HER2 scoring is a method used in cancer diagnostics, primarily for breast and gastric cancers, to determine the level of Human Epidermal growth factor Receptor 2 protein present on a tumor cell’s surface. This process is a crucial step in pathology, as the resulting score directly informs whether a patient is eligible for specific targeted treatments. The score acts as a predictive biomarker, distinguishing tumors driven by an overabundance of this protein from those that are not, thereby guiding oncologists toward the most effective therapeutic plan.
The Role of HER2 in Cell Growth
The HER2 protein is one of four members of the Epidermal Growth Factor Receptor family, residing on the surface of normal, healthy cells. Its usual function involves receiving signals from outside the cell that regulate cell division, growth, and repair. Upon activation, these receptors trigger complex signaling pathways inside the cell, promoting controlled proliferation and differentiation.
In some cancers, a genetic error causes the gene responsible for creating the HER2 protein to be amplified, meaning the cell contains extra copies of the gene. This gene amplification leads to a massive overproduction of HER2 receptors on the cell surface, known as overexpression. The significantly higher number of receptors makes the signaling pathways hyperactive, driving uncontrolled and aggressive tumor growth. This overexpression characterizes a tumor as HER2-positive.
Testing Methods Used to Determine HER2 Status
Determining the HER2 status begins with a tissue sample obtained through a biopsy or surgery. The initial and most common screening method is Immunohistochemistry (IHC), which measures the amount of HER2 protein expressed on the cancer cell membrane. The IHC test uses specific antibodies linked to a colored marker that bind to the HER2 protein, allowing a pathologist to visually assess the intensity and completeness of the staining under a microscope.
IHC is often preferred as it is generally faster and more cost-effective. However, if the IHC result is not definitively positive or negative, a second, more precise test is required to confirm the status. This confirmatory test is typically Fluorescence In Situ Hybridization (FISH) or Chromogenic In Situ Hybridization (CISH).
The FISH or CISH tests directly count the number of HER2 gene copies within the cell nucleus rather than measuring the protein. These methods use fluorescent or colored probes that attach specifically to the HER2 gene and a control gene on the same chromosome. By calculating a gene-to-chromosome ratio, FISH provides a definitive answer regarding whether the HER2 gene is amplified, which is the underlying cause of protein overexpression.
Interpreting the HER2 Scoring System
Pathologists use a standardized scoring system to interpret the IHC results. This system assigns a semiquantitative score from 0 to 3+ based on the observed staining pattern, reflecting the level of HER2 protein overexpression.
A score of 0 or 1+ is classified as HER2 negative. A score of 0 indicates no staining is observed, while 1+ is defined by faint or barely perceptible incomplete membrane staining in a portion of the tumor cells. Historically, these results meant the patient was ineligible for anti-HER2 targeted therapy, but the recent recognition of the HER2-low category has given new clinical significance to the 1+ score.
The most ambiguous result is a score of 2+, classified as “equivocal.” This score is defined by moderate, complete membrane staining observed in at least 10% of the invasive tumor cells. Because this result is borderline and not definitive, guidelines mandate that any tumor with an IHC 2+ score must proceed to a FISH or CISH test for clarification.
A score of 3+ is considered definitively HER2 positive. This result is characterized by intense, strong, and complete membrane staining observed in more than 10% of the invasive tumor cells. A 3+ score on IHC is sufficient to classify the tumor as HER2-positive, indicating that the underlying gene amplification is presumed and the patient is eligible for specific targeted treatments.
Clinical Action Based on HER2 Results
The final HER2 status is the primary determinant for the choice of therapy. Patients classified as HER2-positive (IHC 3+ or IHC 2+ confirmed amplified by FISH) are eligible for targeted anti-HER2 therapies. These treatments work by specifically blocking the HER2 protein’s ability to signal the cell to grow, effectively shutting down the primary driver of the cancer.
Conversely, patients with HER2-negative tumors (IHC 0 or 1+, or IHC 2+ confirmed not amplified by FISH) are generally not candidates for traditional anti-HER2 drugs. For these individuals, alternative strategies, such as hormone therapy or conventional chemotherapy, are pursued. The HER2-negative classification signifies that the tumor growth is not significantly dependent on the HER2 pathway.
HER2-Low Status and New Therapies
A major recent development involves the emerging category of HER2-low status, which includes tumors scoring IHC 1+ or IHC 2+ with a negative FISH result. This status is now clinically significant due to the development of new treatments, specifically antibody-drug conjugates (ADCs). ADCs use the low level of HER2 protein as an anchor to deliver a potent chemotherapy agent directly into the cancer cell. Patients with HER2-low metastatic disease can benefit significantly from these specialized therapies, establishing a new treatment paradigm for a large subset of cancers.