Claudin 18.2 in Gastric and Gastroesophageal Junction Cancer

Claudin 18.2 is a protein that helps cells in the lining of the stomach stick tightly together. It is one of the newest biomarkers in adenocarcinoma of the stomach (gastric cancer) and adenocarcinoma of the esophagus, including cancer of the gastroesophageal junction (the area where the esophagus meets the stomach), because it can be targeted by a recently approved drug. A “biomarker” is a measurable feature of cancer, such as 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 one of these cancers makes enough claudin 18.2 in the right pattern, the tumor may respond to a medicine designed to attack cells that carry this protein.

This article will help you understand what a claudin 18.2 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. Claudin 18.2 testing has become part of the workup for these cancers when they are advanced. A claudin 18.2 result is not an inherited change passed down in families. It is a feature of the cancer itself, and its main purpose is to identify patients who may benefit from claudin 18.2-targeted treatment.

What claudin 18.2 is and what it does

Claudin 18.2 is a tight junction protein, meaning its normal job is to act like a seal between neighboring cells, helping them stick together and keeping the contents of the stomach from leaking between them. It is a specific form of the protein claudin 18, and in healthy tissue it is found almost exclusively in the lining of the stomach. In a normal stomach cell, claudin 18.2 is tucked away in the seals between cells, where the immune system and most drugs cannot reach it.

When a stomach cell becomes cancerous, the cell’s structure breaks down, and claudin 18.2 is exposed on the cell’s outer surface, where it can be reached from the outside. This is what makes it useful as a treatment target. A drug that recognizes claudin 18.2 can bind to the surface of these cancer cells and flag them for destruction by the immune system, while largely sparing normal cells, which keep the protein hidden. Because claudin 18.2 is normally limited to the stomach lining, it is an unusually specific target. Adenocarcinomas of the esophagus and the gastroesophageal junction can also express claudin 18.2, because these cancers arise from gland-forming cells closely related to those of the stomach.

How common is claudin 18.2 expression in gastric and gastroesophageal junction cancer?

Claudin 18.2 is expressed at levels sufficient for treatment in roughly 38 percent of advanced gastric and gastroesophageal junction cancers that are HER2-negative. In other words, a little more than a third of these cancers qualify as claudin 18.2-positive using the threshold that matters for treatment. Claudin 18.2 status is largely independent of the other major gastric biomarkers: it overlaps very little with HER2 and only partly with PD-L1. Because of this, claudin 18.2 testing can identify a treatment option for patients whose cancers do not qualify for HER2-targeted therapy, which is why it is typically tested in HER2-negative tumors.

Why is the test done?

Claudin 18.2 testing in gastric and gastroesophageal junction cancer is done to identify patients who may benefit from claudin 18.2-targeted therapy. Claudin 18.2 is a protein that becomes exposed on the surface of stomach cancer cells, and a positive result indicates that a drug targeting this protein may be effective. Current practice is to test claudin 18.2 in patients with advanced (locally advanced, unresectable, recurrent, or metastatic) HER2-negative gastric or gastroesophageal junction cancer, as part of the standard panel of biomarkers used to plan first-line treatment.

Claudin 18.2 is one of several biomarkers considered together. HER2 is usually assessed first, and claudin 18.2 testing is most relevant in HER2-negative tumors. PD-L1 and mismatch repair (MMR) status are also evaluated because they indicate eligibility for immunotherapy. Together these results help the treatment team decide which targeted or immune treatment to combine with chemotherapy. Claudin 18.2 testing is generally not needed for very early-stage cancers that are removed surgically with no evidence of spread, because the targeted drug is used in the advanced setting.

How the test is performed

Claudin 18.2 testing in gastric and gastroesophageal junction cancer is performed on tumor tissue from a biopsy or a surgically removed specimen, using a method called immunohistochemistry (IHC). In this method, an antibody is used to stain the claudin 18.2 protein on a thin slice of the tumor on a glass slide, and a pathologist examines how strongly, and in what pattern, the protein is present.

The pathologist looks specifically at staining around the outer edge (membrane) of the cancer cells because the membrane is where claudin 18.2 is exposed and accessible to the drug. The staining is scored for both how much of the tumor is stained and how strong the staining is. The strength is graded on a scale from 0 (no staining) to 3+ (strong staining). The test can be performed on tissue from the original tumor or from a site where the cancer has spread.

How results are reported

Claudin 18.2 results in gastric and gastroesophageal junction cancer describe whether the protein is present on the surface of the cancer cells at the level needed for targeted treatment. The report combines the strength of staining and the proportion of cancer cells stained into a positive or negative result.

Claudin 18.2 positive — At least 75 percent of the cancer cells show moderate to strong (2+ to 3+) staining around their membranes. This is the threshold used to qualify for claudin 18.2-targeted therapy. A positive result indicates the cancer may respond to a drug directed against claudin 18.2.
Claudin 18.2 negative — Fewer than 75 percent of the cancer cells show moderate to strong membrane staining. This result indicates that claudin 18.2-targeted therapy is not expected to be effective, and the treatment team will focus on other options based on HER2, PD-L1, and MMR status.

