Retrospective analysis of Claudin18.2 expression in ethnically diverse patients with gastroesophageal adenocarcinoma

Introduction

Globally, gastric cancer is the fifth most common type of cancer and fifth most common cause of cancer-related death (1). Esophageal cancer is less common but still contributes to the global cancer burden, and 7.5% of new malignancies (over 1.4 million) in 2022 were of gastroesophageal origin (1).

While the overall incidence of gastric cancer has been declining in the United States (US) in recent decades, significant racial and ethnic disparities exist. The incidence of gastric cancer is higher in racial and ethnic minorities than in non-Hispanic White patients, with one study reporting that the age-standardized incidence in minority populations was twice that of non-Hispanic White patients (2-4). Additionally, the incidence of non-cardia gastric cancer is increasing in people less than 50 years old. Rates of localized non-cardia gastric cancer are increasing in both non-Hispanic White and Hispanic patients, but rates of advanced stage non-cardia gastric cancer are only increasing in Hispanic patients, especially Hispanic men (3). This divergence suggests a rising disparity in the burden of gastric cancer in young Hispanic patients.

Overall survival (OS) for patients diagnosed with gastric cancer has increased over the past three decades, but this is mainly impacted by patients with localized or regional disease (4). The 5-year survival for patients with advanced disease, who make up one-third of the gastric cancer patients in the US, remains poor, at less than five percent (4).

While survival is increasing, there have been limited advances in treatment of gastroesophageal malignancies. Standard of care for advanced gastric cancer is still combination cytotoxic chemotherapy. While immunotherapy and targeted therapy have been approved for first-line use, these newer therapies have only been shown to have benefit in select populations of patients, including those with human epidermal growth factor receptor 2 (HER2) positive, programmed death-ligand 1 (PD-L1) positive, or microsatellite instability high (MSI-H) tumors (5). Therefore, there is a lack of effective, available targeted therapies in gastroesophageal malignancies, mainly due to the lack of targetable alterations found so far.

Claudin18.2 (CLDN18.2) is a tight junction molecule that is expressed by all non-malignant gastric epithelial cells and becomes exposed on the cell surface during malignant transformation (5-7). The link between this molecule and carcinogenesis is currently being explored, and it is thought that disrupting tight junctions causes decreased cell polarity, therefore increasing the invasive potential of affected cells and contributing to unorganized cell proliferation (5).

As CLDN18.2 is expressed on the surface of some malignant cells, this molecule is currently being studied as a therapeutic target for patients with advanced gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma (5,7). Recent phase III trials (GLOW and SPOTLIGHT) demonstrated improved OS and progression-free survival (PFS) with the addition of a novel anti-CLDN18.2 antibody, zolbetuximab, to first-line chemotherapy in patients with untreated, advanced, HER2-negative gastric and GEJ adenocarcinoma and high levels of CLDN18.2 expression [moderate-to-strong staining intensity on immunohistochemistry (IHC) in ≥75% of tumor cells] (5,7-9). In the US, zolbetuximab was approved for first-line use in combination with chemotherapy in this population in October 2024 (10). Other forms of targeted therapy against CLDN18.2 are also currently being studied, including bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor (CAR) T cells, demonstrating the potential of anti-CLDN18.2 therapies to revolutionize the treatment of advanced gastroesophageal malignancies (5-7,11-13). As the immunosuppressive tumor microenvironment in gastroesophageal malignancies may decrease the effect of anti-CLDN18.2 therapies, there may be utility in combining these therapies with immunotherapy to improve immune cell infiltration and boost the immune response (14).

However, the utility of anti-CLDN18.2 therapies depends on the expression of CLDN18.2 in tumor cells, which varies depending on the method of detecting CLDN18.2 staining and different definitions of high or positive expression (7-9,15-17). While prior studies have reported expression of CLDN18.2 and its association with other biomarkers, these studies have largely included homogenous populations of all White or all Asian patients, and CLDN18.2 expression in other racial and ethnic groups, including Hispanic patients, has been poorly defined (18-28). Inadequate inclusion of racial and ethnic minorities may limit generalizability of findings of these key clinical trials. Therefore, we evaluated CLDN18.2 expression, its association with demographic and clinicopathologic characteristics, and its prognostic potential in a cohort of racially and ethnically diverse patients. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-111/rc).

