The human epidermal growth factor receptor 2 (HER2) is a protein receptor on the surface of cells that regulates cell growth and division. In healthy cells, HER2 maintains normal function. However, in certain cancers, the gene coding for HER2 can be amplified, leading to an excessive number of receptors. This overexpression causes cells to receive too many growth signals, driving uncontrolled cell proliferation and tumor development. Testing for HER2 status is a standard procedure, particularly for breast cancer, because the protein level determines both the prognosis and the most effective treatment strategy.
Understanding the HER2 Scoring System
The standard method for measuring HER2 protein on cancer cells is Immunohistochemistry (IHC). This test uses specialized antibodies that bind to the HER2 protein, causing the cell surface to stain. A pathologist then visually assesses the protein levels, assigning a score from 0 to 3+ based on clinical guidelines.
The IHC scoring system categories are based on the intensity and pattern of staining observed on the cell membrane. A score of 0 indicates no staining or very faint, incomplete staining. A 3+ score signifies strong, complete, and circumferential staining in more than 10% of tumor cells, traditionally defining HER2-positive cancer.
The intermediate scores, 1+ and 2+, represent lower levels of protein expression. A 1+ score is characterized by incomplete membrane staining that is faint or barely visible, but present in more than 10% of the tumor cells. A 2+ score involves weak to moderate complete membrane staining in more than 10% of tumor cells. Because a 2+ result is considered “equivocal,” it requires a second test, such as Fluorescence In Situ Hybridization (FISH), to determine if the HER2 gene is amplified.
The Meaning of a HER2 1+ Result
A HER2 1+ result signifies a low level of HER2 protein expression on the cancer cells. Historically, 1+ scores were grouped with 0 scores and classified as “HER2-Negative,” meaning they were ineligible for therapies targeting high HER2 levels. This classification meant that 80% to 85% of breast cancers were considered HER2-Negative.
The 1+ result now falls into the distinct, newly recognized subcategory known as “HER2-Low.” This reclassification is significant because it acknowledges that even a small amount of HER2 protein can be leveraged for targeted therapy. HER2-Low is clinically defined as having an IHC score of 1+ or an IHC score of 2+ with a negative FISH test result.
Unlike the ambiguous 2+ score, the 1+ score is sufficient on its own to classify a tumor as HER2-Low. This distinction separates tumors with truly absent HER2 protein (IHC 0) from those with minimal, yet detectable, expression. This change in interpretation has created a new population of patients who may benefit from new treatments.
How HER2 1+ Affects Treatment Decisions
The redefinition of HER2 1+ status as HER2-Low has introduced a new treatment paradigm for these patients. Previously, HER2-Negative tumors were limited to standard chemotherapy or hormone therapy, as traditional HER2-targeted drugs were ineffective against low protein levels. The emergence of the HER2-Low category now provides a specialized, targeted option.
This new therapeutic opportunity centers on the use of Antibody-Drug Conjugates (ADCs), such as Trastuzumab deruxtecan (Enhertu). An ADC links a potent chemotherapy drug to an antibody that specifically targets the HER2 protein, acting like a guided missile. For patients with a 1+ result, the antibody component binds to the few HER2 receptors present on the cell surface.
Once bound, the complex is internalized by the cancer cell, releasing the chemotherapy payload directly inside to cause DNA damage and cell death. A beneficial feature of this specific ADC is its “bystander effect,” where the released chemotherapy diffuses out to kill neighboring cancer cells, even those with low or no HER2 expression. This mechanism allows the drug to be effective against HER2-Low tumors, which was not possible with older therapies. The clinical success of ADCs has demonstrated significant improvement in outcomes for patients with HER2-Low metastatic breast cancer.