Research Report on Claudin 18.2 in Gastric Cancer and Gastroesophageal Junction Adenocarcinoma

Background Introduction

Gastric cancer and gastroesophageal junction (G/GEJ) adenocarcinoma are major global health burdens. It is estimated that in 2020 alone, there were approximately 1.7 million new cases of gastric and esophageal cancers worldwide, with 1.3 million related deaths. In the United States, an estimated 48,060 new cases of gastric and related cancers are expected in 2023, with 27,250 deaths. Currently, treatment options for G/GEJ adenocarcinoma are limited, and the five-year relative survival rate for cases with distant metastasis has remained around 10% since 2007. Therefore, there is an urgent need for better understanding of disease characteristics, identification of new biomarkers, and analysis of the impact of clinical and tumor-related features on diagnosis, management, and prognosis.

The Claudin (Claudin, CLDN) family of transmembrane proteins includes at least 27 unique proteins that have distinct expression patterns in normal and cancerous tissues. Claudin 18.2 (CLDN18.2) is present in the gastric mucosa, and when gastric mucosal cells undergo malignant transformation, CLDN18.2 remains retained and can become exposed and accessible when tight junctions are disrupted. Thus, CLDN18.2 has garnered widespread attention as an emerging biomarker and therapeutic target for G/GEJ adenocarcinoma.

Research Source

This research paper was written by Rebecca Waters, Matheus Sewastjanow-Silva, Kohei Yamashita, Ahmed Abdelhakeem, Kenneth K. Iwata, Diarmuid Moran, Dina Elsouda, Abraham Guerrero, Melissa Pizzi, Ernesto Rosa Vicentini, Namita Shanbhag, Anh Ta, Deyali Chatterjee, and Jaffer A. Ajani, with the first author and corresponding author Jaffer A. Ajani being affiliated with the MD Anderson Cancer Center. The paper was published in the JCO Precision Oncology journal on May 23, 2024, and the study utilized cancer patient tissue samples from the center’s biorepository.

Research Content

Research Design and Methods

This study is a retrospective one, utilizing tissue samples from G/GEJ adenocarcinoma patients in the MD Anderson Cancer Center biorepository and extracting clinical data from patient medical records. The research was approved by the MD Anderson Cancer Center Ethics Committee and conducted in accordance with good clinical and pharmacoepidemiology practices and all applicable federal, state, and local laws and regulations.

Samples needed to come from patients histologically confirmed with G/GEJ adenocarcinoma, must be formalin-fixed, paraffin-embedded whole tissue specimens, and the source patients had to provide written informed consent. Tissue samples that were more than 10 years old or lacked clinical outcome data were excluded.

Immunohistochemical staining was used to detect the expression of CLDN18.2 in tumor tissue samples from 304 G/GEJ adenocarcinoma patients, defined as ≥50% or ≥75% of tumor cells having CLDN18.2 staining intensity of 2+ or 3+. The staining results were independently evaluated by two pathologists, using both ≥50% and ≥75% positive criteria.

Results

According to the ≥75% criterion, the CLDN18.2 positive rate was 44.4% across all samples, with a positive rate of 51.4% for gastric adenocarcinoma samples and 34.6% for GEJ adenocarcinoma samples. Based on the ≥50% criterion, the overall CLDN18.2 positive rate was 56.3%, with a positive rate of 64.4% for gastric adenocarcinoma samples and 44.9% for GEJ adenocarcinoma samples.

Analysis of various parameters (including gender, tissue type, cancer staging, etc.) found that CLDN18.2 positivity was significantly associated with gender, gastric adenocarcinoma tissue type, and certain adenocarcinoma subtypes (≥75% criterion), metastatic sites, and tumor grading (≥50% criterion). However, CLDN18.2 positivity was not significantly associated with overall survival using either the ≥50% or ≥75% positive criterion.

For matched primary and metastatic tumor samples, the concordance of CLDN18.2 positivity was 73% (≥75% criterion), while the concordance of CLDN18.2 positivity before and after chemotherapy was 74%.

Conclusion and Value

The study indicates that CLDN18.2 positive expression in G/GEJ adenocarcinoma is not associated with survival, aligning with existing related data. Based on matched sample analysis, CLDN18.2 demonstrated over 70% consistency as a biomarker. The associations found with certain patient and tumor characteristics need further research for confirmation.

The study emphasizes the importance of CLDN18.2 as a biomarker and therapeutic target, and suggests further exploration in future studies of its application value in specific clinical contexts. For example, Zolbetuximab (anti-CLDN18.2 antibody) has shown significant effects in multiple Phase III clinical trials for treating CLDN18.2 positive G/GEJ adenocarcinoma patients, underscoring the importance of further development and evaluation of this therapy.

Research Highlights and Innovations

1. Significant Findings: This study detailed the expression of CLDN18.2 in 304 G/GEJ adenocarcinoma patients, revealing its association with tumor grading, metastatic sites, and gender.
2. No Association with Survival: Despite widespread attention on CLDN18.2, the study clearly shows that its positive expression is not significantly associated with overall survival.
3. Consistency Analysis: Through analysis of matched samples, the study validated the reliability of CLDN18.2 as a biomarker, with over 70% concordance in primary and metastatic tumors and before and after chemotherapy.

This study not only provides valuable data and insights in the field of biomarker research but also offers a scientific basis for developing precise treatments targeting CLDN18.2 in the future.