Methods

Study design and study population

This was a single-center, retrospective cohort study of patients with gastric, GEJ, or esophageal adenocarcinoma in whom CLDN18.2 IHC had been performed at Columbia University Irving Medical Center (CUIMC). CLDN18.2 staining became available as standard reflex testing at CUIMC in 2023, and so the initial study population was limited to patients with tumor samples collected from January 2023 to October 2024, when data collection occurred. Follow-up time, from time of diagnosis to time of data collection, ranged from 10.4 to 100.2 months, with an average of 23.7 months.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the CUIMC Institutional Review Board (No. AAAT8778), and individual consent for this retrospective analysis was waived.

Measures

The primary variable of interest was CLDN18.2 positivity status, defined by IHC staining. Pathology reports were collected from the electronic medical record (EMR) to retrieve information on tumor type and location, grade at diagnosis, CLDN18.2 expression, and other characteristics, including Helicobacter pylori (H. pylori) infection, HER2, mismatch repair (MMR), Epstein-Barr virus (EBV), and PD-L1 status. Information on Lauren’s histological type (diffuse, intestinal, unknown) was collected from pathology reports for patients with gastric cancer only.

Pathology reports from both biopsies and surgical resections were included. Most metastatic patients (83.3%) only had biopsy specimens available as they did not undergo surgical resection. While many non-metastatic patients had surgical specimens available, CLDN18.2 IHC was conducted mainly on biopsies (70.7%), likely because CLDN18.2 IHC is a standard reflex test at our institution, and most patients had biopsies performed prior to surgical resection.

Demographic information was retrieved from the EMR, including age at diagnosis (continuous in years), sex (male/female), race (White, Black, Asian, other, unknown), ethnicity (Hispanic, non-Hispanic, unknown), and tobacco history (yes/no).

Clinical information was also extracted from the EMR, including clinical and pathologic stage at diagnosis (defined by the American Joint Committee on Cancer criteria), date of surgery, pathology reports from biopsies and surgical resections, date of recurrence, treatment lines with dates of initiation and progression, and date of death (29). For patients with localized or locally advanced disease, disease-free survival (DFS) was defined as time (months) from date of surgery to date of recurrence. Patients without recurrence were censored at date of data collection, October 25, 2024. Pathologic complete response (pCR) rate to neoadjuvant treatment was calculated in this subpopulation, based on pathology reports at time of resection. For patients with metastatic disease, PFS on first-line therapy was defined as time (months) from start of treatment to date of progression. Patients without progression were censored at date of data collection, October 25, 2024, and patients who had surgical resection after systemic treatment were censored at date of surgery. For all patients, OS was defined as time (months) from date of diagnosis to date of death. Patients were censored at date of data collection, October 25, 2024. Next-generation sequencing (NGS) data from tumor samples were also retrieved from the EMR to determine if CLDN18.2 status was associated with certain somatic mutations.

Immunohistochemistry and molecular testing

CLDN18.2 expression was determined using the Ventana CLDN18 (43-14A) RxDx assay (30). While this assay also captures Claudin18.1 (CLDN18.1) and is not selective for CLDN18.2, CLDN18.1 is not typically expressed in gastroesophageal mucosa, and the contribution of CLDN18.1 to a positive stain was considered negligible (5). The percentage of cells with moderate-to-strong (2–3 +) staining was recorded as a continuous variable, and a binary CLDN18.2 positivity variable was also created (positive/negative), with ≥75% of tumor cells defined as positive and <75% of tumor cells defined as negative in accordance with the GLOW and SPOTLIGHT trials (8,9). When the percentage of positive cells was provided as a range in pathology reports, the higher end of the range was used.

