When cancer cells produce too much HER2 protein on their surface, they can grow and multiply far more aggressively than normal cells. This condition, known as HER2 protein overexpression, occurs in several types of cancer and has dramatically changed the landscape of cancer treatment over the past decades.

Understanding HER2 and Its Role in Cancer Development

The HER2 gene, also called ERBB2, is found in every person’s body and plays an important role in normal cell growth and repair. This gene produces HER2 proteins, which sit on the surface of cells and act as receptors. These receptors receive signals from outside the cell that tell it when to grow, divide, or repair damage. In healthy cells, this process is carefully controlled and balanced.^[1]

However, sometimes things go wrong. In approximately 10% to 20% of breast cancers, 20% of stomach cancers, and 3% to 5% of colorectal cancers, the HER2 gene malfunctions. Instead of producing the normal amount of HER2 protein, the gene makes too many copies of itself in a process called gene amplification. When this happens, cells produce excessive amounts of HER2 protein on their surface—a condition known as HER2 protein overexpression.^[2][5]

This overabundance of HER2 proteins creates too many receptors on the cell surface, which means the cells receive far more growth signals than they should. The result is uncontrolled cell growth and division, which can lead to cancer formation and progression. When cancer cells have HER2 overexpression, they typically grow faster, spread more readily to other parts of the body, and are more likely to return after treatment compared to cancers without this characteristic.^[1]

The discovery of HER2’s role in cancer occurred in the 1980s, when researchers identified a connection between the HER2 gene and cancer formation. Two independent research teams demonstrated that mutations in the HER2 gene could cause normal cells to grow uncontrollably like cancer cells. This groundbreaking discovery opened the door to developing treatments specifically designed to target this protein.^[4]

It’s important to understand that HER2 gene changes related to cancer are not hereditary. They are not passed from parents to children. These changes happen during a person’s lifetime within certain cells, and researchers are still working to understand exactly what triggers the HER2 gene to start overproducing protein in some people.^[5]

HER2 overexpression has been observed in various cancer types beyond breast cancer. It appears in cancers of the ovary, endometrium, bladder, lung, colon, and head and neck. In these different cancers, HER2 acts as an oncogene—a gene that, when altered, can cause normal cells to become cancerous by disrupting the normal control of cell growth and survival.^[2]

Testing for HER2 Protein Overexpression

Determining whether a cancer has HER2 overexpression is crucial for planning treatment. HER2 status testing is performed on tissue samples taken from the tumor, usually through a biopsy. The test results help doctors understand how aggressive the cancer might be and, more importantly, whether the patient could benefit from HER2-targeted therapies.^[3]

There are several laboratory methods used to test for HER2 overexpression. The two most common are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Each test examines the tumor sample in a different way, and sometimes both tests are needed to get a clear answer.^[1]

The IHC test uses special antibodies created in a laboratory that attach to HER2 proteins. These antibodies are linked to a chemical dye that can be seen under a microscope. The pathologist examines the stained tissue and gives it a score from 0 to 3+ based on how much HER2 protein is present on the cell surfaces. A score of 0 or 1+ means the cancer is HER2-negative—it has normal or slightly elevated levels of HER2 protein. A score of 2+ is considered borderline or equivocal, meaning the results aren’t clear enough to make a definitive determination. When this happens, a FISH test is usually performed. A score of 3+ indicates the cancer is HER2-positive and has high levels of HER2 protein overexpression.^[1][3]

The FISH test works differently. Instead of looking at the protein on the cell surface, it examines the actual HER2 genes inside the cells. Special fluorescent probes attach to the HER2 genes and glow under special lighting, allowing scientists to count how many copies of the HER2 gene are present. Normal cells have two copies of the HER2 gene. If the test shows at least four copies of the gene on average, the cancer is considered HER2-positive due to gene amplification. If the number of gene copies is normal, the result is reported as FISH-negative, meaning the cancer is HER2-negative.^[1][3]

Next-generation sequencing (NGS) is another method that can be used to test HER2 status. This more advanced technology can detect gene mutations and amplifications, and it’s increasingly being used in comprehensive cancer testing panels. However, IHC and FISH remain the standard methods for HER2 testing in most clinical settings.^[5]

