HER2 Protein Overexpression

HER2/neu protein overexpression, ERBB2 protein overexpression

HER2 protein overexpression occurs when cells make too much of a specific protein that controls cell growth, leading to faster cancer development in several types of tumors, particularly breast and stomach cancers.

Table of contents

• What is HER2 and How Does Overexpression Occur?
• How HER2 Overexpression Develops
• Cancers Affected by HER2 Overexpression
• Testing for HER2 Overexpression
• Impact on Cancer Behavior and Prognosis
• Treatment Approaches

What is HER2 and How Does Overexpression Occur?

HER2 (human epidermal growth factor receptor 2), also known as ERBB2, is a gene that makes proteins called HER2 proteins or receptors. These receptors sit on the surface of cells and help control how cells grow, divide, and repair themselves^[1]. In healthy cells, HER2 proteins function normally to support regular cell growth.

HER2 protein overexpression happens when cells produce too many HER2 proteins on their surface. This typically occurs because the HER2 gene makes too many copies of itself, a process called gene amplification^[2]. When there are extra copies of the HER2 gene, the cells are instructed to make too many HER2 receptors. These excess receptors send too many signals telling cells to grow and divide, which can lead to uncontrolled cell growth and cancer development^[1].

The HER2 protein is a 1255 amino acid, 185 kD transmembrane glycoprotein located on chromosome 17^[2]. It belongs to a family of four receptors that includes HER1, HER2, HER3, and HER4. All four members have a similar structure with three main parts: an outer part that can bind to signals from outside the cell, a section that crosses through the cell membrane, and an inner part with tyrosine kinase activity that sends signals inside the cell^[2].

How HER2 Overexpression Develops

When cells have too many HER2 receptors on their surface, these receptors pair up with each other or with other similar receptors. This pairing activates the receptors and starts a chain reaction of signals inside the cell. These signals travel through different pathways, particularly the MAPK/ERK and PI3K/AKT/mTOR pathways, which promote cell growth and survival^[9].

In normal cells, only two copies of the HER2 gene exist. However, in some cancer cells, the number of HER2 gene copies increases significantly. This increase can be caused by gene amplification, where the gene is copied multiple times^[3]. It’s also possible to have HER2 protein overexpression without gene amplification, due to gene mutations or other processes called epigenetic processes^[5].

The changes in HER2 that relate to cancer are not inherited from parents. They develop during a person’s lifetime in specific cells and are called somatic changes^[5][18]. Scientists don’t yet fully understand what causes the HER2 gene to start making too many copies, though researchers are exploring whether environmental factors, lifestyle, or factors within the tumor itself may play a role^[18].

Cancers Affected by HER2 Overexpression

HER2 protein overexpression occurs in several types of cancer. In breast cancer, approximately 10% to 20% of cases show HER2 overexpression^[1][7]. Some sources estimate this may be as high as 15% to 30% of breast cancers^[2]. When HER2 is overexpressed in breast cancer, it is called HER2-positive breast cancer.

Stomach and gastroesophageal cancers also show HER2 overexpression in about 10% to 30% of cases^[2]. Approximately 20% of stomach cancers have HER2 amplification or overexpression^[5]. In colorectal cancer, HER2 abnormalities occur in 3% to 5% of all cases, though the percentage is higher in colorectal cancers that don’t have mutations in other genes like KRAS, NRAS, or BRAF^[5].

HER2 overexpression has also been observed in other cancer types, including ovarian cancer, endometrial cancer, bladder cancer, lung cancer, colon cancer, and head and neck cancer^[2]. However, more research is needed to fully understand how HER2 overexpression affects these tumors^[3].

Testing for HER2 Overexpression

Testing for HER2 status is done on a sample of tissue taken from the tumor through a biopsy^[3]. In breast cancer, HER2 testing is performed on the main tumor at the time of diagnosis. Because HER2 status can sometimes change over time or with treatment, testing may be repeated if the cancer comes back or spreads to other parts of the body^[1][3].

