Human Epidermal Growth Factor Receptor 2 (HER2) is a protein on the surface of cells that helps regulate how they grow, divide, and repair themselves. Some cancers are HER2-positive, meaning they have an overabundance of the HER2 protein or the gene that creates it. This overproduction can cause cancer cells to multiply and spread more aggressively. Identifying a cancer as HER2-positive provides a specific target for therapies designed to interact directly with this protein.
Understanding HER2-Positive Status in Cancer
The HER2 protein, when functioning normally on the surface of healthy cells, is part of a communication system that regulates cellular processes. These proteins act as receptors, receiving signals that instruct the cell when to grow and divide. This regulated system breaks down when cancer cells become HER2-positive, a condition that arises from a mutation in the HER2 gene. This mutation leads to the gene making too many copies of itself, a process called gene amplification, which results in an overproduction of HER2 protein receptors.
This abundance of receptors leads to excessive signaling, creating a constant “on” switch that drives the uncontrolled growth and rapid division characteristic of aggressive cancers. The HER2-positive characteristic is most commonly associated with breast cancer, where it is identified in about 15-20% of invasive cases. It is also observed in some gastric (stomach) and gastroesophageal junction cancers, where knowing the HER2 status is important for determining treatment.
Determining a cancer’s HER2 status is a standard procedure performed on a tumor tissue sample. Two primary laboratory tests are used: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The IHC test measures the amount of HER2 protein on the cancer cells, with results scored on a scale from 0 to 3+. A score of 3+ is HER2-positive, while 0 or 1+ is HER2-negative.
A score of 2+ is considered borderline, which is where the FISH test becomes useful. The FISH test provides a more definitive result by counting the actual number of HER2 gene copies within the cancer cells. This accurate testing directly informs whether medications that specifically target the HER2 protein will be effective.
Key Classes of HER2-Targeted Medications
The discovery of the HER2 protein’s role in driving cancer growth led to the development of targeted therapies. These medications are engineered to specifically recognize and interfere with the HER2 protein. This approach differs from traditional chemotherapy, which affects all rapidly dividing cells. HER2-targeted therapies offer a more precise method of treatment, focusing their action on the cancer cells that exhibit HER2 overexpression.
One of the foundational classes of these drugs is monoclonal antibodies. These are laboratory-produced proteins designed to mimic natural antibodies that identify and attach to the HER2 protein. Prominent examples in this category include Trastuzumab and Pertuzumab. They are often administered intravenously and can be used alone or in combination with chemotherapy.
Another class of medication is the antibody-drug conjugate (ADC), which combines a monoclonal antibody with a chemotherapy drug. An ADC consists of a HER2-targeting antibody linked to a cytotoxic agent. Examples of ADCs include Ado-trastuzumab emtansine (T-DM1) and Fam-trastuzumab deruxtecan (T-DXd).
A third category is tyrosine kinase inhibitors (TKIs). Unlike antibodies, TKIs are small-molecule drugs that can pass through the cell membrane and function internally. Examples include Lapatinib, Neratinib, and Tucatinib. These oral medications are often used in cases where the cancer has spread or as an additional therapy after other treatments have been completed.
How HER2 Medications Work Against Cancer Cells
Monoclonal antibodies, such as Trastuzumab and Pertuzumab, function on the exterior of the cancer cell. They bind directly to the HER2 receptor on the cell surface. This binding physically obstructs the receptor, preventing it from sending growth signals into the cell. This action can also trigger the body’s immune system to attack the cancer by marking the cell for destruction, a process known as antibody-dependent cell-mediated cytotoxicity (ADCC).
Antibody-drug conjugates leverage the HER2 receptor as a gateway to deliver a lethal payload. The antibody portion of the ADC binds to the HER2 protein on the tumor cell’s surface. This prompts the cell to internalize the entire ADC molecule. Once inside, the ADC releases its chemotherapy drug directly within the cancer cell, leading to cell death with minimal impact on surrounding healthy tissue.
Tyrosine kinase inhibitors take an inside-out approach. As small molecules, drugs like Lapatinib and Tucatinib diffuse across the cancer cell’s membrane. Their target is the intracellular portion of the HER2 receptor, specifically the tyrosine kinase domain. By binding to this internal domain, TKIs block a process called phosphorylation, shutting down the entire chain of communication that would otherwise tell the cell to proliferate.
Managing Treatment and Common Side Effects
While HER2-targeted therapies are effective, they are associated with a range of potential side effects that vary depending on the specific medication and patient responses. Common side effects across the different classes of drugs often include fatigue, diarrhea, nausea, and skin rashes. These effects are manageable with supportive care and close communication with the healthcare team.
A concern with some HER2-targeted therapies, particularly monoclonal antibodies and ADCs, is the potential for cardiotoxicity, or damage to the heart muscle. The HER2 protein, while overexpressed in cancer cells, is also present on heart cells where it plays a role in normal cardiac function. Blocking this protein can sometimes lead to a weakening of the heart muscle, reducing its ability to pump blood effectively.
Other specific side effects are linked to particular agents. For instance, some ADCs can be associated with liver problems or lung conditions like interstitial lung disease. Tyrosine kinase inhibitors are frequently associated with severe diarrhea, which requires proactive management to prevent dehydration and other complications. These distinct side-effect profiles necessitate careful selection of therapy based on a patient’s overall health.
Given these potential effects, regular monitoring is a standard part of the treatment protocol. For patients on drugs with known cardiac risks, such as Trastuzumab, healthcare teams will perform routine heart function tests. These tests, which may include an echocardiogram or a MUGA scan, are conducted before treatment begins and at regular intervals to detect any changes in heart function early.
Successfully navigating treatment involves a partnership between the patient and their medical team. Openly discussing any new or worsening side effects allows for prompt intervention, such as adjusting medication dosages or prescribing supportive medications. Patient support systems, including family, friends, and advocacy groups, can also provide emotional and practical assistance.