CLDN 18.2

What is CLDN18.2?

CLDN18.2 is an actionable, predictive biomarker in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. ~38% of patients with G/GEJ adenocarcinoma are CLDN18.2-positive, defined as ≥75% of tumor cells with moderate-to-strong (2+/3+) membranous CLDN18 staining by IHC.1

Lab technician in blue gloves using forceps to prepare a tissue sample.
Lab technician in blue gloves using forceps to prepare a tissue sample.
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend CLDN18.2 testing in patients with gastric or esophagogastric junction adenocarcinoma at time of diagnosis if advanced/metastatic disease is documented or suspected. 2,3

Claudins are present throughout the body, but two specific isoforms of CLDN18 are localized to certain tissue types4,5

  • Claudins are a family of transmembrane proteins6,7
  • As a component of tight junctions, claudins are involved in the regulation of permeability, barrier function, and polarity of epithelial layers6,7
Green lung icon

CLDN18.1

CLDN18.1 is the dominant isoform in normal and malignant lung tissue.4

Green stomach icon

CLDN18.2

CLDN18.2 is the dominant isoform in normal gastric tissue and is often retained in malignant transformation.4

Because CLDN18.2 is the dominant form of CLDN18 in gastric tissue and is retained in malignant transformation, CLDN18 IHC staining in G/GEJ tumor tissue can be attributed to CLDN18.24

Normal and tumor cell CLDN18.2 staining at 2x magnification

Normal and tumor cell CLDN18 staining at 2x magnification.

Preclinical data have shown that CLDN18.2 may become more exposed as gastric tumors develop4,8

Normal gastric mucosa tissue with CLDN18.2 buried within tight junctions
Normal gastric mucosa tissue with CLDN18.2 buried within tight junctions

Confined in healthy tissue

In normal gastric mucosa, CLDN18.2 is typically buried within tight junctions.4,8

CLDN18.2 exposed due to cell polarity disruptions and structure loss
CLDN18.2 exposed due to cell polarity disruptions and structure loss

Retained and exposed in malignant transformation

CLDN18.2 is often retained during malignant transformation. CLDN18.2 may be more exposed when cell polarity disruptions and structure loss occur.4,8,9

CLDN18.2 expressed in lymph node metastases of gastric adenocarcinoma and other metastatic sites
CLDN18.2 expressed in lymph node metastases of gastric adenocarcinoma and other metastatic sites

Maintained in metastatic progression

CLDN18.2 may also be expressed in lymph node metastases of gastric adenocarcinoma as well as other distant metastatic sites.4,10-12

CLDN18.2 expression may be observed in G/GEJ adenocarcinoma, as well as other adenocarcinomas.1

CLDN18.2 is a highly prevalent biomarker in advanced G/GEJ adenocarcinoma1

Based on pooled data from all screened patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma and valid CLDN18 IHC results across two recent global Phase 3 studies (N=4507), ~38% of cases demonstrated ≥75% of viable tumor cells with moderate-to-strong (2+/3+) membranous CLDN18 staining.1

  • Among advanced G/GEJ biomarkers, CLDN18.2 is highly prevalent1,13*
  • CLDN18.2 expression can be readily detected using IHC1
Graphic showing proportions of CDLN18.2 expression among all samples, and proportion of samples with ≥75% of tumor cells expressing of 2+ and 3+ CDLN18.2 staining
Graphic showing proportions of CDLN18.2 expression among all samples, and proportion of samples with ≥75% of tumor cells expressing of 2+ and 3+ CDLN18.2 staining

* The prevalence of CLDN18.2 positivity was 38.4% (922/2403) and 38.4% (808/2104) in two Phase 3 clinical trials.1

According to three recent studies in patients with advanced G/GEJ cancer:

In the context of CLDN18.2 expression, no clear differences have been observed in the prevalence of select biomarkers, including10,14,15*

*Data are from three single-institution studies: Study 1 was conducted in Padua, Italy, and included patients with advanced GCs (n=280) and GECs (n=70).10 Study 2 was conducted in 408 Japanese patients with advanced G/GEJ adenocarcinoma.14 Study 3 was conducted at MD Anderson Cancer Center (MDACC) and included 304 patients with 
G/GEJ adenocarcinoma.15

Despite advances in treatment options, there is still a high unmet medical need in metastatic G/GEJ cancer

Based on recent data:

  • In the United States, only 8.1% of patients with metastatic gastric cancer and 5.3% of patients with metastatic esophageal cancer survive 5 years post diagnosis16,17*
  • In 2026, an estimated 31,510 new cases of gastric cancer will be diagnosed in the United States; ~60% of these will be diagnosed as cancer that has spread (23% regional and 35% distant)16,18