Two main tests are used to determine HER2 status. The IHC test (ImmunoHistoChemistry) measures the amount of HER2 protein in the cancer cells. This test uses a chemical dye to stain the HER2 proteins, which can then be seen under a microscope. The IHC test gives a score from 0 to 3+^[1][3].

A score of 0 or 1+ means the HER2 level has not increased, and the tumor is considered HER2-negative or HER2-low. A score of 2+ is called borderline or equivocal, meaning the results are unclear. When this happens, a second test called the FISH test is usually performed to confirm the HER2 status. A score of 3+ means the HER2 level is higher than normal, and the tumor is HER2-positive^[3].

The FISH test (Fluorescence In Situ Hybridization) looks at the actual number of copies of the HER2 gene in the cancer cells rather than the protein on the cell surface. It uses fluorescent probes that attach to specific parts of chromosomes and glow, making them visible under a microscope^[1][3]. FISH results are reported as negative or positive. A FISH-negative result means the levels of the HER2 gene in the cells are normal. A FISH-positive result means there are at least four copies of the HER2 gene on average in the cells, indicating the tumor is HER2-positive^[3].

Other testing methods include next-generation sequencing (NGS), which can also identify HER2 status^[5]. If test results aren’t clear with one method, the other test may be used to get a more definite result^[3].

Impact on Cancer Behavior and Prognosis

Cancers with HER2 protein overexpression tend to behave more aggressively than those without overexpression. HER2-positive breast cancers typically grow faster and are more likely to spread and return compared to HER2-negative breast cancers^[1][3]. These cancers usually have a higher grade, meaning the cancer cells look more abnormal under a microscope^[3].

HER2 serves as both a prognostic and predictive biomarker. As a prognostic biomarker, it provides information about the likely course of the disease. As a predictive biomarker, it predicts whether a tumor will respond to specific therapies^[5]. Historically, HER2 overexpression was associated with worse outcomes compared to other cancer subtypes, largely because the excess HER2 protein acts as a powerful driver of cancer cell growth^[4].

However, the development of targeted therapies that work specifically against HER2 has dramatically changed outcomes for patients. Since the introduction of HER2-targeted medicines, outcomes for patients with HER2-positive cancers have improved significantly, becoming similar to those with HER2-negative cancers^[4][10].

Treatment Approaches

The identification of HER2 overexpression as a target for treatment has led to the development of several types of medicines. These include specific monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs)^[9].

Monoclonal antibodies are designed to attach to HER2 proteins on the cell surface and block their activity. The first HER2-targeted drug, trastuzumab (Herceptin), was approved almost 25 years ago and works by binding to HER2 receptors. This binding causes the uncoupling of receptor pairs and stops the growth signals from being sent into the cell. It also triggers the immune system to attack the cancer cells through a process called antibody-dependent cell-mediated cytotoxicity (ADCC)^[8][10].

Tyrosine kinase inhibitors are small molecules that work inside the cell to block the signaling pathways activated by HER2. These drugs prevent the HER2 receptor from sending growth signals even when it’s activated^[9].

Antibody-drug conjugates combine a monoclonal antibody with a chemotherapy drug. The antibody part finds and attaches to HER2 proteins on cancer cells, and then delivers the chemotherapy directly to those cells. This targeted delivery helps kill cancer cells while limiting damage to healthy cells^[9].

The introduction of HER2-targeted therapies has dramatically influenced outcomes for patients with HER2-positive breast and gastric/gastroesophageal cancers. In the treatment of breast cancer, adding trastuzumab to standard chemotherapy has been shown to reduce disease recurrence and the risk of death compared to chemotherapy alone^[8]. Multiple clinical trials have demonstrated striking benefits in survival, with some studies showing a 50% reduction in the risk of recurrence when HER2-targeted therapy is used^[7].

However, results with HER2-targeted therapies in other types of cancer that show HER2 overexpression have been less successful^[2]. Treatment decisions are based on the type of cancer, the level of HER2 overexpression in the tumor, and other factors such as the cancer stage and the patient’s overall health^[3].