The human epidermal growth factor receptor 2 (HER2) is a protein found on the surface of human cells, where it functions as a molecular antenna. This receptor is part of a larger family of proteins that regulate fundamental cellular processes, including growth, division, and repair. When the gene responsible for making this protein malfunctions, cells produce an abnormally high number of HER2 receptors. This condition, known as HER2 amplification, results in uncontrolled signaling that drives aggressive cell proliferation.
The Normal Role of the HER2 Protein
HER2 is a receptor tyrosine kinase protein that spans the cell membrane, with a portion outside the cell and a signaling portion inside. Its primary role is to receive signals from the environment and relay them inward to the cell’s nucleus, activating pathways that instruct the cell when to grow or differentiate. Unlike other family members, the HER2 receptor does not have a known direct binding partner (ligand) outside the cell.
Instead, HER2 acts as the preferred partner for “dimerization,” pairing up with other members of the epidermal growth factor receptor family, such as HER1, HER3, or HER4. When a ligand binds to one of these other receptors, HER2 joins the activated pair. This pairing triggers the internal signaling domain, initiating a cascade of messages that promote cell survival and growth.
Genetic Amplification and Protein Overexpression
The term HER2 amplification refers to a genetic abnormality where the cell acquires too many copies of the \(ERBB2\) gene that codes for the HER2 protein. A normal cell contains two copies of this gene, but in certain cancers, the cell’s DNA machinery duplicates the gene multiple times. This duplication can lead to the presence of 25 to 50 copies of the gene per cell.
The consequence of having excessive gene copies is HER2 protein overexpression, meaning the cell surface is saturated with a large number of HER2 receptors. This high concentration of receptors causes them to constantly pair up and activate the internal growth pathways, even without external signals. The continuous “on” signal drives uncontrolled cell division, which is characteristic of aggressive tumor growth.
Cancers exhibiting this high level of protein are classified as “HER2-positive.” This status is frequently seen in approximately 15% to 30% of breast cancers and 10% to 30% of gastric and gastroesophageal junction cancers. Identifying this specific overexpression determines the selection of targeted treatment, as these tumors tend to grow and spread more aggressively than their HER2-negative counterparts.
Clinical Testing for HER2 Status
Determining the HER2 status of a tumor is a necessary step that guides treatment decisions. This diagnosis relies on analyzing a tissue sample, typically obtained through a biopsy, using one of two primary laboratory methods: Immunohistochemistry (IHC) and In Situ Hybridization (ISH). IHC assesses the quantity of HER2 protein on the cell surface, while ISH directly measures the number of \(ERBB2\) gene copies inside the nucleus.
The IHC test uses specialized antibodies to bind to the HER2 protein, causing the cell membrane to stain a visible color. Pathologists assign a score from 0 to 3+ based on the intensity of the staining. A score of 0 or 1+ is considered HER2-negative, meaning the patient is unlikely to benefit from HER2-targeted drugs. A score of 3+ confirms HER2-positive status.
The intermediate score of 2+ is designated as “equivocal.” When an IHC result is equivocal, the sample must undergo reflex testing using Fluorescence In Situ Hybridization (FISH) or a similar ISH technique. FISH involves using fluorescent probes that attach to the \(ERBB2\) gene and a control gene. The final result is expressed as a ratio of HER2 gene signals to the control signals; a ratio of 2.0 or higher confirms gene amplification and a positive HER2 status.
Targeted Treatment Strategies
The goal of treating HER2-positive cancer is to specifically block the overactive signaling pathway caused by protein overexpression. HER2-targeted therapies are designed to interfere directly with the receptor’s function and are categorized into three distinct classes:
Monoclonal Antibodies (mAbs)
This class includes drugs like Trastuzumab and Pertuzumab, which are synthetic versions of immune system proteins. These large molecules physically attach to the external domain of the HER2 receptor, blocking it from receiving growth signals. Trastuzumab binds to one site, while Pertuzumab binds to a different site, preventing the necessary pairing (dimerization) of HER2 with other receptors. This binding also alerts the patient’s immune system to destroy the tagged cancer cells.
Antibody-Drug Conjugates (ADCs)
ADCs combine the precise targeting of an antibody with the cell-killing power of chemotherapy. For example, Trastuzumab emtansine (T-DM1) links the Trastuzumab antibody to a potent chemotherapy drug. The antibody binds to the HER2 receptor, and the complex is internalized. Once inside the cell, the chemotherapy payload is released, delivering a high, localized dose while sparing healthy cells.
Small Molecule Inhibitors (TKIs)
Also known as Tyrosine Kinase Inhibitors, these drugs include Lapatinib and Neratinib. These small molecules pass through the cell membrane to directly target the internal signaling portion of the receptor. By blocking the tyrosine kinase activity, these inhibitors prevent the chemical reactions necessary for the receptor to send growth instructions to the nucleus.