Clinicopathological significance and immunotherapeutic outcome of claudin 18.2 expression in advanced gastric cancer: A retrospective study
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SUBMITTER: Qi C
PROVIDER: S-EPMC10915633 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:BackgroundClaudin 18.2 (CLDN18.2) is a cell surface protein expressed by gastric cancer cells. The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death. A few studies researched the prognostic effect of CLDN18.2 expression in metastatic gastric adenocarcinoma.AimTo identify the prognostic value of CLDN18.2 expression in patients with metastatic gastric adenocarcinoma.MethodsThis study was conducted with 65 patients over the age of 18 who were diagnosed with metastatic gastric adenocarcinoma. We investigated the effect of CLDN18.2 expression on clinicopathological characteristics (age, sex, histological grade, Lauren classification, family history, metastatic site, HER2 expression) and prognosis for patients with metastatic gastric adenocarcinoma.ResultsCLDN18.2 expression was positive in 73.8% (48) of the patients. During the median 17.7-mo follow-up period, 89.2% (58) of the patients died. Median progression-free survival and overall survival (OS) were 6 mo (95% confidence interval: 1.6-10.4) and 12 mo (95% confidence interval: 7.5-16.5). There was no statistically significant correlation between CLDN18.2 expression and clinicopathological characteristics of the patients. In univariate and multivariate Cox regression analysis, there was no correlation between clinicopathological characteristics of patients and progression-free survival or OS.ConclusionCLDN18.2 expression was quite high in patients with gastric adenocarcinoma, identifying the proportion of the patients in whom zolbetuximab would be efficacious. There is no statistically significant correlation with clinicopathological characteristics and OS. CLDN18.2 is not a prognostic marker in patients with gastric adenocarcinoma, although it is predictive.
| S-EPMC9994048 | biostudies-literature
Project description:Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer (GC), but little is known about the heterogeneity of its expression in GC. This study investigated the heterogeneity of claudin 18.2 expression in 166 patients with metastatic GC whose surgical or paired primary-metastatic specimens were available. The prevalence of claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was 47.0%. Claudin 18.2-positive tumors exhibited more frequent peritoneal metastasis and a lower incidence of hepatic and distant lymph node involvement. Survival outcomes were comparable between patients with claudin 18.2-positive and -negative tumors. Intratumoral heterogeneity was noted in 38.5% of surgical specimens. Paired primary-metastatic site analysis revealed that 25.2% of patients had discordant results for claudin 18.2 positivity. Across different metastatic organ categories, peritoneal lesions showed the highest positivity rate (44.3%) and positive concordance rate (31.4%), whereas liver lesions had the lowest positivity rate (17.9%) and concordance rate (12.8%). In conclusion, claudin 18.2 expression exhibits intratumoral and intrapatient spatial heterogeneity in metastatic GC. Claudin 18.2 positivity is associated with more frequent peritoneal metastasis, and peritoneal lesions are more likely to have positively concordant claudin 18.2 results with the primary site than other metastatic sites.
| S-EPMC11291723 | biostudies-literature
Project description:BackgroundAberrant expression of claudin proteins has been reported in a variety of cancers. Previous studies have demonstrated that overexpression of claudin may promote tumorigenesis and metastasis through increased invasion and survival of tumor cells. However, the prognostic significance of claudin-4 in gastric cancer remains unclear.MethodsImmunohistochemistry was used to analyze the expression of claudin-4 in 329 clinical gastric cancer specimens and 44 normal stomach samples, 21 intestinal metaplasia samples, and 21 adjacent precursor lesions dysplasia samples. Statistical analysis methods were used to evaluate the relationship between claudin-4 expression and various clinicopathological parameters. Univariate and multivariate analyses were performed, respectively, to detect the independent predictors of survival.ResultsClaudin-4 expression was present in only 7(15.9%) normal gastric samples, but expression of claudin-4 in the intestinal metaplasia lesions and dysplasia lesions was 90.5% and 95.2%, respectively. The expression of claudin-4 was significantly associated with histological differentiation (P < 0.001) and tumor growth patterns (P < 0.001) but not associated with patient survival. However, intermediate type staining of claudin-4 exhibited a trend of correlation with patients' survival (P = 0.023). The five-year survival rate with low expression of claudin-4 in intermediate type (76.4%) was similar to expanding type (64.5%), while the high expression group (46.6%) was closer to infiltrative type (50.7%).ConclusionsThe findings in this study demonstrate claudin-4 aberrant expression in gastric cancer and precursor lesions. The expression of claudin-4 could serve as a basis for identifying gastric cancer of the intermediate type.
