HER2 positive gastric cancer is a specific type of stomach or gastroesophageal junction cancer where tumor cells produce too much of a protein called HER2. Accurate testing to identify this protein is essential, as it determines which patients can benefit from targeted therapies that have changed the treatment landscape for this challenging disease.

Introduction: Who Should Be Tested for HER2 Positive Gastric Cancer

Anyone diagnosed with stomach cancer or cancer at the gastroesophageal junction—the place where the esophagus meets the stomach—should undergo testing to determine their HER2 status. This testing has become a standard part of diagnosing and understanding gastric cancer because it directly impacts which treatments will be most effective for each individual patient.^[1]

Testing for HER2 is especially important for people with advanced or metastatic gastric cancer, which means the cancer has spread beyond its original location to other parts of the body. About 15 percent of people with advanced stomach cancer and approximately 30 percent of those with advanced gastroesophageal junction cancer have tumors that test positive for HER2.^[2] When looked at overall, roughly 20 percent of all gastric cancers show increased levels of the HER2 protein, making this an important group of patients who may benefit from specific targeted treatments.^[6]

The discovery that some gastric cancers overexpress HER2 represented a significant breakthrough in understanding the disease. Before this knowledge, all stomach cancers were treated similarly, but now doctors recognize that HER2-positive gastric cancer is its own distinct disease entity, similar to how HER2-positive breast cancer is understood.^[1] This distinction matters because it has led to the development and approval of medications that specifically target the HER2 protein, offering better outcomes than traditional chemotherapy alone.

Understanding HER2 and Why It Matters

To understand HER2 testing, it helps to know what HER2 actually is. Human epidermal growth factor receptor 2, or HER2 for short, is a type of protein found on the surface of all cells in the body. In healthy cells, this protein plays a normal role in helping cells grow and divide in a controlled way.^[1]

However, in some cancers, something goes wrong with the gene that controls HER2 production. The gene, called ERBB2, can become amplified, meaning there are too many copies of it. This amplification leads to an overproduction of HER2 protein on the surface of cancer cells. When there are too many HER2 receptors, cancer cells receive too many growth signals, causing them to multiply rapidly and the cancer to grow and spread more aggressively.^[13]

When a cancer has too much HER2 protein, it is called HER2-positive. This overexpression is associated with more aggressive disease behavior and historically was linked to poorer outcomes. However, the identification of HER2 as a target has transformed this from solely a marker of aggressive disease into an opportunity for more effective treatment with targeted therapies.^[1]

Standard Diagnostic Methods for HER2 Testing

Testing for HER2 in gastric cancer requires specialized laboratory techniques performed on tissue samples from the tumor. The process begins when a doctor removes a small piece of tumor tissue through a procedure called a biopsy. This tissue is then sent to a pathology laboratory where trained specialists examine it under a microscope and perform specific tests to measure HER2 levels.

The two main methods used to detect HER2 in gastric cancer are immunohistochemistry, commonly referred to as IHC, and in situ hybridization, often abbreviated as ISH. These methods look at different aspects of HER2—IHC measures the amount of HER2 protein on the cell surface, while ISH looks at whether there are extra copies of the HER2 gene inside the cell.^[4]

Immunohistochemistry is typically the first test performed. This technique uses special antibodies that bind to HER2 protein, and the results are scored on a scale from 0 to 3+. A score of 0 or 1+ means the cancer is HER2-negative. A score of 3+ indicates strong positive staining and means the cancer is HER2-positive. A score of 2+ is considered equivocal or uncertain, and these cases require additional testing with ISH to determine the final HER2 status.^[4]

In situ hybridization testing can be done using different techniques, including fluorescence in situ hybridization (FISH) or other methods. This test looks directly at the tumor cell’s DNA to count how many copies of the HER2 gene are present. If there are too many copies—meaning the gene is amplified—the result is positive, confirming HER2-positive status.^[4]

Challenges in HER2 Testing for Gastric Cancer

One unique challenge with HER2 testing in gastric cancer is something called tumor heterogeneity. This means that within the same tumor, some areas might show high levels of HER2 while other areas show low or no HER2 expression. This variation within a single tumor is more common in gastric cancer than in breast cancer and can make testing more complex.^[6]

Because of this heterogeneity, pathologists must carefully examine multiple areas of the tumor tissue and follow standardized scoring systems. The interpretation requires expertise and adherence to established guidelines to ensure that patients who could benefit from HER2-targeted therapy are correctly identified, while those who would not benefit are not exposed to unnecessary treatments.^[4]

Another consideration is that HER2 status can sometimes change during the course of disease or after treatment. While initial testing is typically done on the primary tumor at diagnosis, in some cases doctors may recommend repeat testing on tissue from metastatic sites or recurrent disease. This helps confirm whether the cancer remains HER2-positive and whether HER2-targeted therapy continues to be appropriate.

