High CLDN18.2 levels could affect treatment response in gastroesophageal cancer

CLDN18.2-high gastroesophageal adenocarcinoma, a form of stomach or gastroesophageal cancer marked by elevated Claudin 18.2 protein, could be more common than previously reported and could influence how patients respond to treatment, according to a February study published in ESMO Open.

The findings sugge

st that patients with high CLDN18.2 levels may respond better to HER2-targeted treatments but may not respond as well to immunotherapy, highlighting the need to use biomarkers to help guide treatment decisions.

Gastroesophageal cancers remain a major global health burden. They are the fifth most diagnosed cancer worldwide and the fourth leading cause of cancer-related death, with about 1.5 million new cases reported in 2022, according to the study. Prognosis is especially poor in advanced or metastatic disease, where platinum- and fluoropyrimidine-based chemotherapy continues to serve as the backbone of treatment.

More recently, improved testing of tumor biology has helped physicians understand how complex these cancers are. Programs such as The Cancer Genome Atlas have shown that tumors can differ based on markers such as HER2, PD-L1, mismatch repair status and CLDN18.2. These markers can also help guide treatment decisions.

Targeted drugs and immunotherapy have improved outcomes for some patients, and the CLDN18.2-targeted drug Vyloy (zolbetuximab) is now a first-line option for certain patients. For example, results from the phase III SPOTLIGHT and GLOW trials revealed that adding zolbetuximab to chemotherapy improved both progression-free and overall survival in patients with CLDN18.2-positive gastroesophageal cancer.

However, doctors are still unsure how to best choose or combine treatments, especially when tumors have more than one biomarker.

To learn more about CLDN18.2, researchers of the Vall d’Hebron University Hospital and the Vall d’Hebron Institute of Oncology in Barcelona, Spain, conducted a multicenter study across 17 hospitals in Spain and Italy. The study included 563 patients with advanced gastroesophageal cancer diagnosed between 2019 and 2025. Reviewed were patient and tumor data focusing on CLDN18.2 and how it relates to other key biomarkers such as HER2, PD-L1 and mismatch repair status.

Tumor samples from the original tumor or from sites where the cancer had spread were tested using immunohistochemistry lab methods and next-generation sequencing. Researchers also looked at patient outcomes across treatment types, including chemotherapy, HER2-targeted therapy and immunotherapy. Statistical methods included Kaplan-Meier survival analysis and Cox regression modeling to analyze the connection between biomarker expression and clinical outcomes.

Out of the 563 patients, the median age was 66 years, and most tumor samples were taken from primary sites. CLDN18.2-high expression was found in 48.3% of patients who could be evaluated, which is higher than what earlier studies have reported. Tumors with high CLDN18.2 levels were more often linked to diffuse-type disease, signet-ring cell features and cancer spread to the lining of the abdomen. However, CLDN18.2 levels were not related to a patient’s sex, ethnicity or where the tumor sample was taken from.

In addition, CLDN18.2-high tumors were observed across multiple molecular subtypes and frequently overlapped with other biomarkers, including PD-L1, HER2, Epstein-Barr virus and mismatch repair deficiency. While these biomarkers typically appeared together, PD-L1 levels were not much different between tumors with high or low CLDN18.2. Genetic testing also showed some differences in mutations and gene changes between the two groups, suggesting these tumors may behave differently.

Patient outcomes also varied based on the type of treatment used. It was found that tumors with high CLDN18.2 were linked to a longer time before the disease worsened, but it did not lead to longer overall survival.

Patients treated with HER2-targeted therapy tended to do better if their tumors had high CLDN18.2. However, those who received immunotherapy showed a trend toward worse outcomes, including shorter survival, in the high CLDN18.2 group. Results with standard chemotherapy were similar regardless of CLDN18.2 status.

Based on study methods and results, its strengths include the large group of patients involved from multiple centers across Europe, which helps make the findings more generalized. It also used standardized CLDN18.2 testing that aligns with phase III trials, and many patients had detailed molecular testing, adding depth to the results.

However, there are limitations. Part of the study was retrospective, which can introduce selection bias. Some biomarker data, including Epstein-Barr virus and PD-L1 status, were missing for a portion of patients, which could affect the results. Lastly, most samples came from primary tumors, which may not fully reflect metastatic disease.

The authors suggest that prospective studies are needed to confirm these findings and refine treatment strategies. They added that future research should focus on integrating biomarker profiles with clinical features, treatment tolerability and patient preferences to better guide personalized care.