HER2 status was determined by IHC staining for HER2/Neu, using the Ventana Pathway HER2 (4B5 clone) kit. IHC scores of 0 or 1+ were considered negative, 2+ were equivocal, and 3+ were positive. For equivocal (2+) results, fluorescence in situ hybridization (FISH; FSG23-000422-B) was performed to determine HER2 status.

MMR status was determined by IHC staining with antibodies for the following DNA MMR proteins: MLH1 (clone G168-15), MSH2 (clone FE11), MSH6 (clone 44), and PMS2 (clone MRQ-28). Patients with loss of expression of any four of these proteins were considered MMR-deficient. Preservation of all four of these proteins was considered MMR-preserved.

PD-L1 testing was performed using the anti-CD274 mouse monoclonal antibody (clone 22c3 lung, GI), according to the manufacturer’s recommendation on the Ventana Benchmark Ultra Platform. Combined positive score (CPS) was calculated by dividing the number of PD-L1 positive tumor cells with complete or partial membranous staining and PD-L1 positive infiltrating immune cells (lymphocytes and macrophages) by the total number of viable tumor cells, multiplied by 100. CPS was reported as a continuous variable.

In situ hybridization (ISH) of the Epstein-Barr virus encoding region (EBER) was used to determine EBV status. Immunostaining for H. pylori was done to determine H. pylori infection status.

Statistical analysis

Associations between CLDN18.2 status (positive/negative) and demographic, clinical, and pathologic variables were assessed using two-sample t-tests or Wilcoxon rank-sum tests for continuous variables and Chi-squared or Fisher’s exact tests for categorical variables. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Kaplan-Meier curves and log-rank tests were used to evaluate the association between CLDN18.2 status and DFS, PFS, and OS. Missing data were labeled as unknown and were analyzed as a separate group for categorical variables. All statistical analyses were performed using R software (version 4.2.2). Cox proportional hazard models were developed using the “survival” package (version 3.8-3), and Kaplan-Meier curves were created using the “survminer” package (version 0.5.0). Oncoprint was developed using “ComplexHeatmap” package (version 2.14.0) (31). P<0.05 was considered statistically significant.

Results

We identified 75 evaluable patients with gastric, GEJ, and esophageal adenocarcinoma with CLDN18.2 IHC testing done during the study period.

Claudin 18.2 positivity

The distribution of CLDN18.2 expression among the study cohort is shown in Figure 1. We identified 32 patients (42.7%) with CLDN18.2-positive tumors, defined as moderate-to-strong (2–3 +) staining intensity in ≥75% tumor cells. The mean percentage of cells with moderate-to-strong CLDN18.2 staining was 43.8% [standard deviation (SD), 33.4%] in the overall cohort, 75.8% (SD 15.4%) in the CLDN18.2-positive group, and 20.1% (SD 21.2%) in the CLDN18.2 negative group.

Figure 1 Distribution of CLDN18.2 expression among patients in final study cohort. CLDN18.2, Claudin18.2.

Demographic, clinical, and pathologic characteristics

Baseline characteristics for the cohort, stratified by CLDN18.2 status, are shown in Table 1. The mean age of the cohort was 66.2 years (SD, 13.2 years), and 34.7% were female. A significant proportion of the cohort (20%) were Hispanic, and 49.3% were White, 12% were Black, 8% were Asian, and 21.3% identified as a different, not-specified race. Race and ethnicity information was missing for 9.3% and 6.7% of the cohort, respectively.

Primary tumor location varied, and 62.7%, 18.7%, and 18.7% of patients had primary gastric, GEJ, and esophageal tumors, respectively. At diagnosis, 32% were metastatic and 68% were localized or locally advanced. Most patients (70.7%) had high-grade disease (grade 3) at diagnosis, and there were no grade 1 tumors in this cohort. Among patients with gastric cancer (N=47), 57.5%, 23.4%, and 19.2% had diffuse, intestinal, or unknown type based on Lauren’s histological classification, respectively. The cohort was evenly split regarding tobacco use, with 54.7% having a prior tobacco use history.

