HER2 in Gastric and Gastroesophageal Junction Cancer

HER2, also known as ERBB2, is a gene that drives cancer cell growth when overactive. HER2 is best known in breast cancer, but it is also one of the most important biomarkers in cancer of the stomach (gastric cancer) and the gastroesophageal junction (the area where the esophagus meets the stomach). A “biomarker” is a measurable feature of cancer, such as a change in a gene or a protein on the surface of cells, that provides doctors with information they cannot get from looking at the cells under the microscope alone. When a gastric or gastroesophageal junction cancer is HER2-positive, the tumor may respond to a group of medicines that specifically target the HER2 protein.

This article will help you understand what a HER2 result means on a pathology report for gastric or gastroesophageal junction cancer, why the test is done, how it is performed, and how the result may guide treatment decisions. HER2 testing is now a standard part of the workup for these cancers when they are advanced. Finding a HER2 alteration does not change what type of cancer you have, and it is not an inherited change passed down in families. It is a change that happened within the tumor itself, and its main importance is that it opens up specific treatment options.

What HER2 is and what it does

HER2 is a gene that provides the instructions for making a protein, the HER2 receptor, that sits on the surface of cells and helps receive signals telling the cell to grow and divide. In a healthy cell, a normal amount of HER2 protein is present and helps regulate growth in a controlled way. When the HER2 gene is amplified, meaning extra copies of the gene are present, the cell produces far too much HER2 protein. This floods the cell surface with receptors that continuously send growth signals, even when the cell should stop dividing. The result is uncontrolled growth that drives the tumor.

In gastric and gastroesophageal junction cancers, HER2 becomes overactive almost always because of a somatic alteration, a change that occurs in the cancer cells during a person’s lifetime rather than one inherited from a parent. The usual mechanism is amplification of the HER2 gene, which leads to overexpression of the HER2 protein on the surface of the cancer cells. Because this overactive protein can be specifically blocked by targeted drugs, identifying it is an important step in planning treatment for advanced disease.

How common is HER2 alteration in gastric and gastroesophageal junction cancer?

HER2 overexpression or amplification is found in approximately 10-15% of gastric and gastroesophageal junction cancers. The frequency is not the same across all these tumors, and a few patterns are worth understanding because they affect the likelihood of a HER2-positive result.

Location — HER2 positivity is somewhat more common in cancers of the gastroesophageal junction and the upper stomach than in cancers of the lower stomach.
Microscopic type — Gastric cancers are often divided into an intestinal type and a diffuse type based on how the cells look and grow under the microscope. HER2 positivity is more common in the intestinal type than in the diffuse type.
Tumor heterogeneity — Gastric cancers are well known for being “heterogeneous,” meaning the HER2 protein may be present in some areas of the tumor and absent in others. This is more pronounced than in breast cancer and is the main reason the testing rules for gastric cancer were designed differently, as described below.

Why is the test done?

HER2 testing in gastric and gastroesophageal junction cancer is done mainly to determine whether the tumor is likely to respond to HER2-targeted therapy. A positive result identifies patients who may benefit from drugs that block the HER2 protein, and current guidelines recommend HER2 testing for all patients with advanced (locally advanced, recurrent, or metastatic) gastric or gastroesophageal junction cancer as part of standard testing. Because HER2-targeted drugs only work when the HER2 protein is overactive, the test is used to decide whether these drugs are an option.

HER2 testing is typically performed at the time the cancer is first found to be advanced, often on the original biopsy. The result is one of several biomarkers, alongside PD-L1 and others, that together shape the choice of first-line treatment. HER2 testing is generally not needed for very early-stage cancers that are surgically removed with no evidence of spread, because HER2-targeted drugs are used in the advanced setting.

How the test is performed

HER2 testing in gastric and gastroesophageal junction cancer is performed on tumor tissue from a biopsy or a surgically removed specimen. Two tests are used, often in sequence, and the criteria for calling a result positive were adapted specifically for gastric cancer because these tumors stain differently from breast cancer and tend to be more heterogeneous.

Immunohistochemistry (IHC)

Immunohistochemistry (IHC) is usually the first step. This test uses antibodies to stain the tissue for the HER2 protein, and a pathologist evaluates the staining pattern and intensity under the microscope. Results are reported on a scale of 0 to 3+:

0 (negative) — No staining, or membrane staining in fewer than 10 percent of tumor cells (on a resection) or in fewer than five clustered cells (on a biopsy). The tumor is HER2-negative.
1+ (negative) — Faint, barely perceptible membrane staining. The tumor is HER2-negative.
2+ (equivocal) — Weak to moderate complete, basolateral, or lateral membrane staining. The result is uncertain and requires additional testing with in situ hybridization to determine whether the HER2 gene is truly amplified.
3+ (positive) — Strong complete, basolateral, or lateral membrane staining. The tumor is HER2-positive.