An important recent development is the recognition of HER2-low cancer. More than half of breast cancers that were previously classified as HER2-negative actually have some extra HER2 proteins on their cell surfaces—just not enough to be considered HER2-positive. These cancers, now called HER2-low (typically IHC 1+ or IHC 2+ with FISH-negative results), represent a newly recognized category. While there’s still some debate about whether HER2-low should be considered a distinct subtype, newer treatments are being developed specifically for this group of patients.^[1]

For breast cancer, HER2 testing is done on the primary tumor at the time of diagnosis, along with hormone receptor testing. For advanced stomach cancer, particularly cancers in the gastroesophageal junction, HER2 testing is also standard practice. Testing for HER2 in other cancer types is less routine in many countries and is often done as part of clinical trials or when doctors are considering targeted therapy options.^[3]

Standard Treatment Approaches for HER2 Overexpression

The development of treatments that specifically target HER2 has transformed the outlook for patients with HER2-positive cancers. Before these targeted therapies existed, HER2-positive breast cancer was associated with worse outcomes than other breast cancer subtypes because of the aggressive nature of the disease. However, the introduction of HER2-targeted medicines has dramatically changed this picture, improving survival rates and quality of life for countless patients.^[7]

Trastuzumab (brand name Herceptin) was the first HER2-targeted therapy approved for clinical use, nearly 25 years ago. This medication is a monoclonal antibody—a laboratory-made protein designed to attach to HER2 receptors on cancer cells. When trastuzumab binds to HER2 receptors, it blocks signals that tell the cancer cells to grow and multiply. It also uncouples HER2-HER3 receptor pairs that would normally work together to promote cell growth. Additionally, trastuzumab triggers the body’s immune system to recognize and destroy the cancer cells through a process called antibody-dependent cell-mediated cytotoxicity.^[8][13]

Trastuzumab is typically given intravenously, meaning through a vein, usually every three weeks. The duration of treatment varies depending on the stage of cancer and whether it’s given in the adjuvant setting (after surgery to prevent recurrence) or for metastatic disease. In the adjuvant setting for breast cancer, trastuzumab is usually given for one year. For metastatic or advanced cancer, treatment may continue as long as it remains effective and side effects are manageable.^[8]

Common side effects of trastuzumab include fever, chills, nausea, and fatigue, especially with the first infusion. A more serious potential side effect is cardiotoxicity—damage to the heart muscle that can weaken the heart’s pumping ability. Because of this risk, doctors monitor heart function with echocardiograms or similar tests before starting treatment and regularly throughout the course of therapy. Most patients tolerate trastuzumab well, but those who develop heart problems may need to stop treatment or adjust their regimen.^[7]

Pertuzumab (brand name Perjeta) is another monoclonal antibody that targets HER2, but it binds to a different part of the HER2 receptor than trastuzumab does. Pertuzumab blocks HER2 from pairing with other receptors in the HER family, which further reduces growth signals to the cancer cells. Pertuzumab is often used in combination with trastuzumab and chemotherapy, and this combination has been shown to be more effective than trastuzumab and chemotherapy alone. The dual blockade of HER2 by both antibodies provides more comprehensive inhibition of HER2 signaling pathways.^[8][10]

Clinical trials have demonstrated remarkable benefits from HER2-targeted antibody therapy. In the adjuvant setting for breast cancer, adding trastuzumab to chemotherapy reduces the risk of disease recurrence by approximately 50% compared to chemotherapy alone. Several large randomized trials established this benefit, leading to trastuzumab becoming standard of care for patients with HER2-positive early breast cancer.^[7][8]

Lapatinib is a different type of HER2-targeted therapy called a tyrosine kinase inhibitor (TKI). Unlike monoclonal antibodies that work outside the cell, lapatinib is a small molecule that enters the cell and blocks the internal part of the HER2 receptor—the tyrosine kinase domain. This prevents the receptor from sending growth signals even when HER2 proteins on the surface are activated. Lapatinib is taken orally as a pill, typically once daily. It’s often used for metastatic HER2-positive breast cancer, sometimes in combination with chemotherapy or hormone therapy.^[8]