All patients had available MMR testing, and 92% were MMR-proficient. HER2 staining was available for almost all patients, and 84% of the cohort was HER2 negative. The mean PD-L1 CPS score for the overall cohort was 9.1 (SD 14.1). Eighty percent of the cohort was PD-L1 positive with a definition of CPS ≥1, and 52% were positive using a definition of CPS ≥5. H. pylori infection status was unknown for 26.7% of the study population, and 17.3% had H. pylori-associated malignancies. About one-third of the cohort (30.7%) did not have information on EBV status, and only 2 patients (2.7%) were EBV-positive.

Association between CLDN18.2 positivity and demographic, clinical, and pathologic characteristics

Among demographic variables, CLDN18.2 positivity was only significantly associated with sex (Table 1). Female sex was positively associated with CLDN18.2 status (P=0.002). While not statistically significant, there were differences in CLDN18.2 status by race and ethnicity, with 53.3% of Hispanic patients being CLDN18.2 positive compared to 38.2% of non-Hispanic patients and 37.8% of White patients. Additionally, there was a difference in CLDN18.2 status by tobacco use, with 50% of non-smokers being CLDN18.2 positive compared to 36.6% of patients with any smoking history, although this was not statistically significant.

CLDN18.2 positivity was not associated with any clinical variables, including primary tumor location, stage at diagnosis, grade at diagnosis, or Lauren’s histological type (for gastric cancer patients only). Regarding molecular features, CLDN18.2 positivity was negatively associated with HER2 status (P=0.03). There was no association between CLDN18.2 positivity and H. pylori infection, MMR, or EBV status. There was also no association between CLDN18.2 positivity and mean PD-L1 CPS score or PD-L1 positivity, using either definition (CPS ≥1 or ≥5).

Association between CLDN18.2 positivity and tumor genetics

NGS testing was performed on tumor samples for 23 patients (30.7%). Within this subgroup, 14 patients (60.9%) were CLDN18.2 positive and nine (39.1%) were CLDN18.2 negative. Figure 2 demonstrates the Oncoprint analysis of this subgroup, stratified by CLDN18.2 status, for 12 specific genes of interest: TP53, KRAS, ARID1A, ERBB2, ATM, CDH1, MET, PIK3CA, EGFR, RHOA, CCNE1, and FGFR2. Twenty-one patients had mutations in at least one of these 12 genes of interest. Mutations in TP53 were by far the most common, found in 15 patients (65.2% of patients with available NGS data). There was no association between CLDN18.2 status and TP53, nor with any other genes of interest. Oncoprint analysis for all genetic alterations, including but not limited to the 12 genes of interest, is shown in Figure S1.

Figure 2 Oncoprint showing alterations in specific genes of interest in all patients with available NGS data. The number of patients with each genetic mutation is shown on the right, and percentage of each alteration from all patients with NGS data (N=23) is shown on the left. NGS, next-generation sequencing.

Prognostic potential of CLDN18.2

Fifty patients (66.7%) had localized or locally advanced tumors. Of these, 23 received neoadjuvant treatment, and the pCR rate to neoadjuvant therapy was 17.4% (4 patients). DFS for patients with localized or locally advanced tumors was measured and reported based on CLDN18.2 status in Figure 3. Median DFS for CLDN18.2-positive patients and CLDN18.2-negative patients with localized or locally advanced tumors was 27 and 19 months, respectively.

Figure 3 Kaplan-Meier curves for DFS in patients with localized or locally advanced gastroesophageal adenocarcinoma who had surgical resection (N=45), by CLDN18.2 status. Tick marks represent patients without recurrence, who were censored at date of data collection. CI, confidence interval; CLDN18.2, Claudin-18.2; DFS, disease-free survival; HR, hazard ratio.

For patients with metastatic disease (32%), PFS on first-line therapy was measured and reported based on CLDN18.2 status in Figure 4. Median PFS on first-line therapy for CLDN18.2-positive patients and CLDN18.2-negative patients with metastatic disease was 9.8 and 9.5 months, respectively. OS for all patients (both metastatic and non-metastatic), stratified by CLDN8.2 status, is shown in Figure 5. The CLDN18.2-negative group did not reach 50% survival in the analysis for OS, so the median OS for the sub-groups was not reported. There was no significant difference in OS by CLDN18.2 status in the overall cohort.

