CLDN 18.2

What is CLDN18.2?

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

What is CLDN18.2?
What is CLDN18.2?
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Global guidelines—including Canada, Japan, China, Germany, Spain, and broader Europe (ESMO)—recommend incorporating CLDN18.2 testing via IHC upon diagnosis or during workup in patients with advanced G/GEJ.3-8

Claudins are present throughout the body, but two specific isoforms of CLDN18 are localised to certain tissue types9,10

  • Claudins are a family of transmembrane proteins11,12
  • As a component of tight junctions, claudins are involved in the regulation of permeability, barrier function, and polarity of epithelial layers11,12
  • Guidelines, including the ESMO Clinical Practice Guidelines, recommend that CLDN18.2 expression by IHC be examined as a biomarker in gastric cancer8
CLDN18.1

CLDN18.1

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

CLDN18.2

CLDN18.2

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

What Is CLDN18.2?

Matteo Fassan, MD, PhD

Normal and tumour cell CLDN18 staining at 5x magnification.

Normal and tumour cell CLDN18 staining at 5x magnification.

Preclinical data have shown that CLDN18.2 may become more exposed as gastric tumours develop9,13


CONFINED IN HEALTHY TISSUE
Confined in healthy tissue

Confined in healthy tissue

In normal gastric mucosa, CLDN18.2 is typically buried within tight junctions.9,13

RETAINED AND EXPOSED IN MALIGNANT TRANSFORMATION
Retained and exposed in malignant transformation

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.9,10,14

MAINTAINED IN METASTATIC PROGRESSION
Maintained in metastatic progression

Maintained in metastatic progression

CLDN18.2 may also be expressed in lymph node metastases of gastric adenocarcinoma as well as other distant metastatic sites.9,15-17

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

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

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=4,507), ~38% of cases demonstrated ≥75% of tumour cells with moderate-to-strong (2+/3+) membranous CLDN18 staining.2

  • In only patients with HER2-negative tumours, ~42% of patients (n/N=1,568/3,705) were CLDN18.2-positive
  • Among advanced G/GEJ biomarkers, CLDN18.2 is highly prevalent18
  • CLDN18.2 expression can be readily detected using IHC
38 percentage

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, including15,19,20

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*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).15 Study 2 was conducted in 408 Japanese patients with advanced G/GEJ adenocarcinoma.19 Study 3 was conducted at MD Anderson Cancer Center (MDACC) and included 304 patients with 
G/GEJ adenocarcinoma.20

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

Based on recent global data, in the year 2022:

  • Over 968,000 individuals globally were diagnosed with stomach cancer21
  • Almost 660,000 individuals globally died from stomach cancer21
  • Over 160,000 individuals in Europe (World Health Organization Europe Region) were diagnosed with stomach cancer22
  • 115,000 individuals in Europe died from stomach cancer22

CLDN18.1=claudin 18 isoform 1. CLDN18.2=claudin 18 isoform 2. dMMR=deficient mismatch repair. ESMO=European Society for Medical Oncology. GC=gastric cancer. GEC=gastroesophageal cancer. HER2=human epidermal growth factor receptor-2. IHC=immunohistochemistry. PD-L1=programmed death ligand 1.

CLDN18.2 expression profile remains consistent across various clinicopathological parameters1,2,23

Prevalence of CLDN18.2-positivity by disease and tumour 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)2

Prevalence of CLDN18.2-positivity by disease characteristics and tumour sample characteristics among all screened patients in two Phase 3 studies (N=4507)2
Prevalence of CLDN18.2-positivity by disease characteristics and tumour sample characteristics among all screened patients in two Phase 3 studies (N=4507)2

Examples of CLDN18 staining based on collection method

RESECTION OF GC

Resection of GC

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

BIOPSY OF GC

Biopsy of GC

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

BIOPSY OF GC

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.16,23

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

86.7%
86.7%

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

86.5%
86.5%

CLDN18.2 expression demonstrates intratumoural heterogeneity

As with other biomarkers (such as HER2), CLDN18.2 expression in G/GEJ cancer exhibits intratumoural heterogeneity, which should be taken into account when sampling tumour tissue.16,24