Common side effects of lapatinib include diarrhea, which can be severe in some patients, as well as nausea, rash, and hand-foot syndrome (redness, swelling, and pain on the palms and soles). Like trastuzumab, lapatinib can also affect heart function, though the risk appears to be lower. Liver function abnormalities can occur, so blood tests to monitor liver enzymes are performed regularly during treatment.^[10]

For gastric and gastroesophageal junction cancers that are HER2-positive, trastuzumab combined with chemotherapy has become a standard treatment option. This combination has been shown to improve survival in patients with advanced HER2-positive gastric cancer compared to chemotherapy alone, though the benefits may not be as dramatic as those seen in breast cancer.^[2]

In HER2-positive colorectal cancer, which represents a small percentage of cases, treatment approaches are still evolving. Standard treatment typically involves combinations of targeted therapies that block both HER2 and another related receptor called EGFR. These combinations may include monoclonal antibodies like trastuzumab and cetuximab or panitumumab together.^[5]

Innovative Treatments in Clinical Trials

The success of first-generation HER2-targeted therapies has spurred extensive research into new and improved treatments. Many promising drugs are currently being tested in clinical trials, offering hope for even better outcomes and options for patients whose cancers have stopped responding to standard therapies.^[9]

Antibody-drug conjugates (ADCs) represent one of the most exciting advances in HER2-targeted therapy. These medications are sometimes called “biological missiles” because they combine a HER2-targeting antibody with a potent chemotherapy drug. The antibody part acts like a guided delivery system, carrying the chemotherapy directly to cancer cells that have HER2 on their surface. Once the ADC attaches to the HER2 receptor, the cancer cell takes it inside, where the chemotherapy is released to kill the cell. This targeted approach means the chemotherapy goes primarily to cancer cells rather than affecting healthy cells throughout the body, potentially reducing side effects while increasing effectiveness.^[9]

Trastuzumab emtansine (T-DM1, brand name Kadcyla) was the first HER2-targeted ADC to be approved. It combines trastuzumab with a powerful chemotherapy agent called DM1. T-DM1 has been approved for HER2-positive breast cancer in various settings, including after prior treatment with trastuzumab and pertuzumab, and as adjuvant therapy for patients with residual disease after neoadjuvant treatment. Common side effects include fatigue, nausea, low platelet counts, and elevated liver enzymes. Compared to traditional chemotherapy regimens, many patients find T-DM1 easier to tolerate, though side effects can still occur.^[10]

Trastuzumab deruxtecan (T-DXd, brand name Enhertu) is a newer ADC that has shown remarkable activity in clinical trials. It combines trastuzumab with a different chemotherapy payload and uses a different linking technology. Clinical trials have demonstrated that trastuzumab deruxtecan can be effective even in patients whose cancers have progressed after multiple prior HER2-targeted therapies. Importantly, it has also shown significant benefit in HER2-low breast cancer, which represents a major breakthrough. This means patients whose cancers were previously considered HER2-negative based on low levels of HER2 expression may now have an effective targeted treatment option.^[9][10]

One potential side effect that requires careful monitoring with trastuzumab deruxtecan is interstitial lung disease—inflammation of the lungs that can cause breathing difficulties. While this side effect is relatively uncommon, it can be serious. Doctors monitor patients for symptoms like cough, shortness of breath, or fever, and may perform lung imaging tests during treatment. If interstitial lung disease develops, the medication is typically stopped, and treatment with corticosteroids may be needed.^[9]

Several other HER2-targeted ADCs are in various phases of clinical development, each with slightly different properties, linking technologies, and chemotherapy payloads. These include molecules with code names being tested in Phase I, Phase II, and Phase III trials around the world. Phase I trials focus on determining the safe dose and identifying side effects. Phase II trials evaluate whether the drug appears effective against the cancer and continues to assess safety in a larger group of patients. Phase III trials compare the new treatment to current standard treatments in large, randomized studies to determine if it offers improved outcomes.^[9]

