Breast cancer treatment is highly individualized, relying on testing the tumor for specific proteins, known as biomarkers, that signal growth. These test results determine the appropriate treatment pathway and provide important information about the tumor’s behavior. Breast cancer is a collection of distinct types, defined by the presence or absence of these receptors. Understanding the status of the Human Epidermal growth factor Receptor 2 (HER2) protein is a fundamental step in this classification.
Understanding the HER2 Protein
The HER2 protein, encoded by the HER2/neu gene, is a member of the human epidermal growth factor receptor family, which sits on the surface of all breast cells. Its normal function is to act as a receptor that receives external growth signals, helping to control how a cell grows, divides, and repairs itself. This process is tightly regulated in healthy tissue.
When the HER2/neu gene malfunctions, it can create too many copies of itself, a process called gene amplification. This leads to an overproduction of HER2 protein receptors on the cell surface. These overexpressed receptors constantly signal the cell to grow and divide uncontrollably, driving the aggressive proliferation seen in HER2-Positive breast cancer. A HER2-Negative status indicates that this particular growth signal is not the primary driver of the cancer.
How HER2 Status is Determined
Determining a tumor’s HER2 status is a standardized laboratory process performed on tissue samples obtained through a biopsy or surgery. The initial test is typically Immunohistochemistry (IHC), which measures the amount of HER2 protein on the cell membrane using a scoring system from 0 to 3+. A result of 0 or 1+ definitively classifies the tumor as HER2-Negative, indicating a normal or very low level of protein expression.
An equivocal IHC result of 2+ requires further testing to confirm the tumor’s status. This confirmation uses Fluorescence In Situ Hybridization (FISH), which physically counts the number of HER2/neu gene copies within the cell nucleus. If the FISH result shows a normal number of gene copies, despite the IHC 2+ protein level, the tumor is confirmed as HER2-Negative.
Implications of a HER2 Negative Result
The designation “HER2 Negative” signifies that the cancer cells are not being fueled by the overactivity of the HER2 protein pathway. This means the tumor will not respond to medications specifically designed to block HER2. The majority of all breast cancers, estimated to be around 70% to 80%, fall into this HER2-Negative category.
HER2-Negative tumors are further sub-classified based on the presence or absence of hormone receptors for estrogen (ER) and progesterone (PR). The most common subtype is Hormone Receptor-Positive/HER2-Negative (HR+/HER2-), where the cancer growth is driven by female hormones. The second major subtype is Triple-Negative Breast Cancer (TNBC), which is negative for all three receptors (ER-, PR-, and HER2-). This sub-classification dictates the systemic treatment strategy.
Treatment Approaches for HER2 Negative Tumors
The treatment for a HER2-Negative tumor depends on its hormone receptor status. Foundational treatments like surgery to remove the tumor and radiation therapy to reduce local recurrence are common for nearly all early-stage breast cancers. Systemic drug therapy, however, is highly specific to the tumor’s internal characteristics.
For the HR+/HER2- subtype, the primary systemic treatment involves endocrine therapy, which aims to block the effects of estrogen or lower its levels. Medications such as selective estrogen receptor modulators (like tamoxifen) or aromatase inhibitors are used for several years to prevent recurrence. For the Triple-Negative subtype, which lacks all three major growth drivers, chemotherapy is the most effective systemic approach.
A newer development is the recognition of HER2-low breast cancer (IHC 1+ or IHC 2+ with negative FISH), which falls within the HER2-Negative group. Patients with this status may now be candidates for specific antibody-drug conjugates, such as trastuzumab deruxtecan. These drugs successfully deliver chemotherapy directly to cells with even small amounts of the HER2 protein.