The ERBB2 gene, also known as HER2 or neu, is found within human cells. This gene provides instructions for creating a specific protein that regulates cell growth and division. The medical importance of ERBB2 stems from its involvement in various cancers, where its altered behavior can significantly influence disease progression and treatment outcomes. Understanding its function and implications is important for developing therapies.
The Role of ERBB2 in Cell Growth
The ERBB2 gene directs the production of a protein called HER2 (Human Epidermal Growth Factor Receptor 2), a type of receptor tyrosine kinase. This HER2 protein resides on the surface of cells, acting like an antenna to receive external signals. When these signals bind to the HER2 receptor, they initiate pathways within the cell that promote normal processes such as cell growth, division, and repair. This signaling is a controlled mechanism, ensuring cells multiply only when necessary for healthy tissue development. Although HER2 is a member of the epidermal growth factor receptor (EGFR) family, it is unique because it does not directly bind to growth factors. Instead, it forms partnerships with other EGFR family members, which then allows for signal activation.
ERBB2 Amplification and Cancer
ERBB2 gene amplification means there are too many copies of the gene within a cell, or it can be overexpressed, leading to excessive HER2 protein production. This overabundance of HER2 on the cell surface results in uncontrolled activation of growth pathways, even without external signals. This sustained signaling drives cells to grow and divide excessively, a hallmark of cancer development.
This amplification or overexpression of ERBB2 is particularly recognized in HER2-positive breast cancer, affecting approximately 15% to 20% of invasive breast carcinomas. In these cases, the elevated HER2 activity contributes to a more aggressive disease, often associated with faster growth and a higher likelihood of spreading to other parts of the body. Beyond breast cancer, ERBB2 amplification or overexpression is also observed in other malignancies, including gastric and gastroesophageal junction cancers, ovarian, lung, bladder, salivary gland, and colorectal cancers. In gastric cancer, HER2 overexpression is linked to an aggressive phenotype.
Diagnosing ERBB2 Status
Determining ERBB2 status in cancer patients is a necessary step, as it directly influences treatment decisions. Pathologists commonly use two primary methods to assess ERBB2 gene amplification or HER2 protein overexpression in tumor tissue samples.
One widely used technique is Immunohistochemistry (IHC), which measures the amount of HER2 protein on the surface of cancer cells. IHC results are reported on a scoring scale from 0 to 3+. A score of 0 or 1+ indicates little to no HER2 protein, classifying the cancer as HER2-negative. A score of 3+ signifies high levels of HER2 protein, indicating HER2-positive status.
If the IHC result is equivocal (often 2+), further testing is needed to confirm ERBB2 status. In such cases, Fluorescence In Situ Hybridization (FISH) or Chromogenic In Situ Hybridization (CISH) are employed. These molecular techniques directly detect the number of ERBB2 gene copies within the cancer cells, with a ratio above 2.0 typically indicating gene amplification and HER2-positive status.
Targeted Therapies for ERBB2-Positive Cancers
Understanding ERBB2’s role in cancer has led to the development of targeted therapies to counteract its effects. These treatments block the overactive HER2 protein or its signaling pathways, inhibiting uncontrolled cell growth.
One class of these therapies involves monoclonal antibodies, such as trastuzumab, which bind directly to the HER2 protein on the cell surface. This binding can prevent HER2 from sending growth signals and can also trigger the body’s immune system to attack cancer cells.
Another type of targeted therapy is antibody-drug conjugates (ADCs), which combine a monoclonal antibody with a potent chemotherapy drug. The antibody delivers chemotherapy directly to HER2-positive cancer cells, minimizing damage to healthy cells. Examples include ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (Enhertu), which has shown effectiveness even in cases with lower HER2 expression.
Tyrosine kinase inhibitors (TKIs) represent a different approach, blocking the activity of the HER2 protein from inside the cell. These small molecules interfere with signaling cascades that promote cell growth and division. Lapatinib and tucatinib are examples of TKIs used in HER2-positive cancers. Tucatinib, a selective HER2 TKI, has shown benefit in advanced HER2-positive breast cancer, including those with brain metastases.
These targeted therapies have significantly improved outcomes for patients with ERBB2-positive cancers.