HER2 protein overexpression – Diagnostics – Overview of Information and Clinical Research

Understanding how to accurately diagnose HER2 protein overexpression can be the key to selecting the right treatment approach and improving outcomes for patients with certain types of cancer.

Introduction: When Should You Consider HER2 Testing?

If you’ve recently been diagnosed with cancer, particularly breast cancer or stomach cancer, your doctor may recommend testing for something called HER2 protein overexpression. This isn’t something to fear—it’s actually valuable information that helps guide your treatment. HER2, which stands for human epidermal growth factor receptor 2, is a protein that sits on the surface of cells and helps control how they grow and divide. When too much of this protein appears on cancer cells, it can make the cancer grow faster, but it also opens the door to targeted treatments designed specifically for this situation.^[1]

Testing for HER2 status is now a standard part of diagnosing breast cancer and is increasingly important for other cancers too. Every person with invasive breast cancer should have their tumor tested for HER2 because knowing this information is essential for planning the most effective treatment.^[3] The same is true for advanced stomach cancer, especially cancer located where the esophagus joins the stomach. For other types of cancer, HER2 testing may be done in specific situations or as part of clinical trials.^[3]

The reason this test matters so much is because it tells your medical team whether you might benefit from medicines that specifically target HER2. About 10 to 20 percent of breast cancers have what doctors call HER2 protein overexpression or HER2 gene amplification, which means the cancer cells have either too many copies of the HER2 gene or too much HER2 protein on their surface.^[1] In colorectal cancer, HER2 overexpression occurs in about 3 to 5 percent of all cases, but this percentage is higher when other common genetic mutations are not present.^[5]

⚠️ Important

If you had breast cancer that comes back after treatment, or if it spreads to another part of your body, your doctor should consider ordering another biopsy to retest your HER2 status. Research has shown that HER2-positive breast cancer can sometimes become HER2-negative over time or with treatment, and the opposite can happen too—a HER2-negative cancer can become HER2-positive.^[1]

Classic Diagnostic Methods for HER2 Protein Overexpression

Determining whether your cancer has HER2 protein overexpression requires laboratory testing on a sample of your tumor tissue. This sample is typically obtained through a biopsy, which is a procedure where a small piece of tissue is removed for examination. In breast cancer, this testing is usually done on the primary tumor at the time of diagnosis, alongside other important tests that look at hormone receptors.^[3] For stomach cancer and other cancers, the approach is similar—testing is performed on tissue from the primary tumor site.^[3]

The Two Main Testing Methods

There are two primary laboratory tests that doctors use to check for HER2 protein overexpression. Each works differently, but both help determine whether your cancer cells have too much HER2. Often, if one test gives an unclear result, the other test will be used to get a more definite answer.^[1]

The first method is called immunohistochemistry, or IHC for short. This test uses special chemicals and dyes to stain the HER2 proteins in your tumor sample. When viewed under a microscope, the pathologist can see how much HER2 protein is present on the surface of the cancer cells. The IHC test provides a score ranging from 0 to 3+, which reflects the amount of HER2 protein detected.^[1]

Here’s what the different IHC scores mean: If your result comes back as 0 or 1+, the cancer is generally considered HER2-negative, meaning it has normal or only slightly elevated levels of HER2 protein. A score of 1+ may sometimes be called HER2-low, which is a newer category that recognizes there’s a small amount of extra HER2 present, though not enough to be HER2-positive.^[1] When the test shows a score of 2+, it’s called borderline or equivocal—the result isn’t clear enough to make a definite determination. In this case, your doctor will likely order a second type of test to clarify your HER2 status.^[1] A score of 3+ indicates HER2-positive cancer, meaning there’s definitely too much HER2 protein present.^[1]

