HER2 amplification is the presence of extra copies of the HER2 gene, which can influence the development and progression of certain cancers. This genetic alteration is a significant factor in oncology, guiding both prognosis and treatment strategies.
The Normal Function of the HER2 Gene
In a healthy body, the HER2 gene, also known as ERBB2, holds the instructions for creating a protein called human epidermal growth factor receptor 2. This protein is a receptor that sits on the outer surface of cells, acting as a communication hub. It is a member of the human epidermal growth factor receptor (HER) family, a group of four proteins that help control cell growth, division, and repair.
The HER2 protein functions as a receptor tyrosine kinase. These receptors wait for signals from outside the cell, and when they receive them, they activate processes inside the cell. Unlike other members of its family, HER2 does not directly bind to a signaling molecule, or ligand. Instead, it pairs up with other HER family members that have bound a ligand, forming a partnership called a heterodimer.
This pairing activates the HER2 protein, triggering a cascade of internal signals that are part of the normal regulation of a cell’s life cycle. These signaling networks tell the cell when it’s time to grow, divide to create new cells, or repair itself, ensuring tissues remain healthy and functional.
How Amplification Drives Cancer Growth
Gene amplification is a cellular process that results in multiple extra copies of a specific gene. When this process affects the HER2 gene, a cell can end up with far more than the standard two copies. This surplus of the HER2 gene leads to a corresponding overproduction of HER2 protein receptors on the cell’s surface, a condition known as overexpression. In some breast cancers, HER2 protein is overexpressed in as many as 25 to 30 percent of cases.
With an excessive number of HER2 receptors, the cell becomes overly sensitive to growth signals. This situation can be compared to an accelerator pedal that is permanently pushed down, constantly telling the cell to divide. The receptors can become so numerous that they begin to pair with each other, forming homodimers, which triggers continuous growth signaling even without external cues.
This relentless signaling overwhelms the cell’s normal regulatory mechanisms, leading to uncontrolled and rapid cell division, which is a hallmark of cancer. The process contributes not only to tumor formation but also to the creation of new blood vessels, a process called angiogenesis, which supplies the tumor with nutrients. HER2 amplification is most commonly associated with breast, gastric, and esophageal cancers.
Diagnostic Testing for HER2 Status
After a cancer diagnosis, determining the tumor’s HER2 status is a standard step. This process involves laboratory tests performed on a tissue sample, or biopsy, taken from the tumor, and the results help guide subsequent treatment decisions. The two primary methods used for this are Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH).
IHC is the first test performed and it measures the amount of HER2 protein on the surface of cancer cells. A pathologist applies a special chemical dye to the tissue sample that stains the HER2 proteins. The results are given as a score from 0 to 3+, where a score of 0 or 1+ is considered HER2-negative and a score of 3+ is considered HER2-positive.
A score of 2+ is deemed equivocal or borderline, meaning it is not definitively positive or negative. In these cases, a follow-up FISH test is required to clarify the HER2 status. The FISH test directly counts the number of HER2 gene copies within the cancer cells using fluorescent probes that bind to the gene. A positive FISH test confirms a HER2-positive status for an IHC 2+ tumor. A newer classification, “HER2-low,” has also emerged for tumors with an IHC score of 1+ or a score of 2+ with a negative FISH result, opening up new treatment avenues.
Targeted Therapies for HER2-Positive Cancers
A HER2-positive diagnosis provides a clear target for specialized treatments. These therapies are designed to specifically attack cancer cells that have an overabundance of HER2 receptors, often leading to better outcomes for patients.
One of the foundational targeted therapies is trastuzumab (Herceptin), a monoclonal antibody. This laboratory-made antibody is designed to recognize and attach to the extracellular domain of the HER2 receptor. By binding to the receptor, trastuzumab blocks it from receiving growth signals and can also alert the immune system to destroy the cancer cell. It is often used in combination with another monoclonal antibody, pertuzumab, which binds to a different part of the HER2 receptor, providing a more comprehensive blockade of signaling pathways.
A more recent advancement is the development of antibody-drug conjugates (ADCs). Drugs like trastuzumab deruxtecan (Enhertu) and ado-trastuzumab emtansine (Kadcyla) represent this class of therapy. These ADCs link a HER2-targeted antibody, like trastuzumab, to a potent chemotherapy drug. The antibody acts as a homing device, delivering the toxic payload directly to the HER2-positive cancer cells, which then internalize the drug. This approach maximizes damage to cancer cells while minimizing exposure to healthy cells, offering a treatment option for patients with HER2-positive and, more recently, HER2-low cancers.