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A predictive biomarker that may help you learn more about your patients with advanced G/GEJ cancer¹
- Claudins are a family of transmembrane proteins.2,3
- As a component of tight junctions, claudins are involved in the regulation of permeability, barrier function, and polarity of epithelial layers.2,3
- The ESMO Clinical Practice Guidelines highlight that CLDN18.2 is an emerging predictive biomarker for patients with advanced gastric cancer.4
Claudins are present throughout the body, but 2 specific isoforms of CLDN18 are localised to certain tissue types5,6
CLDN18.1
CLDN18.1 is the dominant isoform in normal and malignant lung tissue.
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
Preclinical data have shown that CLDN18.2 may become more exposed as gastric tumours develop5,7
CONFINED IN HEALTHY TISSUE
RETAINED AND EXPOSED IN MALIGNANT TRANSFORMATION
MAINTAINED IN METASTATIC PROGRESSION
Detecting CLDN18.2 expression identifies a previously undefined patient population1
According to a monocentric real-world study approximately 70% of locally advanced and mG/GEJ cancers express Claudin18.2 (at any level), approximately 33% of mG/GEJ patients are Claudin 18.2 positive (high expression).1,*
- Among advanced G/GEJ biomarkers, CLDN18.2 is prevalent11,12
- Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers12,13
According to 2 recent monocentric studies in patients with advanced G/GEJ cancer:
No clear differences have been observed in the prevalence of selected biomarkers with respect to CLDN18.2 expression, including1,14:
- HER2
- PD-L1
- dMMR
Despite recent treatment advances, there are still critical needs to address
- In Germany approximately 6% of women and 4% of men with metastatic gastric adenocarcinoma survive 5 years post diagnosis.16
- In 2018, there were an estimated 14.800 new cases of gastric cancer in Germany.16
- About 40% percent of gastric cancer cases have already metastasized by the time of diagnosis (UICC IV).16
*The tumor samples were collected from one single institution, which may affect the representation of these data for the overall population. Furthermore, analyses corrected for multiple testing are lacking.
CLDN18.1, claudin 18 isoform 1; CLDN18.2, claudin 18 isoform 2; dMMR, deficient mismatch repair; ESMO, European Society for Medical Oncology; GCs, gastric cancers; GECs, gastroesophageal cancers; G/GEJ, gastric/ gastroesophageal junction; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; PD-L1, programmed death ligand 1; TNM, tumour node metastases UICC IV.
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.14
High-level concordance between primary and metastatic samples
Data in patients with G/GEJ cancers suggest that CLDN18.2 expression demonstrated high concordance between primary and metastatic tumour samples.9
In a study of 523 primary G/GEJ adenocarcinomas and 135 pair-matched, synchronous nodal metastases9:
CLDN18.2 expression demonstrates intratumoural heterogeneity
As it is the case with other biomarkers such as HER2, CLDN18.2 expression may demonstrate variability within a tumour, and this should be taken into account when sampling.9,15
In the same study that demonstrated high-level concordance between primary and metastatic samples, intratumoural heterogeneity in terms of CLDN18.2 expression was found in9:
- 40.3%
of primary GC tumours
- 33.6%
of primary GEC tumours
- 28.8%
of nodal metastases
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; IHC, immunohistochemistry; TMA, tissue microarray.
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 2021;11(11):1095. 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. ESMO Gastric Cancer Living Guidelines (07-2023). https://www.esmo.org/living-guidelines/esmo-gastric-cancer-living-guideline/diagnosis-pathology-and-molecular-biology/article/diagnosis-pathology-and-molecular-biology. Accessed 09-07-2023. 5. 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. 6. 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. 7. Sahin U, Schuler M, Richly H, et al. A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. Eur J Cancer 2018;100:17-26. 8. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014;15(3):178–96. 9. 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. 10. Rohde C, Yamaguchi R, Mukhina S, Sahin U, Itoh K, Türeci O. 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. 11. Van Cutsem E, Bang YJ, Feng-yi F, et al. HER 2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 2015;18:476-84. 12. Fuchs Cs, Ozguroglu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer 2022;25:197-206. 13. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol 2016;22(19):4619-25. 14. 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. 15. Grillo F, Fassan M, Sarocchi F, et al. HER2 heterogeneity in gastric/gastroesophageal cancers: from benchside to practice. World J Gastroenterol 2016;22(26):5879-87. 16. Robert Koch Institut. Zentrum für Krebsregisterdaten. Krebs in Deutschland für 2017/2018. 13. Ausgabe, 2021.