Human Epidermal growth factor Receptor 2, or HER2, is a protein located on the surface of cells. It is the product of the ERBB2 gene, which gives instructions for making this protein. The HER2 protein plays a part in signaling pathways that regulate cell growth, division, and repair, ensuring tissues develop and maintain themselves properly. The study of HER2 has become a focus in medicine, particularly in oncology, because of its altered function in the development of certain cancers, which has led to specialized treatments.
The Function of HER2 in Cancer
In some cancers, the cellular mechanics that control the ERBB2 gene go awry. This leads to gene amplification, where an excessive number of copies of the ERBB2 gene are produced within the cancer cell. This abundance of gene copies results in the overproduction, or overexpression, of the HER2 protein on the cell’s surface. It is estimated that 15-30% of breast cancers and 10-30% of gastric cancers exhibit this characteristic.
With a vastly increased number of HER2 receptors, the cell surface becomes hyper-responsive to growth signals. This situation can be compared to an accelerator pedal being stuck to the floor, sending a constant and powerful message for the cell to grow and divide without restraint. While most prominently associated with breast cancer, HER2 overexpression is also a feature in some cancers of the stomach, esophagus, ovaries, and bladder.
Testing for HER2 Status
Following a cancer diagnosis where HER2 is a potential factor, determining the tumor’s HER2 status is a standard procedure that provides information to guide treatment decisions. The two principal methods used to assess HER2 status are Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH), both of which analyze a sample of the tumor tissue obtained during a biopsy.
The IHC test measures the amount of HER2 protein on the surface of cancer cells. In this laboratory technique, a tissue sample is treated with antibodies that bind to the HER2 protein, and a chemical dye attached to them reveals the protein’s quantity. The results are reported on a scale from 0 to 3+. A score of 0 or 1+ is considered HER2-negative, while a score of 3+ indicates a HER2-positive result.
A score of 2+ on an IHC test is deemed “equivocal,” meaning the result is not definitive. In these instances, a FISH test is required to clarify the HER2 status. The FISH test directly examines the genetic material within the cancer cells, using fluorescent probes that attach to the ERBB2 gene. By counting the number of gene copies, the FISH test can determine if gene amplification has occurred, providing a clear positive or negative result.
Targeted Therapies for HER2-Positive Cancer
The discovery of HER2’s role in driving cancer growth led to the development of targeted therapies, which are drugs designed to specifically attack cancer cells with minimal damage to normal cells. These treatments interfere with the HER2 protein’s function, a departure from traditional chemotherapy, which affects all rapidly dividing cells.
A primary class of these drugs is monoclonal antibodies. Trastuzumab (Herceptin) and pertuzumab (Perjeta) are two prominent examples. These lab-created antibodies are engineered to recognize and attach to the HER2 protein on the exterior of the cancer cell. By binding to the protein, trastuzumab can block the receptor from receiving growth signals and can also alert the body’s immune system to find and destroy the marked cancer cell. Pertuzumab works in a complementary way, binding to a different part of the HER2 protein to provide a more comprehensive blockade of signaling pathways.
Another advanced approach is the use of antibody-drug conjugates (ADCs). Ado-trastuzumab emtansine (Kadcyla) is an ADC that links the HER2-seeking monoclonal antibody trastuzumab to a powerful chemotherapy drug. Once attached to the cell, the ADC is internalized, and the chemotherapy agent is released inside, killing the cancer cell from within.
Prognosis and Disease Management
Historically, a diagnosis of HER2-positive cancer was associated with a more aggressive disease and a challenging prognosis, as these tumors tended to grow faster and had a higher likelihood of recurrence. However, the landscape of treatment and patient outcomes has been altered by therapies that specifically target the HER2 protein.
The introduction of drugs like trastuzumab has improved survival rates and the quality of life for patients, transforming what was once a difficult diagnosis into a manageable condition.
More recently, cancer research has identified a new classification known as “HER2-low.” This category describes tumors that have some HER2 proteins on their surface but not enough to be classified as HER2-positive by traditional testing standards (IHC 1+ or IHC 2+/FISH-negative). For years, these patients were treated as HER2-negative, but new antibody-drug conjugates are now being developed and approved for this HER2-low population, expanding personalized treatment options.