HER2 testing is a laboratory procedure used to determine if cancer cells produce an unusually high amount of a protein called Human Epidermal growth factor Receptor 2 (HER2). This diagnostic tool is applied primarily to tissue samples from breast and gastric cancers. The test identifies the tumor’s HER2 status, which influences how aggressive the cancer is and guides the selection of the most effective treatment plan. Determining HER2 status is a routine and necessary step in cancer diagnosis and care.
The Biological Function of the HER2 Protein
The HER2 protein is a type of receptor located on the surface of many cells in the body, including those in the breast and stomach. Its normal function is to receive external signals that regulate cellular processes such as growth, division, and repair. HER2 is part of a larger family of receptors and works by pairing with other family members to activate signaling pathways inside the cell.
In certain cancers, the gene that codes for HER2 becomes amplified, meaning the cell has extra copies of the gene. This gene amplification leads to the creation of too many HER2 protein receptors on the cell surface, a condition known as overexpression. The excessive number of receptors causes uncontrolled and accelerated growth and division of the cancer cells, which is associated with more aggressive tumor behavior.
Clinical Reasons for HER2 Testing
Physicians order HER2 testing for patients diagnosed with invasive breast cancer, as well as certain stomach and esophageal cancers. The presence of HER2 overexpression is a predictive biomarker, determining if a patient is eligible for targeted therapies.
These specialized drugs are designed to specifically block or inhibit the HER2 protein, improving patient outcomes. Every invasive breast cancer must be tested for HER2 status because the results are essential for determining the entire course of treatment.
Laboratory Methods Used to Determine HER2 Status
Two main laboratory methods are used to assess the HER2 status of a tumor sample obtained during a biopsy or surgery. The first test is typically Immunohistochemistry (IHC), which measures the amount of HER2 protein present on the surface of the cancer cells. This method uses special antibodies that bind to the HER2 protein, causing the cells to stain and change color. A pathologist then visually estimates the level of protein overexpression.
IHC results are reported on a semi-quantitative scale from 0 to 3+. A score of 0 or 1+ indicates little to no protein and is considered HER2-negative. A score of 3+ indicates a strong, complete staining pattern and is classified as HER2-positive. An IHC score of 2+ is considered equivocal or borderline, meaning the result is unclear.
When the IHC result is equivocal (2+), a second, more precise test called Fluorescence In Situ Hybridization (FISH) is performed as a reflex test. FISH counts the number of HER2 genes within the cell nucleus using fluorescent probes that attach to the gene. This test determines if the HER2 gene is amplified, which is the underlying cause of protein overexpression.
While IHC is faster and less expensive, FISH is considered more accurate and provides a quantitative measure to resolve the equivocal IHC result. A FISH result is either positive, confirming gene amplification, or negative, indicating a normal number of HER2 gene copies.
Interpreting HER2 Test Results and Treatment Implications
The final HER2 status is classified into three main categories, each with distinct treatment implications. A tumor is considered HER2-positive if it scores IHC 3+ or if it has an equivocal IHC 2+ score but a positive FISH test. This status indicates that the patient is eligible for HER2-targeted therapies, such as Trastuzumab, which directly block the overactive HER2 receptor and improve outcomes for this cancer subtype.
A tumor is classified as HER2-negative if it scores IHC 0 or 1+, or if it is IHC 2+ but has a negative FISH result. These tumors lack sufficient HER2 protein to respond to targeted therapies. Treatment typically involves standard chemotherapy, hormone therapy, or a combination of both, and this classification applies to the majority of breast cancers.
A newly recognized category is HER2-low, which includes tumors scoring IHC 1+ or those that are IHC 2+ but FISH-negative. Historically, these were treated as HER2-negative. However, this low level of protein expression has now been shown to be targetable by newer types of drugs called antibody-drug conjugates. This emerging classification offers a new treatment option for patients previously excluded from HER2-targeted treatment.