Figure 4 Kaplan-Meier curves for PFS in patients with metastatic disease who received systemic therapy (N=19), by CLDN18.2 status. Tick marks represent patients who were censored, either at date of surgical resection or at date of data collection for those who had not progressed. CI, confidence interval; CLDN18.2, Claudin-18.2; HR, hazard ratio; PFS, progression-free survival.

Figure 5 Kaplan-Meier curves for OS in all patients (N=75), by CLDN18.2 status. Tick marks represent patients who were censored at date of data collection. CI, confidence interval; CLDN18.2, Claudin-18.2; HR, hazard ratio; OS, overall survival.

Discussion

We evaluated expression of CLDN18.2, the association between CLDN18.2 status with demographic and clinicopathologic characteristics, and the prognostic implications of CLDN18.2 status in a diverse group of patients with gastroesophageal adenocarcinoma.

About 42.7% of the study population had CLDN18.2 positive tumors, defined by the inclusion criteria for the phase III GLOW and SPOTLIGHT trials of zolbetuximab [moderate-to-strong (2–3 +) staining intensity in ≥75% tumor cells] (8,9). This is consistent with the 38% positivity rate seen in the screening populations for these global, multi-center trials (32).

The prevalence of CLDN18.2 positivity reported in prior studies is highly variable, ranging from 10% to 87% based on the method of detection for CLDN18.2 status (i.e., which antibody was used for testing) and the definition of CLDN18.2 positivity (6,7,18-28,33-38). Some studies used the same definition of CLDN18.2 positivity or high expression as this study, whereas others used broader definitions, including the inclusion criteria for the FAST study, which was moderate-to-strong staining intensity in ≥40% of tumor cells (16). Other studies did not use cutoffs based on percentage of tumor cells and instead used H-scores or immunoreactive scores (IRS) (19,23,35,36). Among studies that used the same definition as ours, rates of expression ranged from 24–44.4% (18,20,21,25,26,37). Thus, the prevalence of CLDN18.2 positivity seen in our study is comparable to prior reports.

This study is unique because of the racial and ethnic diversity seen in our study population, with 20% of patients identifying as Hispanic and 12% as Black. Most prior studies on the prevalence and expression of CLDN18.2 have been conducted in homogenous populations without racial or ethnic diversity. For example, five studies in Germany and Italy included only White patients, and several studies in Japan, South Korea, and China included only Asian patients (18-26,28,33-35). Their lack of diversity was likely impacted by the homogeneity seen in their overall populations.

Even within studies conducted in specific racial groups, there is still large variability in CLDN18.2 expression. For example, three studies in Germany report 10% CLDN18.2 positivity using the inclusion criteria from the FAST study, 17.1% using a definition of IRS >8, and 18.4% using a definition of moderate-to-strong staining intensity in ≥49% of tumor cells (19,23,34). Two studies in Italy report 33.4% using the same definition as our study and 29.4% using a H score ≥51 (18,20). The 37.8% CLDN18.2 positivity rate seen among White patients in our study is higher than previously reported in White patients. While results from previous studies may have suggested that White patients may derive less benefit from zolbetuximab and other targeted therapies against CLDN18.2, our findings suggest the opposite. Instead, White patients in the US have moderate rates of CLDN18.2 expression and may benefit from these targeted therapies.

Studies in Asia report 24.4% and 24.0% positivity in Japan using 70% and 75% cutoff values, 29.4% positivity in Korea using a cutoff of 2–3+ staining intensity in ≥51% of tumor cells, 34–35% positivity in Korea using a 75% cutoff value, and 52.5–57.6% positivity in China using the FAST inclusion criteria, and 48.9% using a 70% cutoff value (21,22,24-26,28,33). While the positivity rate in our Asian population (50%) is higher than that previously described using the narrow definition of CLDN18.2 positivity, we are limited by only having six patients who self-identified as Asian in our study.

