HER2/neu is a protein found on the surface of human cells, including those in the breast. It belongs to the human epidermal growth factor receptor (HER) family and is involved in regulating cell growth, division, and repair. While normally present, certain cancer cells can produce HER2/neu in larger than normal amounts. This protein is encoded by the ERBB2 gene, also known as HER2.
Understanding HER2/neu and Its Role in Cancer
The HER2/neu protein functions as a receptor on the cell surface. When activated by growth factors, these receptors trigger signals that tell the cell to divide and proliferate. In healthy cells, this signaling is tightly controlled, ensuring proper cell growth and development.
In some cancers, abnormalities in the HER2 gene can lead to an increase in HER2/neu receptors on the cell surface. This is known as gene amplification, where extra copies of the HER2 gene result in overproduction of the HER2 protein, or protein overexpression. This overexpression causes cells to receive too many “grow and divide” messages, leading to uncontrolled cell division and tumor growth. HER2 overexpression is particularly relevant in cancers like breast and gastric cancers, where it can be associated with more aggressive tumor behavior and a higher risk of recurrence.
Testing for HER2/neu Status
Determining a patient’s HER2/neu status is a routine part of cancer diagnosis, especially for invasive carcinomas. This assessment guides treatment decisions, as HER2-positive cancers often respond to specific targeted therapies. Pathologists primarily utilize Immunohistochemistry (IHC) and in situ hybridization (ISH) techniques, such as Fluorescence In Situ Hybridization (FISH), to evaluate HER2 status.
Immunohistochemistry (IHC) is a staining technique that assesses the level of HER2 protein overexpression on the surface of cancer cells. Results are evaluated on a semi-quantitative scale, typically ranging from 0 to 3+. A score of 0 or 1+ indicates the tumor is HER2-negative. A score of 3+ signifies strong and complete membrane staining, classifying the tumor as HER2-positive.
For cases with an ambiguous IHC score of 2+, further testing with an ISH method like FISH is recommended. FISH directly measures the number of HER2 gene copies within the cell nucleus. The ratio of HER2 gene signals to a reference signal helps determine if the gene is amplified. A FISH score greater than 2 indicates HER2 gene amplification, classifying the tumor as HER2-positive. Both IHC and ISH methods are considered complementary, providing different insights into the HER2 status of a tumor.
Targeted Treatments for HER2-Positive Cancers
The identification of HER2 as a therapeutic target revolutionized the treatment of HER2-positive cancers. Targeted therapies are designed to specifically interfere with the HER2 protein’s signaling pathways, either by blocking its signals or by delivering cytotoxic agents directly to the cancer cells that overexpress HER2. These treatments aim to stop uncontrolled cell division and can also prompt the immune system to destroy cancer cells.
Monoclonal Antibodies
Monoclonal antibodies are a class of targeted drugs that bind to the extracellular domain of the HER2 protein. Trastuzumab (Herceptin) was the first such antibody approved, binding to HER2 to suppress intracellular signaling and inhibit cell cycle progression. This action also mediates antibody-dependent cell-mediated cytotoxicity (ADCC), where immune cells recognize and attack the cancer cells. Pertuzumab (Perjeta) is another monoclonal antibody that binds to HER2, blocking its ability to form pairs with other HER family members, particularly HER3. This dual blockade with trastuzumab and pertuzumab is often used in combination with chemotherapy for HER2-positive metastatic breast cancer and has significantly improved patient outcomes.
Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates (ADCs) represent another advancement, combining the targeting ability of monoclonal antibodies with potent cytotoxic chemotherapy agents. Ado-trastuzumab emtansine (T-DM1, Kadcyla) consists of trastuzumab linked to a microtubule-inhibiting agent. The trastuzumab component directs the drug specifically to HER2-positive cancer cells, and once internalized, the agent is released to disrupt cell division and induce cell death. Another ADC, trastuzumab deruxtecan (Enhertu), links trastuzumab to a different cytotoxic agent, a topoisomerase I inhibitor, via a cleavable linker, allowing for a “bystander effect” where the drug can also kill nearby HER2-negative tumor cells.
Tyrosine Kinase Inhibitors (TKIs)
Tyrosine kinase inhibitors (TKIs) are small-molecule drugs that block the activity of the intracellular portion of the HER2 receptor. Lapatinib (Tykerb) inhibits both HER1 and HER2. Neratinib (Nerlynx) broadly inhibits HER1, HER2, and HER4. These oral medications work by blocking the signaling pathways that promote cell proliferation and survival, thereby slowing tumor growth. TKIs are often used in patients whose disease has progressed on other HER2-targeted therapies or as extended adjuvant treatment.