The second testing method is called fluorescence in situ hybridization, or FISH. Unlike the IHC test, which looks at proteins, the FISH test examines the actual genes inside the cancer cells. It uses fluorescent probes—special molecular markers that glow under certain light—that attach directly to the HER2 genes on the chromosomes. By counting how many copies of the HER2 gene are present, the test can determine if there’s gene amplification, which means the cancer cells have too many copies of the gene.^[1]

FISH test results are reported as either positive or negative. A negative result means the levels of the HER2 gene in the cells are normal, so the tumor is HER2-negative. A positive FISH result means there are, on average, at least four copies of the HER2 gene in the cells, indicating the tumor is HER2-positive.^[3]

Additional Testing Options

Besides IHC and FISH, there’s another advanced method called next-generation sequencing, or NGS. This is a newer technology that can analyze many genes at once, including HER2. NGS is particularly useful in research settings and in some specialized clinical situations, especially when doctors want to look for specific mutations or changes in the HER2 gene rather than just counting how many copies are present.^[5]

The choice of which test to use first often depends on the laboratory’s capabilities and the specific type of cancer being examined. In many cases, the IHC test is performed first because it’s widely available and relatively quick. If the IHC result is clearly negative (0 or 1+) or clearly positive (3+), that may be enough information. But when the result falls in the middle (2+), the FISH test provides additional clarity.^[1]

Understanding HER2-Low and HER2-Ultralow

As scientists have learned more about HER2, they’ve discovered that the old way of simply calling cancers either positive or negative wasn’t telling the whole story. More than half of breast cancers that were traditionally considered HER2-negative actually have some extra HER2 proteins on their cell surfaces—just not enough to meet the threshold for being called HER2-positive.^[1]

This realization has led many doctors to start using new terms like HER2-low and HER2-ultralow to describe these cancers. This matters because some newer treatments have shown promise in treating cancers with even small amounts of extra HER2 protein. However, there’s still some debate in the medical community about whether HER2-low should be considered a distinct subtype of cancer or simply a variation within the HER2-negative category.^[1]

What Makes HER2-Positive Cancer Different

When normal cells function properly, they have two copies of the HER2 gene, which is the right amount to keep cell growth under control. But in some cancer cells, something goes wrong and the gene makes too many copies of itself—this is called gene amplification. All those extra copies tell the cells to produce too many HER2 protein receptors on the cell surface. When there are too many receptors receiving signals, it’s like having too many people shouting instructions at once—the cells respond by growing and dividing in an uncontrolled way.^[1]

Cancers with HER2 protein overexpression tend to be more aggressive than those without it. They often grow faster and are more likely to spread to other parts of the body or come back after treatment. Historically, before targeted treatments became available, HER2-positive cancers were associated with worse outcomes. But the good news is that this has changed dramatically—the discovery of medicines that specifically target HER2 has transformed what it means to have a HER2-positive cancer.^[2]

Testing Requirements for Clinical Trial Participation

If you’re interested in participating in a clinical trial to access new or experimental treatments, HER2 testing becomes even more important. Clinical trials studying treatments for HER2 protein overexpression typically have very specific criteria about who can enroll, and proof of your HER2 status is almost always required.

For clinical trials focused on HER2-targeted therapies, researchers need to confirm not just that your cancer is HER2-positive, but also exactly how positive it is. This is because different experimental treatments may work better for cancers with very high levels of HER2 compared to those with moderate levels. Some trials may accept patients with HER2-low status, while others require a score of 3+ on IHC testing or a positive FISH result.^[6]

Clinical trial protocols often specify which testing method must be used to confirm HER2 status before you can enroll. Some trials may require both IHC and FISH testing, or they may accept only one method. The testing usually needs to be done at a certified laboratory that follows specific quality standards to ensure the results are accurate and reliable. Your oncologist can help you understand what testing documentation is needed if you’re considering a particular trial.

