primary methods are used: Immunohistochemistry (IHC) and In Situ Hybridization (ISH), with Fluorescence In Situ Hybridization (FISH) being a common type of ISH.
Immunohistochemistry (IHC) is the initial test, measuring the amount of HER2 protein on the surface of cancer cells. Pathologists use special stains to visualize and quantify the protein expression, assigning a score from 0 to 3+. This method is faster and less expensive than other tests.
When IHC results are ambiguous, specifically a score of 2+, further testing with In Situ Hybridization (ISH) is performed. FISH is a type of ISH that looks for extra copies of the HER2 gene inside the cancer cells, using fluorescent dyes that bind to the gene. This genetic test helps confirm or reclassify cases not clearly positive or negative by IHC.
Interpreting HER2 Scores
The IHC scoring system provides a semi-quantitative assessment of HER2 protein expression, with results categorized as 0, 1+, 2+, or 3+. Scores of 0 and 1+ are generally considered HER2-negative, meaning there is little to no HER2 protein on the cell surface, and these cancers are unlikely to benefit from HER2-targeted treatments.
A score of 3+ indicates HER2-positive status, characterized by strong, complete membrane staining in a significant percentage of tumor cells, over 10%. These cancers are candidates for HER2-targeted therapies.
An IHC score of 2+ is classified as “equivocal” or “borderline,” meaning the HER2 status is uncertain and requires further investigation. In such cases, an ISH test, often FISH, is performed to determine if there is an amplification of the HER2 gene. The FISH test then classifies the tumor as either HER2-positive (if gene amplification is detected) or HER2-negative (if no gene amplification is found). A HER2/CEP17 ratio of 2.0 or greater indicates HER2 gene amplification, while a ratio below 2.0 suggests no amplification.
A newer classification, “HER2-low,” is emerging, encompassing cancers with an IHC score of 1+ or an IHC score of 2+ with a negative FISH result. This category represents tumors with low but detectable levels of HER2 protein. While previously grouped with HER2-negative cancers, this distinction is important for treatment selection.
Treatment Approaches Based on HER2 Status
Treatment strategies for cancer are influenced by the HER2 status, as different classifications respond to varying therapeutic approaches. Personalized treatment plans consider HER2 status and other factors like hormone receptor status and cancer stage.
For HER2-positive cancers, targeted therapies are employed. These therapies, such as trastuzumab, pertuzumab, ado-trastuzumab emtansine (T-DM1), and fam-trastuzumab deruxtecan-nxki, block the HER2 protein or deliver chemotherapy directly to the cancer cells. These targeted agents are often administered in combination with traditional chemotherapy to maximize their effectiveness.
HER2-negative cancers do not respond to HER2-targeted therapies. Treatment for these cancers involves chemotherapy, hormone therapy if the cancer is hormone receptor-positive, or immunotherapy, depending on the tumor’s characteristics. For instance, hormone receptor-positive/HER2-negative cancers may be treated with drugs that lower hormone levels or block hormone receptors.
The HER2-low category represents an advancement in treatment options for patients previously considered HER2-negative. These cancers may now benefit from antibody-drug conjugates like trastuzumab deruxtecan (Enhertu). This innovative therapy delivers chemotherapy directly to cells with even low levels of HER2 protein, offering a new avenue for patients who previously had limited targeted treatment options.