When breast cancer is diagnosed, testing the tumor tissue for specific proteins defines the cancer’s “status” and guides treatment planning. HER2 status determines whether cancer cells have an excess of the Human Epidermal growth factor Receptor 2 protein. A HER2-negative result is common, signifying that the tumor does not rely on this growth-promoting protein for development. This designation indicates a specific biological profile that directs medical teams toward distinct treatment pathways.
What the HER2 Protein Does
The HER2 protein is a receptor found on the surface of all healthy breast cells, acting like an antenna to receive external growth signals. Upon receiving a signal, the HER2 protein initiates pathways inside the cell that regulate normal functions like cell division, growth, and repair. This protein is encoded by the ERBB2 gene located on chromosome 17.
Problems arise when the ERBB2 gene is amplified, leading to an overproduction of the HER2 protein on the cell surface. This excess of receptors causes the cell to receive too many growth signals, resulting in rapid and uncontrolled cell proliferation, which defines a HER2-positive cancer. In contrast, a HER2-negative tumor has a normal number of HER2 proteins, meaning the cancer growth is driven by different biological mechanisms.
How HER2 Status is Measured
Determining HER2 status begins with a test called Immunohistochemistry (IHC), which measures the amount of HER2 protein present on the surface of the cancer cells. The IHC test uses a chemical stain that binds to the protein, and the resulting score is graded on a scale from 0 to 3+. A score of 0 or 1+ indicates that the protein levels are normal and is classified as HER2 negative.
A score of 3+ is considered HER2 positive, indicating a high level of protein overexpression. The intermediate score of 2+, however, is considered “equivocal” or indeterminate and requires further testing for confirmation. This confirmation is typically done using a different method, such as Fluorescence In Situ Hybridization (FISH) or Chromogenic In Situ Hybridization (CISH).
These secondary tests evaluate the number of copies of the ERBB2 gene itself within the cell nucleus, rather than the amount of protein on the surface. They calculate the ratio of the HER2 gene to a control gene on chromosome 17. If the ratio is below 2.0, the tumor is confirmed as HER2 negative, even if the initial IHC score was 2+. This comprehensive testing approach ensures the accuracy of the HER2 status, providing a reliable foundation for treatment selection.
Treatment Decisions Based on HER2 Negative Results
The implication of a HER2-negative result is that the tumor will not respond to anti-HER2 targeted therapies, such as trastuzumab or pertuzumab, which are designed to block the HER2 protein. Therefore, systemic treatment shifts to targeting other biological features, notably the Estrogen Receptor (ER) and Progesterone Receptor (PR) status. This differentiation identifies two major subtypes of HER2-negative breast cancer, each with a distinct treatment plan.
If the tumor is HER2 negative but tests positive for ER and/or PR, the cancer is known as hormone receptor-positive. This is the most common subtype of breast cancer, and the primary systemic treatment is endocrine therapy, which aims to block the effects of hormones or lower their levels. These therapies, which include selective estrogen receptor modulators like tamoxifen or aromatase inhibitors, are highly effective because they target the hormone-driven growth pathway.
For many patients with hormone receptor-positive, HER2-negative disease, targeted drugs known as CDK4/6 inhibitors may be added to endocrine therapy to enhance its effectiveness. Chemotherapy may also be recommended in addition to hormone therapy, depending on the tumor’s size, lymph node involvement, or a high-risk score from a genomic test. This test predicts the likelihood of recurrence.
The second major subtype of HER2-negative breast cancer is called Triple Negative Breast Cancer (TNBC), which is negative for ER, PR, and HER2. Because TNBC lacks all three receptors, it cannot be treated with either hormone therapy or HER2-targeted drugs. This subtype is considered more aggressive and often requires immediate and intensive systemic treatment.
Chemotherapy, typically a combination of drugs such as anthracyclines and taxanes, is the main systemic treatment for TNBC. It is often given before surgery to shrink the tumor. Newer treatments are available for certain patients with TNBC, including immunotherapy drugs that stimulate the patient’s immune system to attack the cancer cells. Patients with specific genetic changes, such as a BRCA gene mutation, may also be candidates for targeted drugs called PARP inhibitors.