Two features of gastric HER2 scoring differ from those of breast cancer. First, the staining is often “basolateral” or “lateral” rather than wrapping all the way around the cell, resulting in an incomplete U-shaped pattern that still counts as positive. Second, the thresholds differ between a small biopsy and a larger surgical specimen: on a biopsy, even a small cluster of strongly stained cells (at least five) can be enough to call a result positive, because the tumor may be heterogeneous and the biopsy samples only a small part of it. On a resection specimen, staining must be present in at least 10 percent of the tumor cells.

In situ hybridization (ISH or FISH)

In situ hybridization (ISH), including the fluorescent form called FISH, directly quantifies the number of HER2 gene copies in tumor cells. If there are significantly more copies than normal, the gene is amplified, and the result is positive. ISH is usually performed when the IHC result is 2+ (equivocal) to settle whether true amplification is present. An IHC result of 3+ is considered positive without needing ISH, and a result of 0 or 1+ is considered negative.

Next-generation sequencing (NGS)

Next-generation sequencing (NGS) can simultaneously assess many genes and detect HER2 amplification alongside other relevant biomarkers in a single test. As comprehensive molecular profiling becomes more common in advanced gastric and gastroesophageal junction cancer, NGS is increasingly used to detect HER2 amplification together with markers such as MMR status and others. IHC remains the standard starting point for HER2 specifically.

How results are reported

HER2 results in gastric and gastroesophageal junction cancer appear in the biomarker or molecular testing section of the pathology report. Common ways the result is described include:

HER2-negative (IHC 0 or 1+) — The tumor does not show meaningful HER2 protein overexpression. HER2-targeted therapy is not indicated based on this result.
HER2 equivocal (IHC 2+) — The result is uncertain, and in situ hybridization is needed to determine whether the HER2 gene is amplified. The report may note that this reflex testing has been or will be ordered.
HER2-positive (IHC 3+, or IHC 2+ with ISH amplification confirmed) — The tumor overexpresses the HER2 protein and/or shows HER2 gene amplification. This result may make a patient eligible for HER2-targeted therapy.
HER2 amplification by NGS — If tested by next-generation sequencing, the report may describe HER2 amplification as an increase in gene copy number. The interpretation depends on the degree of amplification and the overall testing context.

What the result means

HER2-negative

A HER2-negative result means HER2-targeted therapy is not indicated based on this test. This is the most common result, because most gastric and gastroesophageal junction cancers are HER2-negative. A negative HER2 result does not affect eligibility for other treatments; the care team will consider options based on other findings, including PD-L1 status, mismatch repair (MMR) status, and, in the stomach, Claudin 18.2, each of which is described in its own article.

HER2 equivocal (IHC 2+)

An equivocal result means the IHC staining falls within an intermediate range that cannot, on its own, confirm whether meaningful HER2 overexpression is present. In situ hybridization is then performed to check whether the HER2 gene is amplified. If amplification is confirmed, the tumor is reclassified as HER2-positive; if it is not confirmed, the tumor is reclassified as HER2-negative. If the report currently shows 2+, the care team will explain whether confirmatory testing has been ordered and what to expect next.

HER2-positive

A HER2-positive result, confirmed by IHC 3+ staining or by ISH-confirmed amplification in an IHC 2+ case, is an actionable finding in advanced gastric and gastroesophageal junction cancer. It means the tumor is driven partly by overactivity of the HER2 receptor, and HER2-targeted therapy may be effective. Because gastric cancers can be heterogeneous, a HER2-positive result reflects the areas of the tumor that were tested, which is one reason testing is done carefully and sometimes repeated if a cancer is re-biopsied later.

Treatment implications of HER2-positive gastric and gastroesophageal junction cancer

The HER2 result helps the treatment team determine whether HER2-targeted drugs should be included in the plan. The pathology report does not prescribe treatment; instead, a HER2-positive result identifies an option that the medical oncology team discusses with the patient, weighing it alongside PD-L1 status, the stage of the cancer, prior treatments, and overall health.

Trastuzumab with chemotherapy (first-line)

Trastuzumab (Herceptin) is a monoclonal antibody, a laboratory-made protein that binds to the HER2 receptor on the cell surface and blocks its activity. For advanced HER2-positive gastric and gastroesophageal junction cancer, adding trastuzumab to first-line chemotherapy has been a standard approach since the ToGA trial showed that this combination improved survival compared with chemotherapy alone. This was the first targeted therapy approved for these cancers and remains a foundation of treatment for HER2-positive disease.

