A diagnosis of cancer involves tests to understand a tumor’s characteristics, one of which is the Human Epidermal growth factor Receptor 2 (HER2) test. HER2 is a protein on the surface of cells involved in normal cell growth. In some cancers, the gene that makes this protein is amplified, leading to an excessive amount of the HER2 protein, which can cause cancer cells to grow and divide more rapidly.
To determine the amount of HER2 protein on cancer cells, pathologists use a method called Immunohistochemistry (IHC) on a tissue sample from the tumor. The IHC test uses antibodies that attach to HER2 proteins and a chemical dye that makes them visible under a microscope. The intensity of this dye helps pathologists quantify the level of HER2 protein.
The Purpose of HER2 IHC Testing
The primary reason for a HER2 IHC test is to guide treatment decisions. A tumor’s HER2 status allows oncologists to predict its behavior and select effective therapies. Cancers with high levels of HER2 tend to be more aggressive but are also responsive to specific treatments that target this protein.
This testing is standard for all invasive breast cancers at diagnosis and is also performed for stomach (gastric) and gastroesophageal junction cancers. If a cancer recurs or spreads, the new tumor may be re-tested, as HER2 status can change over time. The test is performed on a tissue sample already obtained, so no additional invasive procedure is required.
Understanding the IHC Scoring System
IHC test results are given as a score from 0 to 3+, reflecting the quantity of HER2 protein detected. A pathologist determines this score by observing the amount and intensity of a chemical dye that stains the tumor cells under a microscope. A brighter, more widespread stain indicates a higher concentration of HER2 proteins.
A score of 0 or 1+ is classified as HER2-negative. This result means few or no HER2 proteins are present on the cancer cells. Therefore, treatments designed to target HER2 would not be effective for these tumors. The majority of breast cancers fall into this HER2-negative category.
Conversely, a score of 3+ is considered HER2-positive. This indicates a significant overexpression of the HER2 protein, meaning the cells have a large number of these receptors. This positive result makes the cancer eligible for HER2-targeted therapies.
A score of 2+ is considered equivocal or borderline. This result means some HER2 protein was detected, but not enough to be definitively classified as positive. This inconclusive result requires additional testing to clarify the tumor’s HER2 status.
Next Steps for Equivocal Results
When an IHC test yields a 2+ score, a follow-up test is necessary to resolve the ambiguity. This next step is most often a Fluorescence In Situ Hybridization (FISH) test, which provides a more precise analysis by looking directly at the genetic level within the cancer cells.
Unlike the IHC test that counts proteins, the FISH test counts the number of HER2 gene copies inside each cell’s nucleus. It uses fluorescent probes that attach to the HER2 gene, which glow under a microscope, allowing pathologists to count them. Normal cells have two copies of the HER2 gene.
FISH test results are reported as either positive or negative. A positive result means there is an abnormally high number of HER2 gene copies, a condition called amplification, confirming the cancer is HER2-positive. A negative result indicates a normal number of HER2 genes, confirming the cancer is HER2-negative.
How Results Guide Treatment
A confirmed HER2-positive result (IHC 3+ or IHC 2+/FISH positive) makes a patient eligible for targeted therapies. These drugs, such as trastuzumab (Herceptin) and pertuzumab (Perjeta), are engineered to block the HER2 receptors on cancer cells. This action stops them from growing and dividing.
For tumors determined to be HER2-negative (IHC 0, 1+, or 2+/FISH negative), HER2-targeted drugs are not effective. Treatment is instead based on other tumor characteristics, like the presence of hormone receptors in breast cancer. These cancers may be treated with hormone-blocking therapies or chemotherapy.
A newer classification, “HER2-low,” has emerged and is changing the treatment landscape. This category includes tumors previously considered negative, specifically those with an IHC score of 1+ or 2+ that is FISH-negative. New antibody-drug conjugates, like trastuzumab deruxtecan (Enhertu), are effective against cancers with these low levels of HER2, providing a new targeted treatment option.