| S-EPMC3717126 | biostudies-literature
Project description:Claudin 18.2 (CLDN18.2) is a tight-junction protein. CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer. Zolbetuximab, the CLDN18.2 antibody, obtained a better clinical benefit in patients compared with the controlled. In phase II trials, combination treatment of epirubicin, oxaliplatin and capecitabine (EOX) + zolbetuximab achieved the optimal effects of overall survival which extended to 13.2 months with tolerable safety events, indicating its greater potential playing the second promising target in gastric cancer. This review will reveal the definitive clinical benefit CLDN18.2-targeting therapies have achieved and update the highlighting development (like chimeric antigen receptor T-cell immunotherapy) to CLDN18.2 positive patients. We then focus on 10 questions arisen from recent progress and anticipate to provide a future perspective for novel cancer treatment.
| S-EPMC7219097 | biostudies-literature
Project description:Targeted therapy and immunotherapy have revolutionized treatment of various cancers in the past decade. Despite targeted therapy with trastuzumab in Her2-positive gastric cancer patients, survival has been dismal, mostly due to disease progression and toxicity related to the treatments. One area of active development is looking for ideal monoclonal antibodies (IMAB) specific to the proteins only on the tumor and hence avoiding unnecessary side effects. Claudin proteins with isoform 2 are one such protein, specific for several cancers, particularly gastric cancer and its metastases, leading to the development of anti-claudin 18.2 specific antibody, claudiximab. This review will highlight the latest development of claudiximab as first in class IMAB for the treatment of gastric cancer.
| S-EPMC5427576 | biostudies-literature
Project description:BackgroundWe conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC).Patients and methodsPatients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression.ResultsAmong 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status.ConclusionsCLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC.
| S-EPMC10024138 | biostudies-literature
Project description:BackgroundAlterations in claudin expression can impair tight junction function, influence signaling pathways, and act as a tumor-promoting event in some epithelial cancers. Recently, zolbetuximab, a highly potent and tumor cell-selective therapeutic antibody against claudin 18.2, has been developed and investigated in clinical trials.MethodsWe conducted a prospective study using claudin 18.2 immunohistochemistry in 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016.ResultsClaudin 18.2 expression was evaluated in 96.3% of the patients (414/430) using immunohistochemistry. In total, 4.1% (17/414) of the patients were claudin 18.2-positive, including patients with pancreatic (16.7%, 1/6), gastric (14.1%, 12/85), biliary tract (6.3%, 1/16), genitourinary/miscellaneous (2.2%, 1/46), and colorectal (0.9%, 2/203) cancers. Twelve of 17 patients positive for claudin 18.2 had gastric cancers (GCs); this subgroup showed no statistical differences by gender, age, disease extent, primary tumor site, pathologic differentiation, human epidermal growth factor receptor 2, or Epstein-Barr virus status with or without claudin 18.2 expression. However, claudin 18.2 was more frequently positive in intestinal-type compared with diffuse-type as assessed by Lauren classification (P=0.026). There was no significant difference in overall survival (OS) between patients with and without claudin 18.2 expression (P=0.101).ConclusionsOur results add to the emerging literature about claudin 18.2 expression in various cancer types and support the need for extended clinical exploration of zolbetuximab.
| S-EPMC8797704 | biostudies-literature
Project description:An increasing number of tumor markers have been discovered to have potential efficacy as diagnostic and prognostic tools in gastric cancer. We aimed to assess putative correlations between claudin 18.2 expression and pathological or prognosis features in patients with gastric cancer. MEDLINE, Web of Science, EBSCO, and ClinicalTrials.gov were used to search for relevant studies from their inception to 30 October 2020. Finally, a total of six articles were included in this meta-analysis. Review Manager 5 software was applied to examine the heterogeneity among the studies and to calculate the odds ratio with 95% CI by selecting corresponding models, in evaluating the strength of the relationship. Publication bias test was also conducted. No bias and no significant correlations were found between CLDN 18.2 and TNM stages, Lauren classification, HER2, grading, or overall survival. This meta-analysis expounded that the relationship with CLDN 18.2 and pathological features depends on the percentage of staining of tumor cells for which CLDN 18.2 is considered positive. Our pooled outcomes suggest that targeted therapy for CLDN 18.2 could be effective if certain criteria were established.
