PD-L1 in Gastric and Gastroesophageal Junction Cancer

PD-L1 (programmed death-ligand 1) is a protein that some cancer cells use to hide from the immune system. Testing for PD-L1 is one of the most important biomarkers in advanced cancer of the stomach (gastric cancer) and the gastroesophageal junction (the area where the esophagus meets the stomach), because the result helps determine whether immunotherapy is likely to help. A “biomarker” is a measurable feature of a cancer, such as a protein on the surface of the cells, that gives doctors information they cannot get from looking at the cells under the microscope alone.

This article will help you understand what a PD-L1 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. PD-L1 testing is now a standard part of the workup for these cancers when they are advanced. A PD-L1 result is not an inherited change passed down in families. It is a feature of the cancer itself, and its main purpose is to help the treatment team judge whether immunotherapy belongs in the plan.

What PD-L1 is and what it does

PD-L1 is a protein that can sit on the surface of cancer cells and on nearby immune cells. It acts like an “off switch” for the immune system. When PD-L1 connects with a matching protein called PD-1 on an immune cell, it sends a signal telling that immune cell to stand down. Normal tissues use this switch to keep the immune system from attacking healthy cells. Many cancers, including gastric and gastroesophageal junction cancers, take advantage of the same switch to avoid being attacked.

A group of immunotherapy drugs called immune checkpoint inhibitors work by blocking this off switch. When the switch is blocked, the immune system is freed to recognize and attack the cancer. In general, a cancer that displays more PD-L1 is more likely to respond to these drugs, which is why measuring PD-L1 helps predict who is most likely to benefit from immunotherapy.

How common is PD-L1 expression in gastric and gastroesophageal junction cancer?

PD-L1 expression is common in gastric and gastroesophageal junction cancers, but how often a tumor counts as “positive” depends entirely on the threshold used. PD-L1 is measured on a sliding scale rather than as a simple yes or no, and different treatments use different cut-off points. Using the lowest common threshold, a large share of these cancers show some PD-L1 expression; using higher thresholds, the proportion that qualifies is smaller. This is why the specific score on the report matters more than the word “positive” or “negative” alone, and why the same tumor can meet the requirement for one drug but not another.

Why is the test done?

PD-L1 testing in gastric and gastroesophageal junction cancer is done mainly to help determine whether immunotherapy with an immune checkpoint inhibitor is likely to be effective. A higher PD-L1 score identifies patients who are more likely to benefit from these drugs, and PD-L1 testing is now recommended for all patients with advanced (locally advanced, recurrent, or metastatic) gastric or gastroesophageal junction cancer as part of standard testing. The result helps the treatment team decide whether to add immunotherapy to chemotherapy in the first-line setting.

PD-L1 is usually tested at the time the cancer is first found to be advanced, often on the original biopsy, and it is one of several biomarkers considered together. In particular, PD-L1 is interpreted alongside HER2 status, because the combination of the two results helps shape the choice of first-line treatment. PD-L1 testing is generally not needed for very early-stage cancers that are removed surgically with no evidence of spread, because immunotherapy is used in the advanced setting.

How the test is performed

PD-L1 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 PD-L1 protein on a thin slice of the tumor on a glass slide, and a pathologist examines the slide to judge how much PD-L1 is present.

For these cancers, PD-L1 is reported using a measure called the Combined Positive Score (CPS). The CPS counts the number of PD-L1-positive cells, including both the cancer cells and the surrounding immune cells, divides that by the total number of cancer cells, and multiplies by 100. Because it includes both the tumor cells and the nearby immune cells, the CPS captures PD-L1 activity across the whole tumor environment rather than in the cancer cells alone. The CPS is the standard scoring method for gastric, gastroesophageal junction, and esophageal cancers, which is different from lung cancer, where a different score (the Tumor Proportion Score, or TPS) is used.

One technical point is worth understanding: PD-L1 testing uses specific laboratory assays and antibodies, and the assay used can matter. For gastric and gastroesophageal junction cancer, a particular antibody (called 22C3) is the standard, and the laboratory will note which assay was used. If you are unsure, it is reasonable to ask which assay was performed, because eligibility for a specific drug can depend on it.

How results are reported

PD-L1 results in gastric and gastroesophageal junction cancer appear in the biomarker or molecular testing section of the pathology report, usually as a CPS number. The report describes the result in relation to the thresholds that matter for treatment.

CPS less than 1 — Little or no PD-L1 expression was detected. Immunotherapy is less likely to add benefit based on this result, although it may still be considered in certain situations.
CPS 1 or higher — PD-L1 expression is present at a level that may make immunotherapy beneficial in combination with chemotherapy, depending on the specific drug and threshold being considered.
CPS 5 or higher, and CPS 10 or higher — These higher thresholds are used for certain immunotherapy regimens. A higher CPS generally indicates a greater likelihood of benefit, and some drugs are approved specifically at these higher cut-offs.