Until now, only one other study characterizing the expression of CLDN18.2 has been reported in the US (37). However, this study included predominantly White patients (79.3%) with only 11.8% Hispanic, 8.9% Black, and 3.9% Asian patients. This study did not find significant racial or ethnic associations with CLDN18.2 status (37). While smaller, our study has a more diverse population with a larger proportion of Hispanic patients.

Despite our increased racial and ethnic diversity, we also did not find statistically significant differences in CLDN18.2 expression by race or ethnicity. However, 53.3% of Hispanic patients were CLDN18.2 positive compared to 38.2% of non-Hispanic patients and compared to 37.8% of White, 44.4% of Black, and 50% of Asian patients. This suggests an ethnic difference in expression and, therefore, potential increased benefit of CLDN18.2 therapies in Hispanic patients. Our findings also suggest that Black patients may derive benefit from CLDN18.2-targeted therapies as well. These findings are crucial as the incidence of gastric cancer is higher in racial and ethnic minorities than in their non-Hispanic White counterparts and as rates of advanced stage non-cardia gastric cancer are rising in Hispanic men (2-4).

Hispanic patients are more likely to have diffuse-type and genomically stable (GS) disease, features that are associated with poorer prognosis, decreased response to adjuvant chemotherapy, and worse outcomes (39-43). They are also less likely to have MSI-H disease and thus less likely to be treated with or respond to immunotherapy (39-41). Reports of HER2 status in Hispanic patients are variable, with some studies reporting higher prevalence of HER2 overall but lower prevalence in younger patients, who often present with more advanced disease (43,44). Notably, none of the Hispanic patients in our cohort were HER2 positive. Thus, there is a need for additional targeted therapy, including anti-CLDN18.2 therapy, for Hispanic patients and for advancing precision medicine in underserved populations. To ensure benefit from anti-CLDN18.2 therapies and other novel agents, testing for relevant biomarkers and mutations is essential.

Similar to prior reports, we found that female sex was positively associated with CLDN18.2 expression, and HER2 status was negatively associated with CLDN18.2 status (25,28,34,37). Prior to the approval of zolbetuximab, there was a lack of targeted therapies available for patients without HER2-positive disease. Thus, the inverse relationship between CLDN18.2 and HER2 status suggests that anti-CLDN18.2 therapies can help address this gap in patients with HER2-negative disease.

We did not find other significant associations with demographic, clinical, or pathologic variables, including no association with H. pylori, MMR, EBV, or PD-L1. This is similar to prior studies, many of which have also not found significant associations with other biomarkers (19-22,26,27,37,38). Some studies have suggested an association between CLDN18.2 and EBV status (18-20,25,27). However, our ability to evaluate this association was limited by having only two EBV-positive patients. A few studies have reported associations between CLD18.2 and PD-L1. One study reports a positive association, and the other reports a negative association, demonstrating the large variability and lack of consensus regarding the relationship between CLDN18.2 and other biomarkers (25,28).

Some prior studies have also found associations between CLDN18.2 and markers of poor prognosis, including advanced stage, higher grade, diffuse histologic type, signet ring features, nodal involvement, and peritoneal involvement (20,22,24,27,28,33,37). We did not find any association between CLDN18.2 and stage, grade, or Lauren’s histological type (for gastric cancer patients only), and we did not report detailed clinical information, including sites of metastasis. Despite prior reports linking CLDN18.2 expression with poor prognostic features, this has not translated to worse outcomes and decreased survival in patients with CLDN18.2 positive tumors. In fact, most studies have shown no association between CLDN18.2 status and survival, similar to our findings (6,20,21,25-27,34-36,38). In one study, Jia et al. found that CLDN18.2-positivity was associated with shorter median OS (23.3 vs. 36.6 months) in patients with gastric cancer in China (22). However, the sample size in this study was small (80 patients), and CLDN18.2 positivity was defined using the FAST inclusion criteria, which may have allowed for a larger number of CLDN18.2 positive patients and thus more rigorous findings (22). Overall, there is no clear association between CLDN18.2 status and survival, and our findings are consistent with previously published data.

