Human Epidermal Growth Factor Receptor 2 (HER2) is a protein found on the surface of cells throughout the body, playing a role in regulating normal cell growth, division, and repair. In certain cancers, such as those affecting the breast, stomach, and esophagus, the HER2 gene can produce an excess of this protein. This overexpression can lead to uncontrolled cell growth and more aggressive tumor behavior. Therefore, HER2 testing is standard in diagnosing and managing these cancers, guiding treatment decisions.
Decoding HER2 Status
HER2 testing categorizes tumors to determine treatment strategies. The three classifications are HER2-positive, HER2-negative, and HER2-equivocal, reflecting the amount of HER2 protein or gene copies in cancer cells.
A HER2-positive result indicates cancer cells have significantly higher HER2 protein levels or increased gene copies, suggesting the cancer may grow and spread more rapidly. Conversely, a HER2-negative result means cancer cells have normal or low HER2 protein levels and typical gene copies. These cancers behave less aggressively and do not respond to HER2-targeted therapies.
An “equivocal” HER2 result falls into an uncertain category. This outcome suggests borderline HER2 protein expression or gene amplification, not meeting clear thresholds for positive or negative classification. Such a result highlights the need for further investigation to clarify the true HER2 status, as it significantly impacts treatment planning.
The Science Behind Equivocal Results
An equivocal HER2 result arises from the technical aspects of the testing methodologies. Two primary methods are commonly used to assess HER2 status: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC measures the amount of HER2 protein on the surface of cancer cells, while FISH detects the number of HER2 gene copies inside the cells.
When using IHC, an equivocal result is assigned a score of 2+, indicating moderate protein overexpression. This score does not definitively confirm HER2 overexpression, necessitating further analysis. For FISH testing, an equivocal result occurs when the ratio of HER2 gene copies to chromosome 17 (a control chromosome) falls within a borderline range, often between 1.8 and 2.2. This range suggests an ambiguous level of gene amplification, not clearly meeting the criteria for either amplification or no amplification.
Another contributing factor to equivocal results is tumor heterogeneity. This phenomenon occurs when different areas within the same tumor exhibit varying levels of HER2 protein expression or gene amplification. Such variability can make it challenging to obtain a conclusive overall HER2 status from a single biopsy sample, leading to an equivocal finding that reflects this mixed cellular landscape.
Navigating an Equivocal Diagnosis
Receiving an equivocal HER2 result means that further diagnostic steps are needed to clarify the cancer’s status. This additional testing is performed to ensure the most accurate classification of the tumor. The initial equivocal finding, such as an IHC 2+ score, prompts a follow-up test using FISH or another in situ hybridization (ISH) method on the same tissue sample.
If the initial biopsy sample is insufficient or does not yield a definitive result after secondary testing, a new biopsy may be recommended. This ensures that enough tumor tissue is available for comprehensive analysis. Consulting with both oncologists and pathologists is an important step in this process, as they collaboratively interpret the test results and decide on the subsequent course of action. Their combined expertise helps navigate the complexities of an equivocal diagnosis and guides the selection of the most appropriate subsequent tests.
Treatment Implications and Patient Outlook
An equivocal HER2 result directly impacts treatment decisions, particularly regarding HER2-targeted therapies. Medications such as trastuzumab or pertuzumab are specifically designed to block the HER2 protein and are highly effective for cancers that are definitively HER2-positive. Since an equivocal result signifies uncertainty about the HER2 status, these targeted treatments cannot be prescribed until a clear positive or negative determination is made.
The primary goal of clarifying an equivocal result is to ensure that patients receive the most personalized and effective treatment plan. While waiting for definitive results can be concerning, it is a necessary step to avoid administering therapies that may not be beneficial or to ensure that appropriate targeted treatments are not missed. Patients should understand that an equivocal finding is not uncommon and that the subsequent, more detailed testing aims to provide clarity, ultimately leading to better therapeutic strategies tailored to their specific cancer profile.