HER2 (Human Epidermal Growth Factor Receptor 2) is a protein found on the surface of various cells in the body. It plays a role in regulating normal cell functions, including growth, division, and repair processes. Think of HER2 as a tiny antenna on a cell, receiving signals that tell the cell when to grow and multiply.
This protein is encoded by the HER2 gene, also known as ERBB2. HER2’s presence and activity make it a measurable indicator of a cell’s biological state, known as a “biomarker.” In healthy cells, the amount of HER2 protein is carefully controlled to ensure balanced cell behavior.
The Role of HER2 in Cancer
When the HER2 gene undergoes a change, such as amplification, it leads to an excessive number of HER2 protein copies on the surface of cells. This overexpression means the cell receives too many signals for growth and division, leading to uncontrolled proliferation and tumor development.
This overexpression of HER2 is linked to more aggressive forms of cancer and a higher likelihood of the disease spreading. While HER2 alterations can be found in various cancer types, including bladder, colon, and lung cancers, its role is particularly significant in breast cancer, where about 15-20% of primary tumors show overexpression. HER2 overexpression also occurs in approximately 10-30% of gastric and gastroesophageal junction cancers, influencing their behavior. Identifying HER2 status is an important step in guiding treatment decisions.
Diagnosing HER2 Status
HER2 status in tumor tissue is determined using specific diagnostic techniques. The most common method is Immunohistochemistry (IHC), which measures the amount of HER2 protein present on the cell surface. Pathologists examine stained tissue samples under a microscope and assign a score based on the intensity and completeness of membrane staining in tumor cells.
The IHC scoring system ranges from 0 to 3+. A score of 0 or 1+ indicates HER2-negative status, meaning there is no or very low HER2 protein overexpression. A score of 3+ signifies HER2-positive status, indicating strong overexpression of the protein. For ambiguous results, such as an IHC score of 2+, further testing is required to confirm HER2 status.
Fluorescence In Situ Hybridization (FISH) is used to resolve these equivocal IHC 2+ results. FISH directly detects amplification of the HER2 gene within the tumor cells by using fluorescent probes that bind to the gene. A HER2-positive result by FISH indicates that the HER2 gene is amplified, leading to increased protein production. Accurate HER2 testing is important because it dictates whether a patient is eligible for HER2-targeted therapies.
HER2-Targeted Treatments
HER2-targeted therapies interfere with the HER2 pathway, inhibiting the growth and survival of cancer cells that overexpress HER2. These treatments have improved outcomes for patients with HER2-positive cancers.
Monoclonal antibodies are a class of HER2-targeted drugs that bind to the HER2 receptors on the surface of cancer cells. Trastuzumab, for example, binds to the extracellular portion of HER2, which can lead to HER2 protein downregulation and inhibit the formation of HER2-containing protein complexes. Another monoclonal antibody, pertuzumab, binds to a different site on HER2, preventing it from partnering with other HER receptors, particularly HER3, important for activating growth signals.
Antibody-drug conjugates (ADCs) represent another type of targeted therapy, combining a monoclonal antibody with a chemotherapy agent. These drugs, such as trastuzumab emtansine and trastuzumab deruxtecan, act like guided missiles, delivering chemotherapy directly to HER2-expressing cancer cells. The antibody portion binds to HER2 on the tumor cell surface, and then the entire complex is internalized, releasing the chemotherapy payload inside the cancer cell to cause cell death.
Tyrosine kinase inhibitors (TKIs) are small molecules that work by blocking signaling pathways inside the cell. Lapatinib, neratinib, and tucatinib are examples of TKIs that inhibit the activity of the HER2 tyrosine kinase, an enzyme involved in cell growth signaling. These inhibitors bind to the ATP-binding site of the kinase, disrupting the signals that promote cancer cell proliferation and survival. HER2-targeted treatments are used in combination with traditional chemotherapy or other targeted agents to enhance their effectiveness against cancer.