In the same study showing high concordance between primary and metastatic tumour samples, intratumoural heterogeneity in CLDN18.2 expression was observed in16

CLDN18.2 expression demonstrates intratumoural heterogeneity
CLDN18.2 expression demonstrates intratumoural heterogeneity

CLDN=claudin. CLDN18.2=claudin 18 isoform 2. GC=gastric cancer. GEC=gastroesophageal cancer. G/GEJ=gastric/gastroesophageal junction. HER2=human epidermal growth factor receptor-2.

Learn more about sample preparation and testing

References:

  • 1.Fassan M, Kuwata T, Matkowskyj KA, et al. Claudin-18.2 immunohistochemical evaluation in gastric and gastroesophageal junction adenocarcinomas to direct targeted therapy: a practical approach. Mod Pathol. 2024;37(11):100589.
  • 2.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.
  • 3.Brezden-Masley C, Fiset PO, Cheung CC, et al. Canadian consensus recommendations for predictive biomarker testing in gastric and gastroesophageal junction adenocarcinoma. Curr Oncol. 2024;31(12):7770-7786.
  • 4.Japanese Gastric Cancer Association. JGCA Biomarker Testing Guide for Unresectable Advanced/Recurrent Gastric Cancer, 2nd ed. May 2025.
  • 5.Wang FH, Zhang XT, Tang L, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2023. Cancer Commun (Lond). 2024;44(1):127-172.
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  • 7.Alsina Maqueda M, Teijo Quintáns A, Cuatrecasas M, et al. Biomarkers in gastroesophageal cancer 2025: an updated consensus statement by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). Clin Transl Oncol. 2025;27(9):3580-3594.
  • 8.ESMO Gastric Cancer Living Guidelines. Version 1.4. September 2024. Accessed June 16, 2025. https://www.esmo.org/guidelines/living-guidelines/esmo-living-guideline-gastric-cancer/diagnosis-pathology-and-molecular-biology
  • 9.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.
  • 10.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.
  • 11.Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci. 2019;44(2):141-152.
  • 12.Hu YJ, Wang YD, Tan FQ, Yang WX. Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep. 2013;40:6123-6142.
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  • 14.Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelialmesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-196.
  • 15.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. J Pers Med. 2021;11(11):1095.
  • 16.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.
  • 17.Rohde C, Yamaguchi R, Mukhina S, et al. 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.
  • 18.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.
  • 19.Kubota Y, Kawaoe A, Mishima S, et al. Comprehensive clinical and molecular analysis of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open. 2023;8(1):100762.
  • 20.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. JCO Precis Oncol. 2024;8:e2300543.
  • 21.Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.
  • 22.Global Cancer Observatory. Cancer Today. International Agency for Research on Cancer. Accessed August 8, 2025. https://gco.iarc.fr/today/en/dataviz/tables?mode=population&group_populations=0&multiple_populations=1&populations=100_112_191_196_203_208_233_246_250_268_276_300_31_348_352_372_376_380_398_40_417_428_440_442_470_498_499_51_528_56_578_616_620_642_643_688_70_703_705_724_752_756_762_792_795_8_804_807_826_860&cancers=7 and https://gco.iarc.fr/today/en/dataviz/tables?mode=population&group_populations=0& multiple_populations=1&populations=100_112_191_196_203_208_ 233_246_250_268_276_300_31_348_352_372_376_380_398_40_417_428_440_442_470_498_499_51_528_56_578_616_620_642_643_688_70_703_705_724_752_756_762_792_795_8_804_807_826_860&cancers=7&types=1%22
  • 23.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.
  • 24.Grillo F, Fassan M, Sarocchi F, et al. HER2 heterogeneity in gastric/gastroesophageal carcinoma: assessment of 3D heterogeneity in gastric and gastroesophageal junction cancers. World J Gastroenterol. 2016;22(25):5879-5887.