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. 2021 Oct 26;11(11):1095.
doi: 10.3390/jpm11111095.

Association of CLDN18 Protein Expression with Clinicopathological Features and Prognosis in Advanced Gastric and Gastroesophageal Junction Adenocarcinomas

Antonio Pellino  1 , Stefano Brignola  2   3 , Erika Riello  2 , Monia Niero  3 , Sabina Murgioni  1 , Maria Guido  2   3 , Floriana Nappo  1 , Gianluca Businello  2 , Marta Sbaraglia  2 , Francesca Bergamo  1 , Gaya Spolverato  4 , Salvatore Pucciarelli  4 , Stefano Merigliano  5 , Pierluigi Pilati  6 , Francesco Cavallin  7 , Stefano Realdon  8 , Fabio Farinati  9 , Angelo Paolo Dei Tos  2 , Vittorina Zagonel  1 , Sara Lonardi  10 , Fotios Loupakis  1 , Matteo Fassan  2   11
Affiliations

Association of CLDN18 Protein Expression with Clinicopathological Features and Prognosis in Advanced Gastric and Gastroesophageal Junction Adenocarcinomas

Antonio Pellino et al. J Pers Med. .

Abstract

The tight junction protein claudin-18 (CLDN18), is often expressed in various cancer types including gastric (GC) and gastroesophageal adenocarcinomas (GECs). In the last years, the isoform CLDN18.2 emerged as a potential drug target in metastatic GCs, leading to the development of monoclonal antibodies against this protein. CLDN18.2 is the dominant isoform of CLDN18 in normal gastric and gastric cancer tissues. In this work, we evaluated the immunohistochemical (IHC) profile of CLDN18 and its correlation with clinical and histopathological features including p53, E-cadherin, MSH2, MSH6, MLH1, PMS2, HER2, EBER and PD-L1 combined positive score, in a large real-world and mono-institutional series of advanced GCs (n = 280) and GECs (n = 70). The association of IHC results with survival outcomes was also investigated. High membranous CLDN18 expression (2+ and 3+ intensity ≥75%) was found in 117/350 (33.4%) samples analyzed. CLDN18 expression correlated with age <70 (p = 0.0035), positive EBV status (p = 0.002), high stage (III, IV) at diagnosis (p = 0.003), peritoneal involvement (p < 0.001) and lower incidence of liver metastases (p = 0.013). CLDN18 did not correlate with overall survival. The predictive value of response of CLDN18 to targeted agents is under investigation in several clinical trials and further studies will be needed to select patients who could benefit from these therapies.

Keywords: CLDN18.2; biomarkers; gastric adenocarcinoma; immunohistochemistry.

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Conflict of interest statement

Fotios Loupakis had roles as consultant or advisor for Roche, Bayer, Amgen and Genentech. Sara Lonardi had roles as consultant or advisor for Amgen, Bayer, Merck Serono, Lilly; she received research funding from Amgen, Merck Serono and she is part of speakers’ bureau of Lilly, BMS. Vittorina Zagonel received honoraria and had roles as consultant or advisor for Bristol-Mayers Squibb, Bayer, Roche, Pfizer, Janssen, Novartis, Astellas, Servier; he had roles as consultant or advisor for Celgene, Merck. Matteo Fassan received research funding from Astellas Pharma, Macrophage Pharma and QED Therapeutics and had roles as consultant or advisor for Astellas Pharma, GSK-Tesaro, Roche and Diaceutics. All the other authors declare no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
(A) Representative example of intratumor CLDN18 heterogeneity; two biopsies from the same primary cancer show dissimilar CLDN18 status. (B) Sensitivity and specificity of CLDN18 testing according to the number of virtual biopsies scored. (C) Two examples of a heterogeneous CLDN18 tumor (left panel) and a gastric adenocarcinoma with a homogeneous CLDN18 status in all the analyzed areas. The selected virtual biopsy area was drawn on the luminal part of the sample, thus simulating superficial biopsy samples obtained at endoscopy. (Original magnifications 1×, 5× and 20×).
Figure 2
Figure 2
Overall survival time in patients with CLDN18 expression (cut-off of 75% and 50%) compared with patients who were claudin-18 negative (<50%).
See this image and copyright information in PMC

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