Human Epidermal Growth Factor Receptor 2, known as HER2, is a protein located on the surface of breast cells. It regulates cell growth and division. In about 15% to 20% of invasive breast cancers, the HER2 protein can be present in abnormally high amounts, called overexpression. This often results from extra copies of the gene that produces the HER2 protein. When overexpressed, HER2 can lead to uncontrolled cell multiplication and more aggressive tumor growth. Determining HER2 status is a significant step in breast cancer diagnosis, as it directly influences treatment strategies.
What Equivocal HER2 Means
An “equivocal” HER2 result indicates that the initial test outcome is not definitively positive or negative. The primary method for initial HER2 testing is Immunohistochemistry (IHC), which measures the amount of HER2 protein present on the surface of cancer cells. Pathologists evaluate the staining intensity and pattern of the cell membrane to assign a score.
The IHC scoring system ranges from 0 to 3+. A score of 0 or 1+ is considered HER2-negative, indicating little to no protein overexpression. A score of 3+ signifies HER2-positive status, showing high protein overexpression. An IHC score of 2+ is categorized as “equivocal,” suggesting an intermediate protein level. This equivocal result can occur due to moderate protein expression or technical factors during laboratory processing, such as tissue handling or fixation.
Following Up on Equivocal Results
When an initial HER2 IHC test yields an equivocal (2+) result, confirmatory testing is the standard next step. This commonly involves Fluorescence In Situ Hybridization (FISH) or Chromogenic In Situ Hybridization (CISH). These tests examine the number of HER2 gene copies within the cancer cells, rather than the protein itself. FISH uses fluorescent probes to visualize the HER2 gene and a control gene on chromosome 17, allowing for the calculation of a HER2 to chromosome 17 centromere (CEP17) ratio.
The interpretation of FISH or CISH results involves assessing the HER2 gene amplification ratio. A ratio of less than 2.0 typically indicates a negative result. A ratio of 2.0 or greater, or a high average HER2 copy number, is considered positive. Some cases may still be equivocal by FISH. In such situations, additional follow-up actions may be considered, such as re-evaluating the original biopsy sample or obtaining a new biopsy.
Implications for Treatment and Outlook
The final HER2 status, determined after confirmatory testing, significantly influences breast cancer treatment decisions. If the tumor is ultimately classified as HER2-positive (IHC 3+ or IHC 2+ with positive FISH), targeted anti-HER2 therapies are generally recommended. These therapies, such as trastuzumab and pertuzumab, specifically target the HER2 protein on cancer cells, hindering their growth and division. They are often given in combination with chemotherapy, and significantly improve outcomes for patients with HER2-positive breast cancer.
Conversely, if confirmatory tests establish a definitively HER2-negative status, these targeted anti-HER2 therapies are typically not used. Treatment for HER2-negative breast cancer often involves other approaches such as chemotherapy, hormone therapy (if hormone receptor-positive), or immunotherapy, depending on tumor characteristics. In rare instances, even after extensive testing, results may remain ambiguous. In such cases, clinical judgment, often involving a team of specialists, guides the treatment strategy, considering all available information. While HER2-positive cancers were historically associated with a more aggressive outlook, effective targeted therapies have significantly improved outcomes, often making the prognosis comparable to, or even better than, some HER2-negative cancers when appropriately treated.