For patients diagnosed with gastric or gastroesophageal junction (G/GEJ) adenocarcinoma:

What is CLDN18.2?

Detecting the presence of CLDN18.2 identifies a previously undefined patient population.1

Detecting the presence of CLDN18.2 identifies a previously undefined patient population.1

An emerging biomarker

  • Claudins are a family of transmembrane proteins2,3
  • As a component of tight junctions, claudins are involved in the regulation of permeability, barrier function, and polarity of epithelial layers2,3

CLDN18.2: the biomarker that gastric cancer reveals

Preclinical data have shown that CLDN18.2 may become more exposed as gastric tumors develop.4,6

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

CLDN18.1

Lung Icon

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

CLDN18.2

Stomach Icon

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

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

CLDN18.1

Lung Icon

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

CLDN18.2

Stomach Icon

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

CONFINED IN HEALTHY TISSUE

confined in healthy tissue graph

In normal gastric mucosa, CLDN18.2 is typically buried within tight junctions.4,6

RETAINED AND EXPOSED IN MALIGNANT TRANSFORMATION

RETAINED AND EXPOSED IN MALIGNANT TRANSFORMATION graph

CLDN18.2 is often retained during malignant transformation. CLDN18.2 may be more exposed and accessible to antibodies when cell polarity disruptions and structure loss occur.4,6,7

MAINTAINED IN METASTATIC PROGRESSION

MAINTAINED IN METASTATIC PROGRESSION graph

CLDN18.2 may also be expressed in lymph node metastases of gastric adenocarcinoma as well as other distant metastatic sites.1,4,8,9

The information provided above is based on the current understanding of data.

CLDN18.2 expression may also be observed
in esophageal, pancreatic, and ovarian
mucinous adenocarcinoma as well as in
non–small cell lung cancer4

CLDN18.2 is prevalent in
advanced G/GEJ cancers

According to two recent global studies in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma10,11:

~38% of cases
demonstrated ≥75% of tumor cells
with moderate-to-strong
membranous CLDN18 staining10,11,*
*

Data from 2 global randomized Phase 3 studies: the first study included 2,403 assessable patients, of which 922 had ≥75% of tumor cells demonstrating moderate-to-strong CLDN18 staining; and the second study which included 2,104 assessable patients, of which 808 had ≥75% of tumor cells demonstrating moderate-to-strong CLDN18 staining. CLDN18.2 status was determined by central IHC using the investigational VENTANA CLDN18 (43-14A) RxDx Assay.10,11

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

No clear differences have been observed in the prevalence of select biomarkers with respect to CLDN18.2 expression, including1,12,†:

HER2
PD-L1
dMMR
†

Data from 2 single-institution studies. The first study was undertaken in Padua, Italy and included a large series of advanced GCs (n=280) and GECs (n=70).1 The second study was undertaken in 408 Japanese patients with advanced G/GEJ cancers.12

Despite recent treatment
advances, there are still
critical needs to address

  • In the United States, approximately 6% of patients with metastatic G/GEJ cancer survive 5 years post diagnosis13,14, ‡,¶
  • In 2023, an estimated 26500 new cases of gastric cancer (61% advanced§ stage) and ∼21600 new cases of esophageal cancer (71% advanced§ stage) will be diagnosed in the US13-15
‡

US SEER 22 (excluding IL/MA) 2013-2019, gastric and esophageal cancers, distant stage.13,14

SEER data do not have a separate classification for GEJ apart from esophageal cancer; therefore, true GEJ projections are unknown.14

§

Locally advanced (stage II and III) and metastatic (stage IV) G/GEJ cancer per TNM staging classification as described in NCCN Guidelines.16,17

CLDN, claudin; CLDN18.1, claudin 18 isoform 1; CLDN18.2, claudin 18 isoform 2; dMMR, deficient mismatch repair; GCs, gastric cancers; GECs, gastroesophageal cancers; G/GEJ, gastric/gastroesophageal junction; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; mGC, metastatic gastric/gastroesophageal cancer; PD-L1, programmed death ligand 1; TNM, tumor node metastases.

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

No clear differences have been observed in the prevalence of select biomarkers with respect to CLDN18.2 expression, including1,12,†:

HER2
PD-L1
dMMR
†

Data from 2 single-institution studies. The first study was undertaken in Padua, Italy and included a large series of advanced GCs (n=280) and GECs (n=70).1 The second study was undertaken in 408 Japanese patients with advanced G/GEJ cancers.12

Implementation of reflexive testing protocols for cancer biomarkers can reduce time to identification18

Peer perspectives

Our international team of pathology experts is working to provide new content on CLDN18.2, including consensus-scored cases, quizzes, and more.

Sign up below to receive notifications whenever new content is made available.

Matteo Fassan is a cancer researcher with expertise in molecular pathology and histopathology of the gastrointestinal tract. He received his medical education and his specialty training in Surgical Pathology at Padua University and was a postdoctoral fellow at the Kimmel Cancer Center of Philadelphia (2006-2007) and visiting scholar at the Ohio State University of Columbus (2013).