Newer tyrosine kinase inhibitors are also being developed and tested. Some of these are designed to overcome resistance to first-generation TKIs like lapatinib. Others are designed to be more potent or to target multiple receptors simultaneously. Neratinib and tucatinib are examples of newer-generation TKIs that have been approved or are in late-stage development. These drugs have shown particular promise in treating HER2-positive cancers that have spread to the brain, an area where treatment options have historically been limited.^[10]

Combination strategies are a major focus of current research. Scientists are investigating combinations of different HER2-targeted agents used together, such as combining two monoclonal antibodies, or combining antibodies with tyrosine kinase inhibitors, or using ADCs in combination with other targeted therapies. The rationale is that blocking HER2 in multiple ways simultaneously may be more effective and may prevent cancer cells from developing resistance. Clinical trials are testing these combinations in both early-stage and advanced disease settings.^[8]

Immunotherapy approaches are another exciting area of development. These treatments work by helping the patient’s immune system recognize and attack cancer cells. Strategies being tested include immune checkpoint inhibitors, which remove the “brakes” that prevent immune cells from attacking cancer, and cancer vaccines, which train the immune system to recognize HER2 as a target. Some clinical trials are combining immunotherapy with HER2-targeted therapies to try to achieve even better results.^[10]

Bispecific antibodies are innovative molecules engineered to bind to two different targets simultaneously. HER2-targeted bispecific antibodies might bind to HER2 on the cancer cell with one arm and to an immune cell marker like CD3 with the other arm, physically bringing immune cells and cancer cells together to promote cancer cell killing. These molecules are in early-stage clinical testing, but preliminary results have been encouraging.^[10]

Many of these clinical trials are being conducted in multiple countries, including locations in Europe, the United States, and other regions. Eligibility criteria vary by trial but typically depend on factors such as the type and stage of cancer, previous treatments received, HER2 status, and overall health. Patients interested in clinical trials should discuss options with their oncologists, who can help identify appropriate trials and assess whether participation might be beneficial.^[9]

Most common treatment methods

• Monoclonal Antibodies
  • Trastuzumab (Herceptin) binds to HER2 receptors on cancer cells, blocking growth signals and triggering immune system attack on cancer cells, typically given intravenously every three weeks
  • Pertuzumab (Perjeta) targets a different part of the HER2 receptor, preventing HER2 from pairing with other growth factor receptors, often used in combination with trastuzumab
  • Combination therapy with both antibodies plus chemotherapy provides more complete blockade of HER2 signaling pathways
• Tyrosine Kinase Inhibitors
  • Lapatinib is an oral medication that blocks the internal signaling portion of HER2 and EGFR receptors, preventing growth signals from being transmitted inside the cell
  • Newer agents like neratinib and tucatinib show promise in treating cancers resistant to earlier therapies and those that have spread to the brain
  • These medications are taken as pills daily and work by entering cancer cells to block HER2 signaling from inside
• Antibody-Drug Conjugates
  • Trastuzumab emtansine (T-DM1, Kadcyla) combines trastuzumab with a potent chemotherapy agent, delivering chemotherapy directly to HER2-positive cancer cells
  • Trastuzumab deruxtecan (T-DXd, Enhertu) uses advanced linking technology and has shown effectiveness in HER2-positive and HER2-low cancers
  • These “biological missiles” reduce side effects by targeting chemotherapy specifically to cancer cells with HER2 on their surface
• Combination Chemotherapy and Targeted Therapy
  • Standard approach often includes HER2-targeted antibodies combined with chemotherapy drugs like docetaxel or paclitaxel
  • For gastric and gastroesophageal junction cancers, trastuzumab plus chemotherapy is standard for HER2-positive disease
  • Triple combination regimens with pertuzumab, trastuzumab, and chemotherapy used in both early-stage and metastatic breast cancer
• Emerging Immunotherapy Approaches
  • Immune checkpoint inhibitors being tested in combination with HER2-targeted therapies to enhance immune system recognition of cancer cells
  • HER2-targeted cancer vaccines in development to train the immune system to attack HER2-positive cancer cells
  • Bispecific antibodies designed to simultaneously bind HER2 on cancer cells and immune cell markers to promote cancer cell destruction