*SEER data do not have a separate classification for GEJ apart from esophageal cancer; therefore, true GEJ projections are unknown.17

CLDN18.2 expression profile remains consistent across various clinicopathological parameters1,19

Prevalence of CLDN18.2-positivity by disease and tumor sample characteristics based on pooled data from all screened patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma and valid CLDN18 IHC results across two recent global Phase 3 studies (N=4507)1

Prevalence of CLDN18.2 positivity chart
Prevalence of CLDN18.2 positivity chart

Examples of CLDN18 staining based on collection method

5x magnification of CLDN18-stained normal gastric epithelium and tumor cells

Resection of GC

5x magnification of CLDN18-stained normal gastric epithelium and tumor cells

5x magnification of CLDN18-stained tumor sample with surrounding normal gastric glands.

Biopsy of GC

5x magnification of CLDN18-stained tumor sample with surrounding normal gastric glands

20x magnification demonstrating CLDN18 staining

Biopsy of GC

20x magnification demonstrating CLDN18 staining

Primary and metastatic samples show high concordance

Data in patients with G/GEJ cancers suggest high concordance of CLDN18.2 expression between samples of primary and metastatic tissue.11, 19

Lymph node metastases: A study of 523 primary G/GEJ adenocarcinomas and 135 matched, synchronous nodal metastases demonstrated:

Peritoneal metastases: A study of 74 primary G/GEJ adenocarcinomas and paired peritoneal metastases demonstrated:

Learn more about sample preparation and testing

CLDN18, claudin 18; CLDN18.1, claudin 18 isoform 1; CLDN18.2, claudin 18 isoform 2; dMMR, deficient mismatch repair; GC, gastric cancer; GEC, gastroesophageal cancer; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; NCCN, National Comprehensive Cancer Network; PD-L1, programmed death-ligand 1; SEER, Surveillance, Epidemiology, and End Results.

References:

  • 1.Shitara K, Xu RH, Ajani JA, et al. Global prevalence of claudin 18 isoform 2 in tumors of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Gastric Cancer. 2024;27(5):1058-1068.
  • 2.Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.3.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed June 4, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  • 3.Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancers V.3.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed June 4, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.
  • 4.Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624-7634.
  • 5.Niimi T, Nagashima K, Ward JM, et al. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 2001;21(21):7380-7390.
  • 6.Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci. 2019;44(2):141-152.
  • 7.Hu YJ, Wang YD, Tan FQ, Yang WX. Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep. 2013;40:6123-6142.
  • 8.Sahin U, Schuler M, Richly H, et al. Eur J Cancer. 2018;100:17-26.
  • 9.Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelialmesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-196.
  • 10.Pellino A, Brignola S, Riello E, et al. Association of CLDN18 protein expression with clinicopathological features and prognosis in advanced gastric and gastroesophageal junction adenocarcinomas [published online October 26, 2021]. J Pers Med. 2021. Accessed April 3, 2026. https://www.mdpi.com/2075-4426/11/11/1095
  • 11.Coati I, Lotz G, Fanelli GN, et al. Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. Br J Cancer. 2019;121(3):257-263.
  • 12.Rohde C, Yamaguchi R, Mukhina S, et al. Comparison of claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol. 2019;49(9):870-876.
  • 13.Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18:476-484.
  • 14.Kubota Y, Kawaoe A, Mishima S, et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer [published online January 5, 2023]. ESMO Open. 2023. Erratum in: [published online January 8, 2024]. ESMO Open. 2024. Accessed February 17, 2025. https://www.esmoopen.com/action/showPdf?pii=S2059-7029%2822%2900396-9
  • 15.Waters R, Sewastjanow-Silva M, Yamashita K, et al. Retrospective study of claudin 18 isoform 2 prevalence and prognostic association in gastric and gastroesophageal junction adenocarcinoma [published online May 23, 2024]. JCO Precis Oncol. 2024. Accessed May 11, 2026. https://ascopubs.org/doi/pdf/10.1200/PO.23.00543
  • 16.National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. Accessed May 7, 2026. https://seer.cancer.gov/statfacts/html/stomach.html
  • 17.National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: esophageal cancer. Accessed May 7, 2026. https://seer.cancer.gov/statfacts/html/esoph.html
  • 18.National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: common cancer sites. Accessed June 23, 2026. https://seer.cancer.gov/statfacts/html/common.html
  • 19.Angerilli V, Callegarin M, Govoni I, et al. Heterogeneity of predictive biomarker expression in gastric and esophago-gastric junction carcinoma with peritoneal dissemination. Gastric Cancer. 2025;28(4):569-578.