HER2 (Human Epidermal Growth Factor Receptor 2) is a protein on the surface of cells that regulates cell growth, division, and repair. In healthy cells, HER2 helps maintain normal functions by promoting controlled proliferation. However, alterations in HER2 can lead to uncontrolled cell growth, a hallmark of cancer. Understanding these genetic changes, known as HER2 mutations, is important because they influence how cancer develops and how it might be treated.
What is HER2 and Its Role?
HER2 is a protein belonging to the human epidermal growth factor receptor (HER/EGFR/ERBB) family, encoded by the ERBB2 gene. It resides on the cell membrane, acting as a receptor tyrosine kinase. When activated, HER2 initiates signaling pathways within the cell that regulate processes like cell growth, survival, and differentiation.
Unlike other HER family members, HER2 does not directly bind to growth factors. Instead, it exists in an open conformation, making it a preferred partner for dimerization with other HER receptors. When HER2 forms pairs, it activates downstream signaling pathways, such as the PI3K/Akt/mTOR and Raf/MAPK cascades. These pathways promote cell proliferation, survival, and migration, which are tightly controlled in healthy cells.
Distinguishing HER2 Mutations from Amplification
The term “HER2-positive” cancer, frequently discussed in breast and gastric cancers, commonly refers to HER2 gene amplification or protein overexpression. Gene amplification means cancer cells have an abnormally high number of ERBB2 gene copies, leading to an excessive amount of HER2 protein on the cell surface. This overabundance drives uncontrolled cell growth and division.
In contrast, a HER2 mutation involves a specific change within the ERBB2 gene’s DNA sequence, rather than an increase in gene copies. These mutations can constantly activate the HER2 protein, effectively locking it into an “on” position. Both amplification and mutation result in abnormal HER2 activity that contributes to cancer, but they are distinct molecular changes that often require different therapeutic strategies. Some HER2-mutant cases, for example, may not show HER2 amplification.
How HER2 Mutations Are Identified
Detecting HER2 mutations requires precise genetic testing. Next-Generation Sequencing (NGS) is a primary method used to identify these specific alterations in the ERBB2 gene. NGS can analyze the entire sequence of genes of interest, providing a comprehensive view of genetic changes within tumor tissue. This method is particularly useful for identifying both known and novel mutations.
Liquid biopsies, which involve analyzing circulating tumor DNA (ctDNA) from blood samples, represent another non-invasive approach. This technique offers the advantage of being easier to perform repeatedly and can provide real-time information about the tumor’s genetic landscape. Traditional HER2 testing methods, such as Immunohistochemistry (IHC) for protein overexpression or Fluorescence In Situ Hybridization (FISH) for gene amplification, are primarily designed to detect changes in protein levels or gene copy numbers. These conventional tests may not always identify specific HER2 mutations, highlighting the need for more detailed genetic sequencing.
Implications for Cancer Development and Treatment
Identifying HER2 mutations is important because these genetic changes significantly influence how a cancer behaves and is treated. These mutations can act as “oncogenic drivers,” promoting cancer cell growth and survival, potentially making tumors more aggressive. In some cases, HER2 mutations emerge as a mechanism of acquired resistance to existing therapies, including HER2-targeted treatments or endocrine therapies.
The presence of a HER2 mutation guides the selection of targeted therapies. For instance, tyrosine kinase inhibitors (TKIs) block the activity of mutated HER2 proteins, inhibiting uncontrolled signaling. Monoclonal antibodies and antibody-drug conjugates (ADCs) are also explored for their effectiveness. HER2 mutations are particularly relevant in several cancer types, including non-small cell lung cancer (NSCLC), where they are found in approximately 1% to 7% of cases. They are also significant in breast cancer, where activating HER2 mutations have been identified in patients without gene amplification, and in gastric cancer. Clinical trials are actively investigating various HER2-targeted drugs to improve patient outcomes.