Determining a cancer’s Human Epidermal growth factor Receptor 2 (HER2) status is a fundamental step in the diagnostic process for several cancer types, particularly breast cancer. This status dictates which treatment options will be most effective for a patient. Understanding specific findings, such as a “HER2 FISH Negative” result, is crucial. This result provides clarity regarding the biological nature of the tumor and directly informs the subsequent therapeutic strategy.
Understanding the HER2 Gene and Protein
HER2 is a protein found on the surface of all human cells, including those in the breast. The protein is encoded by the ERBB2 gene, and its normal role involves receiving and transmitting growth signals to the cell nucleus. This signaling helps regulate cell division, growth, and repair in a controlled manner.
In some cancers, the ERBB2 gene becomes amplified, meaning the cell acquires many extra copies of the gene. This genetic change causes the cell to produce an excessive number of HER2 proteins on its surface. The resulting overabundance of receptors leads to constant, uncontrolled signaling for the cell to grow and divide, which drives the tumor’s aggressive behavior.
The Purpose of FISH Testing
Initial testing for HER2 status often begins with an Immunohistochemistry (IHC) assay, which measures the amount of HER2 protein present on the cell surface. IHC results are reported on a scale from 0 to 3+. A score of 0 or 1+ is considered negative, and 3+ is considered positive.
A score of 2+ is considered equivocal, meaning the HER2 status cannot be definitively determined by IHC alone. In this scenario, a Fluorescence In Situ Hybridization (FISH) test is performed to provide a clear result. FISH is a molecular genetic test that uses fluorescent probes to physically bind to and illuminate the HER2 gene within the cell nucleus.
The pathologist microscopically counts the number of HER2 gene copies relative to a control gene, which provides a precise ratio. This technique directly measures gene amplification rather than protein levels, making it a highly specific method to confirm the tumor’s status. The FISH test is considered the gold standard for determining HER2 gene status when IHC results are unclear.
What a HER2 Negative Result Indicates
A “HER2 FISH Negative” result signifies that the cancer cells do not possess an excessive number of HER2 gene copies. This confirms that the tumor is not driven by HER2 gene amplification and subsequent protein overexpression. The diagnostic criterion for a negative result is typically a ratio of the HER2 gene copies to the control gene copies that is less than 1.8.
This finding classifies the tumor as HER2-negative, meaning the cancer is biologically distinct from HER2-positive tumors. HER2-negative cancers are less aggressive than their HER2-positive counterparts, which are characterized by rapid growth and a higher rate of recurrence. The negative result establishes that the tumor’s growth is fueled by other cellular pathways.
Some HER2-negative tumors may still express a low level of the protein, sometimes classified as “HER2-low,” which is defined as an IHC score of 1+ or an IHC score of 2+ with a negative FISH result. While this distinction is becoming increasingly relevant for emerging treatment strategies, the fundamental interpretation of a HER2 FISH Negative result remains that the cancer is not primarily driven by HER2 gene amplification.
Treatment Pathways Following a Negative Result
The most immediate clinical implication of a HER2 FISH Negative result is the exclusion of anti-HER2 targeted therapies. Medications designed to block the HER2 receptor, such as trastuzumab, will not be effective because the cancer is not dependent on this pathway for its growth. These treatments are avoided, sparing the patient from unnecessary side effects and cost.
Instead, the treatment plan focuses on other biological characteristics of the tumor, most importantly its hormone receptor (HR) status. If the tumor also tests positive for estrogen receptors (ER) or progesterone receptors (PR), it is considered hormone receptor-positive. This allows for the use of hormone therapy, which works by lowering hormone levels or blocking their action on the cancer cells.
If the tumor is hormone receptor-negative and HER2-negative, it is classified as triple-negative breast cancer, which is treated with chemotherapy. For HR-positive, HER2-negative cancers, targeted therapies, such as CDK4/6 inhibitors, may be utilized in combination with hormone therapy. The negative FISH result provides the necessary information to move forward with a treatment strategy tailored to the tumor’s driving biology.