Adding immunotherapy (pembrolizumab)

More recently, the immune checkpoint inhibitor pembrolizumab (Keytruda) has been added to trastuzumab plus chemotherapy as a first-line option for HER2-positive gastric and gastroesophageal junction cancer, based on the KEYNOTE-811 trial. This is one reason HER2 and PD-L1 are often considered together: the combination of a HER2-positive result and PD-L1 status helps the team decide whether to add immunotherapy to HER2-targeted treatment. Your oncologist will explain how your specific results fit together.

Trastuzumab deruxtecan (Enhertu; T-DXd)

Trastuzumab deruxtecan (T-DXd; Enhertu) is an antibody-drug conjugate. It links the HER2-targeting antibody trastuzumab to a chemotherapy payload. The antibody acts as a delivery vehicle that finds cells expressing the HER2 receptor; once the drug binds to HER2 and is taken up by the cancer cell, it releases the chemotherapy inside, killing the cell from within. T-DXd is approved for HER2-positive gastric and gastroesophageal junction cancer that has progressed after prior HER2-targeted treatment, based on the DESTINY-Gastric trials, and provides an option in the later-line setting. T-DXd carries a specific safety concern, interstitial lung disease (inflammation of the lung tissue), that requires monitoring, which the oncology team will discuss if this drug is considered.

How the options fit together

For most patients with advanced HER2-positive disease, trastuzumab combined with chemotherapy (with pembrolizumab added in appropriate cases) is used first, and T-DXd is considered later if the cancer progresses. The exact sequence depends on PD-L1 status, prior treatments, overall health, and the specific features of the cancer. Because HER2 status can occasionally change over time or differ between the original tumor and sites of spread, retesting is sometimes considered when a cancer is re-biopsied.

Does HER2 status have hereditary implications?

In gastric and gastroesophageal junction cancer, HER2 amplification is almost always somatic, meaning it arises within the cancer cells during a person’s lifetime and is not inherited. A HER2 result, therefore, does not indicate an inherited cancer risk for family members and does not, on its own, prompt genetic counseling or family testing. Inherited risk for gastric cancer is evaluated through other pathways, such as testing related to mismatch repair (MMR) status and certain inherited syndromes, rather than through HER2 status. A HER2 result on the pathology report is about guiding treatment for the cancer that is already present.

What happens next

Once HER2 testing is complete, the result becomes part of the information the treatment team uses to plan care. The next steps depend on the result:

If the result is HER2-negative (IHC 0 or 1+), HER2-targeted therapy is not indicated, and the treatment plan proceeds based on other biomarkers (such as PD-L1, MMR status, and Claudin 18.2 in the stomach) and the stage of the cancer.
If the result is HER2 equivocal (IHC 2+), in situ hybridization is performed to determine whether the HER2 gene is amplified, and the care team explains the next steps once that confirmation is complete.
If the result is HER2-positive, the oncology team discusses HER2-targeted treatment, typically trastuzumab with chemotherapy as first-line therapy (with pembrolizumab added in appropriate cases), and T-DXd in later-line settings, taking into account PD-L1 status, prior treatments, and overall health.

Care for these cancers usually involves a multidisciplinary team that may include a medical oncologist, a surgeon, a radiation oncologist, a gastroenterologist, and a pathologist. The medical oncologist generally leads decisions about systemic therapy. If HER2-targeted therapy is started, patients are monitored for response and side effects, and regular imaging and follow-up visits are used to track the canceris response.

Questions to ask your doctor

Was my gastric or gastroesophageal junction cancer tested for HER2, and what was the result?
If my result was IHC 2+ (equivocal), has in situ hybridization been ordered to confirm or rule out HER2 amplification?
If my tumor is HER2-positive, am I a candidate for trastuzumab with chemotherapy?
Should immunotherapy with pembrolizumab be added to my treatment, and how does my PD-L1 result affect that decision?
If my cancer progresses, would trastuzumab deruxtecan (T-DXd) be an option for me?
What side effects should I watch for with HER2-targeted therapy, including the lung-related risks associated with T-DXd?
Could my HER2 result differ between the original tumor and other sites, and might I need to be retested?
How do my other biomarker results, such as PD-L1, MMR status, and Claudin 18.2, fit together with my HER2 result?
If my tumor is HER2-negative, what treatment options are available to me?
Does my HER2 result have any implications for my family members?