Because the same tumor can meet one threshold but not another, the report gives the actual CPS number rather than a simple positive or negative. The treatment team interprets that number against the threshold required for the specific drug being considered.

What the result means

The PD-L1 result helps the treatment team judge how likely the cancer is to respond to immunotherapy. It does not, on its own, prescribe a treatment; instead, the CPS is weighed together with HER2 status, the stage of the cancer, prior treatments, and overall health when the medical oncology team discusses options with the patient. In gastric and gastroesophageal junction cancer, immunotherapy is generally added to chemotherapy rather than used alone in the first-line setting, and the PD-L1 score helps decide whether that addition is appropriate.

It is also important to know that a low PD-L1 score does not always rule out immunotherapy. Some patients with low PD-L1 expression still benefit, and other findings, such as mismatch repair (MMR) status, can independently support the use of immunotherapy regardless of the PD-L1 score. The PD-L1 result is one piece of a larger picture rather than a single deciding factor.

Treatment implications of PD-L1 in gastric and gastroesophageal junction cancer

For advanced gastric and gastroesophageal junction cancer, the PD-L1 score helps determine whether an immune checkpoint inhibitor is added to first-line chemotherapy and which drug may be appropriate. The two immunotherapy drugs used most often in this setting are nivolumab (Opdivo) and pembrolizumab (Keytruda), both of which block the PD-1/PD-L1 off switch.

Nivolumab with chemotherapy — Nivolumab added to chemotherapy is an approved first-line option for HER2-negative gastric and gastroesophageal junction cancer with a CPS of 1 or higher, based on the CheckMate 649 trial. The benefit is generally more pronounced at higher CPS levels.
Pembrolizumab with chemotherapy — Pembrolizumab combined with chemotherapy is approved for gastric and gastroesophageal junction cancer at higher CPS thresholds (CPS 5 or higher, or 10 or higher, depending on the regimen and jurisdiction), based on trials including KEYNOTE-590 and KEYNOTE-811. For HER2-positive disease, pembrolizumab may be combined with trastuzumab and chemotherapy.

This is why PD-L1 and HER2 are considered together. In a HER2-positive cancer, the team weighs HER2-targeted therapy and immunotherapy together; in a HER2-negative cancer, the PD-L1 score becomes one of the main factors deciding whether immunotherapy is added. The exact choice and combination depend on the CPS value, HER2 status, the specific regimen available, and the patient’s overall health, and the oncology team will explain how these fit together.

PD-L1 also matters in cancers of the esophagus. In esophageal and gastroesophageal junction adenocarcinoma, the same considerations as for gastric cancer generally apply. In esophageal squamous cell carcinoma, a different and related cancer type, pembrolizumab with chemotherapy is approved at a CPS of 10 or higher, and nivolumab-based treatment is also approved in that setting. If your cancer is at the junction, your report and care team will clarify which set of considerations applies.

Does PD-L1 status have hereditary implications?

PD-L1 expression is a feature of the cancer and its surrounding immune cells, not a feature of the genes a person is born with. It is not inherited and is not passed down to children, and it does not appear on a test for inherited cancer risk or carry implications for family members. This is different from some other biomarkers that can indicate an inherited syndrome. Inherited risk for gastric cancer is evaluated through other pathways, such as mismatch repair (MMR) status and certain inherited syndromes, rather than through PD-L1. A PD-L1 result on the pathology report is about guiding treatment for the cancer that is already present.

What happens next

Once PD-L1 testing is complete, the CPS result becomes part of the information the treatment team uses to plan care. The next steps depend on the result and on the other findings:

If the CPS is high enough to support immunotherapy, the oncology team will discuss adding an immune checkpoint inhibitor (such as nivolumab or pembrolizumab) to chemotherapy, taking HER2 status into account.
If the CPS is low, immunotherapy may still be considered in some situations, and the team will look at other findings, such as MMR status, when deciding. Chemotherapy and, where relevant, HER2-targeted therapy remain part of the plan.
In HER2-positive cancers, PD-L1 and HER2 results are considered together, because immunotherapy may be combined with HER2-targeted therapy and chemotherapy.

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 immunotherapy is started, patients are monitored for response and for immune-related side effects, which occur because these drugs increase immune activity throughout the body. 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 PD-L1, and what was my CPS score?
Which assay or antibody was used for my PD-L1 test?
Does my CPS score make immunotherapy a good option for me?
Would immunotherapy be combined with chemotherapy, and which drug would you consider?
How do my PD-L1 and HER2 results fit together in deciding my treatment?
If my CPS score is low, could immunotherapy still help me, and would my MMR status change that?
What immune-related side effects should I watch for, and how are they managed?
If my cancer is at the gastroesophageal junction, do the esophageal or gastric considerations apply to me?
Are there clinical trials of immunotherapy that I should know about?
Does my PD-L1 result have any implications for my family members?