Some reports also describe the staining intensity and the percentage of cells stained separately, which the pathologist combines to reach the positive or negative result. Because claudin 18.2 can be present in some areas of a tumor and absent in others, the result reflects the tissue that was tested.

What the result means for treatment

The claudin 18.2 result helps the treatment team decide whether a claudin 18.2-targeted drug belongs in the plan for advanced HER2-negative gastric or gastroesophageal junction cancer. The pathology report does not prescribe treatment; instead, a positive result identifies an option for the medical oncology team to discuss with the patient, weighing it alongside PD-L1 status, MMR status, the stage of the cancer, and overall health.

The first drug of this kind is zolbetuximab (Vyloy), a monoclonal antibody, which is a laboratory-made protein designed to attach to a specific target. Zolbetuximab binds to claudin 18.2 on the surface of the cancer cells and flags them for destruction by the immune system. For advanced HER2-negative, claudin 18.2-positive gastric or gastroesophageal junction cancer, adding zolbetuximab to first-line chemotherapy has been shown to improve survival compared with chemotherapy alone, in the clinical trials known as SPOTLIGHT and GLOW. Zolbetuximab is given together with standard chemotherapy rather than on its own.

Because zolbetuximab acts on claudin 18.2 in the stomach lining, its most common side effects are nausea and vomiting, particularly with the first doses. The treatment team manages this with anti-nausea medicines and by adjusting how the drug is given. When a cancer is claudin 18.2-negative, this drug is not expected to help, and the team focuses on other approaches, including immunotherapy when PD-L1 or MMR status supports it. Beyond zolbetuximab, other claudin 18.2-directed treatments, including antibody-drug conjugates and cell-based therapies, are being studied in clinical trials.

How claudin 18.2 fits with other gastric biomarkers

Claudin 18.2 is one of several biomarkers tested together in advanced gastric and gastroesophageal junction cancer, and it occupies its own place among them. HER2, a protein that when overactive can be blocked by HER2-targeted drugs, is usually assessed first; claudin 18.2 is most useful in HER2-negative tumors. PD-L1, measured by a combined positive score (CPS), and mismatch repair (MMR) status both point toward immunotherapy. Because claudin 18.2 overlaps little with HER2 and only partly with PD-L1, it often identifies a treatment option for patients who would otherwise have few targeted choices. The treatment team interprets all of these results together to decide what to combine with chemotherapy. HER2, PD-L1, and MMR testing are each described in their own articles.

Does claudin 18.2 status have hereditary implications?

Claudin 18.2 expression is a feature of cancer cells, not of the genes a person is born with. It reflects a protein that becomes exposed on the surface of stomach cancer cells, and it is not inherited, is not passed down to children, and does not appear on a test for inherited cancer risk. A claudin 18.2 result therefore has no implications for family members. Inherited risk for gastric cancer is evaluated through other pathways, such as mismatch repair (MMR) status and certain inherited syndromes, rather than through claudin 18.2. A claudin 18.2 result on the pathology report is about guiding treatment for the cancer that is already present.

What happens next

Once claudin 18.2 testing is complete, the result becomes part of the information the treatment team uses to plan care for advanced gastric or gastroesophageal junction cancer. The next steps depend on the result:

If the result is claudin 18.2 positive, the oncology team discusses adding the claudin 18.2-targeted drug zolbetuximab to first-line chemotherapy, taking PD-L1 and MMR status into account.
If the result is claudin 18.2 negative, claudin 18.2-targeted therapy is not indicated, and the plan proceeds based on the other biomarkers, including PD-L1 and MMR status for immunotherapy, and the stage of the cancer.

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 claudin 18.2-targeted therapy is started, patients are monitored for response and for side effects such as nausea. Regular imaging and follow-up visits are used to track how the cancer is responding.

Questions to ask your doctor

Was my gastric or gastroesophageal junction cancer tested for claudin 18.2, and what was the result?
Was my tumor HER2-negative, and is that why claudin 18.2 testing was done?
If my tumor is claudin 18.2 positive, am I a candidate for zolbetuximab with chemotherapy?
How do my claudin 18.2, HER2, PD-L1, and MMR results fit together in deciding my treatment?
What side effects should I expect from claudin 18.2-targeted therapy, and how will nausea be managed?
If my tumor is claudin 18.2 negative, what treatment options are available to me?
Could my claudin 18.2 result differ between the original tumor and other sites, and might I need to be retested?
Are there clinical trials of claudin 18.2-targeted therapies that I should know about?
Will claudin 18.2-targeted therapy be combined with immunotherapy in my case?
Does my claudin 18.2 result have any implications for my family members?