Human epidermal growth factor receptor 2, more commonly known as HER2, is a protein that plays a part in cell growth. It is created by instructions from a gene called ERBB2. In some cancers, this gene and its corresponding protein are altered, making HER2 an important biomarker—a substance that can be measured to provide information about a disease. While famously associated with breast cancer, altered HER2 status is also found in a portion of stomach and esophageal cancers, making its identification a key step in determining a patient’s treatment path.
The Role of HER2/neu in Cell Growth
On the surface of normal cells, the HER2 protein functions as a receptor, waiting for signals that instruct the cell when to grow, divide, and repair itself. These receptors are part of a regulated system ensuring cells multiply only when necessary. In healthy tissue, there are two copies of the ERBB2 gene, which produce a controlled number of HER2 receptors to maintain this balance.
In certain cancers, this regulatory process is disrupted. The disruption begins with the ERBB2 gene, which undergoes gene amplification, meaning the cell makes numerous extra copies. Breast cancer cells, for instance, can have up to 50 copies of the ERBB2 gene. This amplification leads to the overexpression of the HER2 protein, with as many as 2 million receptors crowding the cell surface and bombarding it with constant growth signals.
This state of overexpression is often compared to a car’s gas pedal being stuck to the floor. The cancer cells receive continuous instructions to divide and multiply, which drives the formation and growth of tumors. The result is a cancer that tends to be more aggressive and grow faster than cancers without this alteration.
Testing for HER2 Status
Determining a tumor’s HER2 status is a standard part of the diagnostic process and is performed on a tissue sample obtained from a biopsy or surgery. Two primary testing methods are used to evaluate the amount of HER2 gene activity, and the results guide decisions about the most effective course of treatment.
The most common initial test is Immunohistochemistry (IHC). This method measures the amount of HER2 protein present on the surface of cancer cells. A pathologist assigns a score on a scale from 0 to 3+. A score of 0 or 1+ is classified as HER2-negative, while a score of 3+ is considered HER2-positive, signifying a clear overexpression of the protein.
When IHC results are ambiguous, a second test is often employed. This test, called Fluorescence In Situ Hybridization (FISH), directly counts the number of ERBB2 gene copies within the cancer cells. FISH is particularly useful for clarifying an IHC score of 2+, which is considered borderline. A positive FISH test confirms the presence of gene amplification.
A newer classification has emerged from this testing: “HER2-low.” This category is defined as a tumor with an IHC score of 1+, or a score of 2+ combined with a negative FISH test. For many years, these tumors were grouped with HER2-negative cancers, limiting treatment options. Recognizing HER2-low status is now a distinct classification that opens the door to a different set of therapies.
Targeted Therapies for HER2-Positive Cancer
The discovery of the HER2 pathway’s role in cancer growth led to the development of targeted therapies. These drugs are engineered to specifically attack cancer cells that overexpress HER2. This distinguishes them from traditional chemotherapy that affects all rapidly dividing cells, both cancerous and healthy.
One class of drugs is monoclonal antibodies. Medications like trastuzumab (Herceptin) and pertuzumab (Perjeta) are designed to attach to the part of the HER2 receptor on the outside of the cell. By binding to this external domain, they act like a shield, blocking the receptor from receiving signals that tell the cell to grow and divide.
A more recent innovation is the antibody-drug conjugate (ADC), often described as a “smart bomb.” These drugs, such as ado-trastuzumab emtansine (Kadcyla) and fam-trastuzumab deruxtecan (Enhertu), use a monoclonal antibody as a homing device to locate and bind to HER2-positive cancer cells. Once attached, the ADC releases a potent dose of chemotherapy directly into the cancer cell, minimizing damage to surrounding healthy tissues.
A third category of treatment is kinase inhibitors. These small-molecule drugs, including lapatinib (Tykerb) and neratinib (Nerlynx), pass through the cell membrane and work inside the cell. They function by blocking the internal part of the HER2 receptor, known as the tyrosine kinase domain. This action stops growth signals from being sent throughout the cell’s interior, providing another way to halt cancer cell proliferation.
Prognosis and Evolving Classifications
The outlook for individuals diagnosed with HER2-positive cancer has been transformed over the past few decades. Before the advent of targeted treatments, a HER2-positive diagnosis was associated with a poor prognosis. The aggressive nature of these cancers meant they were more likely to recur, presenting challenges for effective treatment and long-term survival.
With therapies like trastuzumab and other targeted agents, the prognosis for HER2-positive breast cancer has improved significantly. For many patients, the outlook is now more favorable than for some types of HER2-negative cancer. Early diagnosis combined with HER2-targeted therapy can lead to high survival rates.
This evolution in treatment has also led to a refined understanding of HER2 status. The “HER2-low” classification now identifies a large group of patients who were previously considered HER2-negative and thus ineligible for HER2-targeted drugs. It has been discovered that certain advanced treatments, particularly antibody-drug conjugates like fam-trastuzumab deruxtecan (Enhertu), are effective in this HER2-low population. This has expanded treatment possibilities for many individuals.