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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 expression may be examined by IHC, if available.4
Claudins are present throughout the body, but two specific isoforms of CLDN18 are localized 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 two recent global studies in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma, ~38% of cases demonstrated ≥75% of tumour cells with moderate-to-strong (2+/3+) membranous CLDN18 staining.11,12
- Among advanced G/GEJ biomarkers, CLDN18.2 is prevalent11-14
- Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers11,12,14,15
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, including1,16:
- HER2
- PD-L1
- dMMR
Data from two 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.16
Over 1 million new cases of G/GEJ cancers were diagnosed worldwide in 2020, making it the 5th most diagnosed cancer.17
- In Canada, estimates indicate that age-standardized 5-year net survival of patients diagnosed with stomach cancer is 25% (2008–2010).*,18
- Among patients who survive at least one year after diagnosis, approximately 55% survive for 5 years post-diagnosis (2015–2017).†,19
- In 2022, it was estimated that 4100 new cases of stomach cancers would be diagnosed in Canada (excluding Quebec).20
*Age-standardized 5-year net survival estimates for primary sites of cancer, both sexes, three years combined.
†Ages 15–99 years in Canada (excluding Quebec).
CLDN18.2 expression profile is similar across multiple histopathological parameters21
- Between resection (37.6%) and biopsy (38.6%) samples of G/GEJ cancer
- In gastric (39.9%) vs gastroesophageal junction (GEJ) (37.5%) cancer
- Between proximal (44%) and distal (45.3%) locations in G/GEJ cancer
RESECTION OF GASTRIC CANCER
BIOPSY OF GASTRIC CANCER
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 modal metastases9:
CLDN18.2 expression demonstrates intratumoural heterogeneity
As 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.9,23
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
To submit a question to the Medical Information department or any other queries, you can contact us at medinfo.ca@astellas.com
CLDN, claudin; CLDN18.1, claudin 18 isoform 1; CLDN18.2, claudin 18 isoform 2; ESMO, European Society for Medical Oncology; 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, 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):870-6. 11. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-68. 12. Xu RH, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L Claudin-18.2+ (CLDN18.2+)/HER2– locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW. Presented at: March American Society of Clinical Oncology Plenary Series; March 22, 2023. 13. 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. 14. 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. 2021;25:197-206. 15. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol. 2016;22(19):4619-25. 16. 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. 17. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. 18. Statistics Canada. Table 13-10-0160-01. Age-standardized five-year net survival estimates for primary sites of cancer, by sex, three years combined. November 27, 2020. https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310016001. Accessed 11-10-2022. 19. Canadian Cancer Statistics Advisory Committee in collaboration with the Canadian Cancer Society, Statistics Canada and the Public Health Agency of Canada. Canadian Cancer Statistics 2021. Toronto, ON: Canadian Cancer Society; 2021. 20. Brenner DR, Poirier A, Woods RR, et al. Projected estimates of cancer in Canada in 2022. CMAJ. 2022. 194:E601–607. 21. Shitara K, Xu R, Moran D, et al. Global prevalence of CLDN18.2 in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Biomarker analysis of two zolbetuximab phase 3 studies (SPOTLIGHT and GLOW). Presented at the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL, USA. 22. Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor‑targeted immunotherapy. Biomarker Research. 2022;10:38. 23. 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.