| S-EPMC7969651 | biostudies-literature
Project description:BackgroundThis study aimed to investigate the prevalence of claudin 18.2 (CLDN18.2) positivity, with a particular focus on intratumoral heterogeneity, and its association with clinicopathological features in metastatic or unresectable gastric cancer (GC).Patients and methodsWe investigated 400 patients who received systemic chemotherapy for unresectable, metastatic, or recurrent GC. Immunohistochemistry for CLDN18 (43-14A), human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and fibroblast growth factor receptor 2, as well as HER2 silver in situ hybridization (ISH), Epstein-Barr virus (EBV) ISH, and microsatellite instability testing were carried out. CD3+, CD8+, CD4+, and Foxp3-positive immune cell densities were calculated using digital image analysis.ResultsIn GC cases with any CLDN18.2 expression, more than half of the cases (61.3%) showed different expression results between four different tissue microarray (TMA) cores. When comparing CLDN18.2 status between whole tissue sections and the combined results from the four TMA cores, discrepancies were observed in only 2 out of 85 GC cases (2.4%), with 1 false positive and 1 false negative. After considering intratumoral heterogeneity, a CLDN18.2 positivity rate of 31.3% was observed among the 400 GC patients. CLDN18.2 positivity was rare in GCs located in the antrum (or lower third) and in HER2-positive cases but was common in EBV-positive GCs (P < 0.05). No differences in overall survival (OS) were observed according to CLDN18.2 positivity (P = 0.116). Additionally, there was no association between OS and CLDN18.2 positivity in patients treated with fluoropyrimidine plus platinum, chemotherapy plus trastuzumab, paclitaxel with or without ramucirumab, and immuno-oncologic agents. CLDN18.2-positive/PD-L1-high GCs showed statistically significantly longer OS than others (P = 0.025) and higher CD8+ T-cell densities in both the tumor center and periphery (P < 0.001).ConclusionsCharacterizing unresectable, metastatic, or recurrent GC with positive CLDN18.2 expression and evaluating intratumoral heterogeneity and prognostic implications of various therapeutics help advance treatment strategies and develop new therapies for patients with GC.
| S-EPMC11648117 | biostudies-literature
Project description:BackgroundClaudin 18.2 (CLDN18.2) is a promising target for targeted therapies in gastric cancer (GC). This study investigated the prevalence of CLDN18.2 expression in patients with stages II-IV GC or gastroesophageal junction (GEJ) adenocarcinoma and its correlation with clinicopathologic features and other crucial GC biomarkers.MethodsWe enrolled 1000 patients diagnosed with stages II-IV GC after surgical treatment. Immunohistochemistry for CLDN18 (43-14A clone), PD-L1 (22C3 pharmDx), HER2, and FGFR2 was performed. CLDN18.2 positivity was defined as moderate-to-strong (2+/3+) membranous staining in ≥75% of tumor cells. CLDN18.2 expression was compared with biomarker expression, Epstein-Barr virus (EBV) association and microsatellite instability status, and clinicopathologic features.ResultCLDN18.2 was positive in 34.4% of the patients. CLDN18.2 positivity was significantly higher in the middle and upper thirds than in the lower third gastric location (P < .001), but there was no correlation with age, sex, or stage (P > .05). CLDN18.2 positivity was rare (2.8%) in mucinous adenocarcinoma but frequent (90.9%) in a majority of gastric carcinomas with lymphoid stroma. CLDN18.2 positivity was higher in EBV-associated (P < .001) and PD-L1-positive (PD-L1 CPS ≥ 5) GC (P = .014) but lower in HER2 positive GC (P = .005). CLDN18.2 positivity was not significantly associated with overall survival and disease-free survival.ConclusionThis study provides a comprehensive evaluation of CLDN18.2 status and its correlation with the clinicopathologic characteristics of patients with stages II-IV GC in Korea and with crucial biomarkers. It may be valuable for guiding future drug development, expanding treatment options, and ultimately improving patient outcomes in GC.
| S-EPMC11881060 | biostudies-literature