HER2, or Human Epidermal Growth Factor Receptor 2, is a protein found on the surface of various cells throughout the body. It plays a role in regulating cell growth, division, and repair, acting as a receiver for signals that instruct cells to perform these functions. This protein is encoded by the ERBB2 gene, which provides the blueprint for its production. While HER2 is naturally present in all healthy cells, it exists at normal, controlled levels to maintain proper cellular processes.
What is HER2?
HER2 is one of four members of the human epidermal growth factor receptor (HER/EGFR/ERBB) family, alongside HER1, HER3, and HER4. These receptors are transmembrane tyrosine kinases, meaning they span the cell membrane and have an intracellular part that can activate signaling pathways. Unlike other family members, HER2 does not directly bind to a specific activating ligand. Instead, it becomes activated by forming pairs, or dimers, with other HER family members, such as HER1 or HER3, or by pairing with another HER2 protein when its concentration is high. This dimerization leads to the activation of intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways, which are involved in cell proliferation, survival, and differentiation.
HER2 in Cancer Development
When the ERBB2 gene is amplified, meaning there are too many copies of the gene, it leads to an excessive production of HER2 protein on the surface of cancer cells. This abundance of HER2 receptors causes uncontrolled signaling within the cell, constantly triggering the cancer cells to divide and grow at an accelerated rate.
This uncontrolled cell division and growth can lead to more aggressive tumor behavior and a higher likelihood of the cancer spreading. A mutation in the HER2 gene, rather than amplification, can also lead to increased signaling and tumor growth. The presence of excessive HER2 makes cancer cells particularly responsive to therapies that specifically target this protein.
Testing for HER2 Expression
Determining HER2 status is an important step in cancer diagnosis, particularly for certain types like breast and gastric cancers. The two primary methods used to assess HER2 expression are Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH).
Immunohistochemistry (IHC) is the initial test, which evaluates the amount of HER2 protein on the surface of cancer cells using special stains. IHC results are reported on a scale of 0 to 3+. A score of 0 or 1+ indicates HER2-negative, meaning there is little to no HER2 protein, and these cancers do not respond to HER2-targeted drugs. A score of 3+ signifies HER2-positive, indicating a high level of HER2 protein, and these cancers are candidates for HER2-targeted therapies. An IHC score of 2+ is considered equivocal or uncertain, and requires further testing with a more quantitative method like FISH.
Fluorescence In Situ Hybridization (FISH) is used to confirm equivocal IHC 2+ results or as a primary test, as it directly measures the number of copies of the HER2 gene within the cell nucleus. FISH results are reported as positive or negative based on the ratio of HER2 gene copies to copies of chromosome 17, where the HER2 gene is located. A HER2/CEP17 ratio less than 2.0 is considered not amplified (negative), while a ratio greater than or equal to 2.0 is considered amplified (positive).
Targeted Therapies for HER2-Positive Cancers
Targeted therapies for HER2-positive cancers are designed to specifically interfere with the HER2 protein’s function, thereby inhibiting cancer cell growth. These therapies work by blocking the signals that promote cell division or by delivering cytotoxic agents directly to cancer cells. The development of these treatments has improved outcomes for patients with HER2-positive diseases.
Monoclonal antibodies, such as trastuzumab and pertuzumab, are a class of targeted therapies that bind to specific regions of the HER2 protein on the cell surface. Trastuzumab, for example, binds to the extracellular domain of HER2, preventing it from activating growth signals and also marking the cancer cell for destruction by the immune system. Pertuzumab works by inhibiting the dimerization of HER2 with other HER family members, particularly HER3, which is a common mechanism of HER2 activation. These antibodies can be used alone or in combination with chemotherapy to enhance their anti-tumor effects.
Antibody-drug conjugates (ADCs) combine the precise targeting ability of a monoclonal antibody with a potent chemotherapy drug. For instance, ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) link a HER2-targeting antibody to a chemotherapy agent. The antibody component guides the drug directly to HER2-overexpressing cancer cells, where the chemotherapy is released, minimizing damage to healthy cells and increasing the concentration of the therapeutic agent at the tumor site.
Tyrosine kinase inhibitors (TKIs), such as lapatinib, neratinib, and tucatinib, are small molecules that work by entering the cell and blocking the activity of the HER2 protein’s intracellular tyrosine kinase domain. This action prevents the phosphorylation events that initiate downstream signaling pathways responsible for cell growth. These oral medications offer an alternative or complementary approach to antibody-based therapies, particularly in cases where the cancer has spread to the brain, as some TKIs can cross the blood-brain barrier.
Understanding HER2 Status and Prognosis
A patient’s HER2 status influences their cancer prognosis and informs the personalized treatment strategy. Historically, HER2-positive cancers were considered more aggressive and associated with a poorer outlook. However, the introduction of targeted therapies has changed this landscape.
Knowing the HER2 status allows clinicians to select specific treatments that directly counteract the mechanisms driving HER2-positive cancer growth. This targeted approach has led to improved survival rates and better disease control for many patients. The ability to personalize treatment based on HER2 status has improved the management of these cancers, offering a more precise and effective approach.