Additional Testing for Treatment Planning

While HER2 testing is the most critical biomarker for determining targeted therapy options, doctors may also test for other markers that influence treatment decisions. One such marker is PD-L1, a protein that helps cancer cells hide from the immune system. Testing for PD-L1 levels has become increasingly important because newer treatment approaches combine HER2-targeted drugs with immunotherapy medications.^[2]

PD-L1 testing uses a scoring system called the combined positive score, or CPS. This score helps doctors determine whether adding an immunotherapy drug to the treatment regimen is likely to be beneficial. For example, recent clinical trials have shown that for HER2-positive gastric cancer, adding pembrolizumab (an immunotherapy drug) to trastuzumab (a HER2-targeted drug) and chemotherapy improved outcomes, but primarily in patients whose tumors had a PD-L1 CPS of 1 or greater.^[2]

In fact, current treatment guidelines now specify that the combination of pembrolizumab with trastuzumab and chemotherapy should only be used in HER2-positive gastric cancer patients whose tumors also show elevated PD-L1 levels. Patients whose tumors had little or no PD-L1 did not benefit from this combination and may have had worse outcomes compared to treatment without immunotherapy.^[2]

Diagnostic Testing for Clinical Trial Enrollment

Patients interested in participating in clinical trials for HER2-positive gastric cancer must undergo specific testing to confirm they meet the study’s eligibility requirements. These tests typically include confirmation of HER2 status using approved testing methods, and often require that the testing has been done recently or at a certified laboratory.

Clinical trials may have very specific criteria for what level of HER2 expression qualifies a patient for enrollment. For instance, some trials may require IHC 3+ or IHC 2+/ISH+ results, meaning patients need either the highest level of protein expression or a combination of moderate protein expression with confirmed gene amplification.^[10]

Beyond HER2 testing, clinical trial participation often requires additional assessments to confirm the cancer’s stage, location, and whether it has been previously treated. Many trials are designed for specific settings, such as first-line treatment (meaning the patient has not yet received any systemic therapy for metastatic disease) or second-line or later treatment (after previous therapies have stopped working). The KEYNOTE-811 trial, for example, enrolled patients with previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer and required both HER2 and PD-L1 testing.^[2]

Other clinical trials may test new HER2-targeted drugs or combinations. The DESTINY-Gastric trials, for instance, evaluated an antibody-drug conjugate called trastuzumab deruxtecan in patients with HER2-positive gastric cancer. These studies had specific HER2 testing requirements to ensure enrolled patients had sufficient HER2 expression to potentially benefit from the treatment being studied.^[20]

Other Diagnostic Tests Used in Gastric Cancer Care

While HER2 and PD-L1 testing are biomarker tests done on tumor tissue, patients with gastric cancer also undergo various other diagnostic procedures to determine the extent of disease and monitor response to treatment. These include imaging studies such as computed tomography (CT) scans, which create detailed cross-sectional pictures of the body to show where cancer is located and whether it has spread to other organs.

An endoscopy is another common procedure where a thin, flexible tube with a camera is passed through the mouth into the stomach to directly visualize the tumor and obtain biopsy samples. This is often the first procedure done when gastric cancer is suspected and is the source of tissue for HER2 testing.

Blood tests are routinely performed to assess overall health, check organ function, and sometimes to measure tumor markers, although no blood test can definitively diagnose HER2 status. The HER2 determination must be made from tumor tissue itself. Other imaging studies like ultrasound, magnetic resonance imaging (MRI), or positron emission tomography (PET) scans may be used in certain situations to better characterize the cancer or assess treatment response.

The Role of FDA-Approved Tests

For HER2 testing to be used in making treatment decisions, it must be performed using methods that have been validated and approved by regulatory agencies such as the Food and Drug Administration (FDA) in the United States. These approved tests, often called companion diagnostics, have been specifically evaluated to ensure they accurately identify patients who will benefit from particular HER2-targeted therapies.^[9]

When clinical trials demonstrate that a HER2-targeted drug is effective in gastric cancer, the drug’s approval is typically linked to a specific HER2 testing method. This ensures that in clinical practice, patients are selected for treatment using the same testing approach that was used in the successful clinical trials. Healthcare providers should specify that HER2 testing should be performed using an FDA-approved test when ordering these studies.^[4]