At present, he is associate professor at Padua University. He focuses his research on microRNA dysregulation in human pathology and microRNA use as innovative biomarkers to be included in clinical practice. He also has long-standing interests in murine models of human disease. He has published more than 300 articles in international scientific journals and coauthored 5 books’ chapters on these topics. He is an active fellow/member of the Italian Society of Pathology (SIAPeC-IAP), and the American Association for Cancer Research (AACR).

Takeshi Kuwata is chief of the Department of Genetic Medicine and Services at the National Cancer Center Hospital East in Tokyo. In addition to being a board-certified pathologist, molecular pathologist, and medical geneticist, he is also an executive board member of the Japanese Gastric Cancer Association and a committee member for the Japanese classification of gastric carcinoma, the Japanese guidelines for HER2 testing in breast/gastric cancer, and the Japanese treatment guidelines for gastric cancer. Specializing in molecular and pathological diagnosis of GI tract and hereditary cancers, he is also involved in the development and standardization of new diagnostics.

Kristina Matkowskyj is a professor in the Department of Pathology and Laboratory Medicine at the University of Wisconsin School of Medicine and Public Health and a staff pathologist at William S. Middleton VA Medical Center. She serves as faculty director of the Translational Sciences BioCore (TSB) at the University of Wisconsin Carbone Cancer Center as well as the Translational Research Initiatives in Pathology (TRIP) Laboratory in the Department of Pathology & Laboratory Medicine. She holds professional memberships with organizations, including the United States & Canadian Academy of Pathologists (USCAP), the College of American Pathologists (CAP), the Wisconsin Society of Pathologists, and the Rodger C. Haggitt Gastrointestinal Pathology Society. Dr Matkowskyj is also an editorial board member for the Journal of Medicine and Human Pathology and an ad hoc reviewer for several other peer-reviewed scientific journals.

Professor Dr Christoph Röcken is director of the Department of Pathology at the University Hospital Schleswig Holstein (UKSH) and was elected vice dean of the Faculty of Medicine in 2012. He was a consultant in the Department for Pathology for the Faculty of Medicine at the Otto-von-Guericke University after completing his PhD and rose to become associate professor in the specialist field of pathology at the Faculty of Medicine in 2005. From 2006 to 2009 he was university professor and vice director of the Institute of Pathology, Charité University-Hospital Berlin, and since 2009 he has been university professor and director of the Institute of Pathology, Christian-Albrechts-University Kiel. Professor Röcken is a member of the American Association for Cancer Research and the European Society of Pathology. He is also chairman of the Working Group of Pathology, German Cancer Society as well as board member of the German Society of Pathology and the German Society for Amyloid Diseases. He has published 426 articles in hepato-gastrointestinal pathology/diagnostics in several peer-reviewed journals.

Professor Dr Rüschoff is senior consultant in pathology at Discovery Life Sciences in Kassel, Germany. His prior positions include full professor at the Institute of Pathology at the University of Regensburg, director of the Institute of Pathology at Klinikum Kassel, and acting director of the Department of Gastroenteropathology at the University of Göttingen and CMO Institute of Pathology Nordhessen. He cofounded the clinical research organization Targos Molecular Pathology GmbH in 2005 and has participated in more than 300 clinical trials pertaining to breast, gastric, lung, and skin cancers. He is also extensively published, with more than 300 original articles, review articles, and book chapters.

The experts above have been contracted as paid advisors through Astellas Pharma Inc. and have received compensation for their time.

The content on this website has been created by Astellas Pharma Inc. and may or may not reflect the views of the experts shown above.

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References: 1. 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 (Epub) 10-26-2021. 2. Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci 2019;44(2):141-52. 3. Hu YJ, Wang YD, Tan FQ, Yang WX. Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep 2013;40:6123-42. 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):7624-34. 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):7380-90. 6. Sahin U, Schuler M, Richly H, et al. Eur J Cancer 2018;100:17-26. 7. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelialmesenchymal transition. Nat Rev Mol Cell Biol 2014;15(3):178–96. 8. 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):257-63. 9. Rohde C, Yamaguchi R, Mukhina S, Sahin U, Itoh K, Türeci. 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):870-6. 10. Shitara K, Lordick F, Bang YJ, et al. Lancet 2023 Apr 14:S0140-6736(23)00620-7. 11. Xu RH, Shitara K, Ajani JA, et al. #405736. Presented at: March American Society of Clinical Oncology Plenary Series; March 22, 2023. 12. Kubota Y, Kawazoe A, Mishima S, et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open. 2023;8(1):100762. 13. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. https://seer.cancer.gov/statfacts/html/stomach.html. Accessed 04-24-2023. 14. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: esophageal cancer. https://seer.cancer.gov/statfacts/
html/esoph.html. Accessed 05-11-2023. 15. American Cancer Society. Cancer Facts & Figures 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf. Accessed 01-19-2023. 16. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.1.2023. National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed 03-13-2023. 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. 17. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancers V.2.2023. National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed
03-13-2023. To view the most recent and complete version of the guideline, go online to NCCN.org. 18. Gregg JP, Li T, Yoneda KY. Molecular testing strategies in non-small cell lung cancer: optimizing the diagnostic journey. Trans Lung Cancer Res 2019;8(3):286-301.