It’s also worth knowing that some clinical trials may offer free HER2 testing as part of the screening process to determine if you’re eligible. If your original diagnosis didn’t include HER2 testing, or if your cancer has changed since your initial diagnosis, the trial sponsors might arrange for new testing to be done. This can be particularly valuable if you’re concerned about the cost of repeat testing or if you need more detailed analysis than what was done initially.^[5]

⚠️ Important

The HER2 gene is also known by another name—ERBB2, which stands for Erb-B2 receptor tyrosine kinase 2. You might see it referred to by this name in some research studies, pathology reports, or clinical trial documents. They’re the same thing, just different names used by scientists and doctors.^[1] Don’t be confused if you see both terms; they refer to the exact same gene and protein.

Some research studies are specifically looking at what happens when HER2 status changes over time. These trials may require testing samples from both your original tumor and any new tumors or metastases that have developed. This repeated testing helps scientists understand how cancer evolves and how treatments might need to change as well. If you had HER2-positive cancer initially but later developed new tumors, knowing whether those new tumors are still HER2-positive is crucial information for both treatment and research purposes.^[1]

Clinical trials are also exploring treatments for cancers in organs where HER2 overexpression is less common but still occurs. While HER2 testing is standard for breast and stomach cancers, it’s being studied more actively in ovarian, bladder, lung, and colon cancers. If you have one of these cancer types and are interested in a clinical trial, you may need to have HER2 testing done even though it’s not routinely performed for your particular cancer.^[3] This is how medical science advances—by testing whether treatments that work for one type of cancer might help patients with other HER2-positive cancers as well.

Prognosis and Survival Rate

Prognosis

The outlook for patients with HER2 protein overexpression has changed dramatically over the past few decades. Historically, before targeted treatments were available, HER2-positive cancers were associated with more aggressive disease and worse outcomes. These cancers tended to grow faster, spread more readily to other parts of the body, and were more likely to come back after treatment compared to HER2-negative cancers.^[1]

However, the development of medicines specifically designed to target HER2 has completely transformed the prognosis for these patients. Today, many doctors note that outcomes for HER2-positive breast cancer have become comparable to other subtypes of breast cancer when appropriate HER2-targeted treatments are used. The key factor affecting prognosis now is whether the cancer is identified as HER2-positive early enough to receive targeted therapy, and how well the cancer responds to treatment.^[7]

Several factors influence the prognosis beyond just HER2 status. These include the stage of cancer at diagnosis, whether it has spread to lymph nodes or other organs, the grade of the tumor, and other characteristics like hormone receptor status. The combination of these factors helps doctors predict outcomes and plan the most effective treatment strategy. For breast cancer specifically, when HER2-positive disease is caught early and treated with the combination of chemotherapy and HER2-targeted therapy, the reduction in risk of recurrence can be as much as 50 percent compared to chemotherapy alone.^[7]

Survival rate

While specific survival statistics for HER2 protein overexpression vary depending on the type of cancer, stage at diagnosis, and treatment received, the introduction of HER2-targeted therapies has led to significant improvements in both disease-free survival and overall survival. For HER2-positive breast cancer patients receiving modern targeted treatments, studies have shown dramatic benefits compared to the era before these medicines were available.^[7]

In the setting of early-stage HER2-positive breast cancer treated with surgery, chemotherapy, and HER2-targeted therapy, many patients achieve long-term remission. The exact survival rates depend on many individual factors including tumor size, lymph node involvement, and response to treatment. What’s most encouraging is that even patients with metastatic HER2-positive breast cancer—where the cancer has spread to other organs—can sometimes experience remissions lasting years when treated with HER2-targeted therapies, although these remissions may be temporary.^[7]

It’s important to remember that survival statistics are based on groups of people and cannot predict what will happen to any individual patient. Each person’s cancer is unique, and factors like overall health, specific tumor characteristics, response to treatment, and access to newer therapies all play important roles in determining outcomes. The field of HER2-targeted treatment continues to evolve rapidly, with new medicines and treatment combinations regularly becoming available, which means that survival rates continue to improve over time.

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