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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 a new predictive biomarker for patients with advanced gastric cancer.4
Claudins are present throughout the body, but 2 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 tumors develop5,7
CONFINED IN HEALTHY TISSUE
RETAINED AND EXPOSED IN MALIGNANT TRANSFORMATION
MAINTAINED IN METASTATIC PROGRESSION
The information provided above is based on the current understanding of data.
Detecting the presence of CLDN18.2 identifies a previously undefined patient population1
According to 2 recent global studies in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma, ~38% of cases demonstrated ≥75% of tumor cells with moderate-to-strong (2+/3+) membranous CLDN18 staining.11,12*
- Among advanced G/GEJ biomarkers, CLDN18.2 is highly prevalent11-14
- Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers11,12,14,15
*Data from 2 global randomized phase 3 studies: the first study included 2403 assessable patients, of which 922 were CLDN18.2 positive; and a second study which included 2104 assessable patients, of which 808 were CLDN18.2 positive.11,12
According to 3 recent studies in patients with advanced/metastatic G/GEJ cancer:
No clear differences have been observed in the prevalence of select biomarkers with respect to CLDN18.2 expression, including1,16,17:
- HER2
- PD-L1
- dMMR
Data from 3 single-institution studies. The first study was undertaken in Padua, Italy and included advanced GCs (n=280) and GECs (n=70).1 The second study was undertaken in 408 Japanese patients with advanced G/GEJ cancers.16 The third study at MD Anderson Cancer Center (MDACC) involved 304 patients.17
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 diagnosis18,19*
- In 2024, an estimated 26,900 new cases of gastric cancer (61% advanced† stage) will be diagnosed in the US19,20
*US SEER 22 (excluding IL/MA) 2014-2020, gastric and esophageal cancers, distant stage.18,19
†Locally advanced (stage II and III) and metastatic (stage IV) G/GEJ cancer per TNM staging classification per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual.21
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, tumor node metastases.
CLDN18.2 expression profile is similar across multiple histopathological parameters22
- Between resection (37.6%; n=327/870) and biopsy (38.6%; n=1403/3632) samples of G/GEJ cancer
- In gastric (39.9%; n=1341/3357) vs gastroesophageal junction (GEJ) (37.5%; n=338/901) cancer
- In gastric, between proximal (44%; n=393/894) and distal (45.3%; n=502/1109) locations
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 samples of primary and lymph node metastases.9
In a study of 523 primary G/GEJ adenocarcinomas and 135 pair-matched, synchronous nodal metastases9:
CLDN18.2 expression demonstrates intratumoral heterogeneity
As is the case with other biomarkers such as HER2, CLDN18.2 expression may demonstrate variability within a tumor, and this should be taken into account when sampling.9,23
In 2021, data was published demonstrating the sensitivity and specificity of CLDN18 testing according to the number of virtual biopsies scored on 93 surgically treated cases (77 GC, 16 GEJ).1
- Based on a single-institution study in Italian patients with G/GEJ adenocarcinoma evaluated by 2 blinded pathologists
- Sensitivity increased from 2 to 9 biopsies (93-100%); after 6 biopsies, increase was minimal (~97.7-100%)
- Specificity stable between 6-8 biopsies (98.5-98.9%)
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.
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Stay up to date on CLDN18.2
By signing up, you will receive updates about testing for CLDN18.2. You
may also be contacted by an Astellas representative.
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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(11):6123-42. 4. ESMO Gastric Cancer Living Guidelines (10-2023). https://www.esmo.org/living-guidelines/esmo-gastric-cancer-living-guideline/diagnosis-pathology-and-molecular-biology/article/diagnosis-pathology-and-molecular-biology. Accessed 01-08-2024. 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. 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. Shitara K, Lordick F, Bang YJ, et al. Lancet 2023;401(10389):1655-68. Errata in: Lancet 2023;402(10398):290; Lancet 2024;403(10421):30. 12. Shah MA, Shitara K, Ajani JA, et al. Nat Med 2023;29(8):2133-41. 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(3):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 2022;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 (Epub) 01-05-2023. 17. 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. 18. National Cancer Institute. SEER Cancer Stat Facts: Esophageal Cancer. https://seer.cancer.gov/statfacts/html/esoph.html. Accessed 05-06-2024. 19. National Cancer Institute. SEER Cancer Stat Facts: Stomach Cancer. https://seer.cancer.gov/statfacts/html/stomach.html. Accessed 04-26-2024. 20. American Cancer Society. Cancer Facts & Figures 2024. Accessed March 7, 2024. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf. 21. Gress DM, Edge SB, Greene FL, et al. Principles of cancer staging. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Chicago, IL: American Joint Committee on Cancer, 2017:3-30. 22. Shitara K, Xu R, Moran D, et al. Presented at the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL, USA. 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.