While NGS is widely used in clinical practice to inform potential treatment decisions, studies have not previously reported the association between CLDN18.2 and NGS data. Our genes of interest were based on potential molecular alterations that may have therapeutic implications in ongoing clinical trials (NCT05052801, NCT06487221, NCT05147350). Both CLDN18.2 positive and negative groups had similar frequencies of TP53 mutation, and we did not find a significant association between CLDN18.2 and other genes of interest (KRAS, ARID1A, ERBB2, ATM, CDH1, MET, PIK3CA, EGFR, RHOA, CCNE1, and FGFR2).

Strengths of this study include the racial and ethnic diversity of the study population, strict definition of CLDN18.2 based on inclusion criteria from phase III trials, and in-depth manual chart review that was done to ensure accuracy of information. Compared to other studies with uniform study populations, our findings are more generalizable to patients in the US. Defining CLDN18.2 positivity based on inclusion criteria from phase III clinical trials may have limited the number of patients who were determined to be CLDN18.2 positive, but it ensured that our findings have relevance regarding the clinical application of zolbetuximab and other CLDN18.2 targeted therapies.

Limitations include the retrospective nature of the study, data from only one institution, short study period with limited follow-up for recently diagnosed patients, and small sample size. Additionally, missing or unknown EMR data on race, ethnicity, and clinical and pathologic information (including H. pylori and EBV) may have limited our findings and prohibited meaningful conclusions regarding the application of CLDN18.2 targeted therapies in specific subgroups. Furthermore, there may have been some misclassification of patients as CLDN18.2 positive or negative as some pathology reports provided a range of percentage positive cells rather than one number.

Conclusions

In conclusion, this study adds to our understanding of CLDN18.2 expression in an ethnically diverse population of patients with gastroesophageal adenocarcinoma. Our findings suggest that Hispanic patients may have higher rates of CLDN18.2 positivity than non-Hispanic patients and may have increased benefit from anti-CLDN18.2 therapies, which needs to be validated in larger cohorts. Our findings highlight the importance of including racial and ethnic minorities in efforts to identify novel targetable alterations and their corresponding therapeutic agents. We also demonstrate the association between CLDN18.2 positivity and female sex and HER2-negative status and the lack of association with survival, consistent with published data. Future research should further investigate differences in CLDN18.2 expression and identify subpopulations of patients who may benefit from CLDN18.2 targeted therapies.

Acknowledgments

Preliminary results from this study were previously presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting in Chicago, Illinois, on April 29, 2025, and the abstract was published in volume 85, issue 8 of Cancer Research.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-111/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-111/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-111/prf

Funding: This study was supported by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30CA013696); National Institutes of Health (K08CA263304 to R.H.M.); Gastric Cancer Foundation (to R.H.M.); the US Department of Defense (HT9425-24-1-0419 to R.H.M.); the Columbia University Vagelos College of Physicians & Surgeons (Gerstner Scholar Award to R.H.M.); and the National Institutes of Health/National Cancer Institute Molecular Oncology Training Program (5T32CA203703-09 to L.W.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-111/coif). All authors report that this study was supported by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30CA013696). L.W.W. reports that this study was supported by the National Institutes of Health/National Cancer Institute Molecular Oncology Training Program (5T32CA203703-09). R.H.M. reports that this study was supported by National Institutes of Health (K08CA263304); Gastric Cancer Foundation; the US Department of Defense (HT9425-24-1-0419); the Columbia University Vagelos College of Physicians & Surgeons (Gerstner Scholar Award). R.H.M. reports receiving advisory board and consulting fees from Puretech Health, IDEAYA Biosciences, Nimbus Therapeutics, and Bristol Myers Squibb, research funding grants from Nimbus Therapeutics and Repare Therapeutics, support for attending meetings from Nimbus Therapeutics, and honoraria for lectures from Curio and MDoutlook, outside of the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the CUIMC Institutional Review Board (No. AAAT8778), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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