When breast cancer is diagnosed, determining the tumor’s specific biological makeup is necessary before planning treatment. Tumors are classified not just by size or spread, but by the presence of certain proteins on the cell surface. This molecular profiling allows oncologists to classify cancer into subtypes that respond differently to various medications. Testing for the Human Epidermal Growth Factor Receptor 2 (HER2) is highly informative, as the result dictates whether a patient will benefit from specific targeted therapies.
Understanding the HER2 Protein and Testing Scale
The HER2 protein is a receptor found on the surface of many cells, regulating growth, division, and repair. In healthy breast cells, these receptors are present at low levels. However, in about 15 to 20 percent of invasive breast cancers, a genetic change causes cancer cells to produce too many HER2 receptors, known as protein overexpression.
This overproduction creates excessive signaling pathways, instructing cancer cells to grow and multiply rapidly. The initial test used to check for this is Immunohistochemistry (IHC), which uses special antibodies that bind to the HER2 protein, causing the cell surface to stain a specific color. A pathologist examines the intensity and completeness of this staining to assign a score from 0 to 3+.
A score of 0 or 1+ indicates the HER2 protein is absent or present at very low levels, classifying the tumor as HER2-negative. Conversely, a score of 3+ signifies strong, complete, and intense staining across more than ten percent of the invasive tumor cells. This 3+ result is definitive for HER2-positive status and signals a high likelihood of response to targeted therapy.
The Meaning of an Equivocal Result
The term “equivocal” specifically describes an IHC score of 2+. This result is uncertain because it falls between the clearly negative (0 or 1+) and clearly positive (3+) categories. An equivocal result means the tumor cells show some HER2 protein presence, but the staining is not intense or widespread enough to confidently label the cancer as HER2-positive.
A pathologist assigns a 2+ score when tumor cells exhibit weak to moderate complete membrane staining in over ten percent of the cells, or intense staining in a smaller percentage. This ambiguity stems from limitations inherent in the IHC process, which assesses protein levels. Factors like tissue sample quality, preservation time, or subtle variations in staining technique can influence the final visual assessment.
Since the 2+ score is a borderline finding, it cannot determine a patient’s treatment path alone. The distinction between a true HER2-positive tumor and one with slightly elevated protein levels is clinically significant. Therefore, an IHC 2+ result automatically triggers mandatory, more precise testing on the same tissue sample to resolve the uncertainty and ensure accurate final classification.
Clarifying the Status with Secondary Testing
To resolve the uncertainty of an IHC 2+ result, the next step is a molecular test examining the tumor’s genetics rather than its protein levels. This mandatory secondary testing uses Fluorescence In Situ Hybridization (FISH) or Chromogenic In Situ Hybridization (CISH/ISH) to count the actual number of HER2 genes present within the cancer cell nucleus.
Unlike IHC, which measures protein overexpression, ISH measures gene amplification, the underlying cause of high HER2 protein levels. The test uses probes that attach specifically to the HER2 gene and a control area on chromosome 17 (CEP17). The pathologist counts the number of HER2 gene signals relative to the chromosome 17 signals in multiple cells.
The final determination is made by calculating the HER2/CEP17 ratio. A ratio of 2.0 or higher indicates the HER2 gene has been amplified, confirming the tumor as HER2-positive. If the ratio is below 2.0, the tumor is classified as HER2-negative, despite the initial 2+ protein test. This two-step process provides the necessary genetic confirmation, transforming the equivocal result into a clear, actionable status.
Treatment Pathways Based on Final Status
The final, clarified HER2 status is crucial for selecting the most effective treatment strategy. If reflex testing confirms the tumor is HER2-positive (gene amplified), the patient is eligible for specific anti-HER2 therapies. These targeted drugs, such as Trastuzumab, are monoclonal antibodies designed to attach directly to the overexpressed HER2 receptors on the cancer cell surface.
By binding to the receptors, these drugs block growth signals and significantly improve the patient’s prognosis. The addition of these targeted agents to standard chemotherapy and surgery has transformed the outlook for HER2-positive breast cancer. This approach represents a powerful precision medicine strategy, directly attacking the molecular driver of the cancer’s growth.
Conversely, if the final status is confirmed as HER2-negative, the targeted anti-HER2 drugs are ineffective because the cancer cells lack sufficient receptors. In these cases, the treatment strategy is guided by other tumor characteristics, such as hormone receptor presence. Treatment for HER2-negative tumors typically involves a combination of surgery, radiation, standard chemotherapy, and hormone therapy, if applicable. The resulting positive or negative classification leads to fundamentally different therapeutic plans.