{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:17:00Z","timestamp":1788254220235,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Claudin 18.2 (CLDN18.2) is expressed in a substantial proportion of pancreatic ductal adenocarcinoma (PDAC) and has emerged as a promising therapeutic target. However, the positivity threshold for enrollment in CLDN18.2-directed trials remains undefined, and ongoing studies use different criteria. We quantified how different CLDN18.2 thresholds influence the size of the candidate population within the same PDAC cohort. Methods: In this retrospective single-center study, CLDN18.2 was assessed by immunohistochemistry (43-14A clone, Ventana BenchMark) in 99 PDAC patients (metastatic, n = 71; non-metastatic, n = 28). The candidate population was evaluated at three thresholds: two used in current CLDN18.2 trials (any-intensity [1+\/2+\/3+] staining in \u226540% and moderate-to-strong [2+\/3+] staining in \u226575% of tumor cells) and an exploratory lower bound of any detectable expression (\u22655%). Between-threshold reclassification was analyzed as paired data; clinicopathological and survival analyses were exploratory. Results: The candidate proportion was 40.4% (40\/99) at \u226575%, 43.4% (43\/99) at \u226540%, and 64.6% (64\/99) at \u22655%; among metastatic patients, it was 36.6%, 38.0%, and 59.2%, respectively. Lowering the threshold from \u226575% to \u226540% caused virtually no reclassification (1\/71 metastatic, 1.4%; McNemar p = 1.0), whereas lowering it to \u22655% reclassified 16 metastatic patients (22.5%; 95% CI, 14.4\u201333.5; p &lt; 0.001) as candidates. Among the 64 tumors with detectable expression, median staining was 80% (IQR, 20\u201390%). Survival analyses were exploratory and underpowered (52 deaths; 80% power for HR \u2265 2.24); no association between CLDN18.2 and overall or progression-free survival was detected at any threshold. Conclusions: The stringent thresholds used in current drug development identified nearly identical candidate populations, whereas relaxation to any detectable expression substantially enlarged the pool; CLDN18.2 behaved as a targetable rather than a prognostic biomarker. Our findings highlight the need for a PDAC-specific, response-based CLDN18.2 threshold.<\/jats:p>","DOI":"10.3390\/cancers18172827","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:31:13Z","timestamp":1788251473000},"page":"2827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Claudin 18.2 Positivity Thresholds and Candidate Populations for Targeted Therapy in Pancreatic Ductal Adenocarcinoma: A Real-World Retrospective Cohort"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-317X","authenticated-orcid":false,"given":"G\u00fcner","family":"Akg\u00fcner","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6142-9001","authenticated-orcid":false,"given":"Elif","family":"Haznedaro\u011flu Benlio\u011flu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4139-067X","authenticated-orcid":false,"given":"\u00d6zgen Ahmet","family":"Y\u0131ld\u0131r\u0131m","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0333-1388","authenticated-orcid":false,"given":"Ay\u015feg\u00fcl \u0130lhan","family":"G\u00fcle\u015fen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3929-6086","authenticated-orcid":false,"given":"Batuhan","family":"G\u00fcnel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ata T\u00fcrker","family":"Ar\u0131k\u00f6k","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6m\u00fcr Berna","family":"\u00c7akmak \u00d6ks\u00fczo\u011flu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadriye Bir","family":"Y\u00fccel","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths: Pancreatic cancer","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer","volume":"364","author":"Conroy","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine","volume":"369","author":"Ervin","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/s43018-022-00349-2","article-title":"Translational advances in pancreatic ductal adenocarcinoma therapy","volume":"3","author":"Hosein","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1056\/NEJMoa2605555","article-title":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","volume":"395","author":"Wainberg","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7624","DOI":"10.1158\/1078-0432.CCR-08-1547","article-title":"Claudin-18 splice variant 2 is a pan-cancer target","volume":"14","author":"Sahin","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1002\/ijc.28400","article-title":"Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms","volume":"134","author":"Schlitter","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S0140-6736(23)00620-7","article-title":"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","volume":"401","author":"Shitara","year":"2023","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1038\/s41591-023-02465-7","article-title":"Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: The randomized, phase 3 GLOW trial","volume":"29","author":"Shah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4017","DOI":"10.1200\/JCO.2025.43.16_suppl.4017","article-title":"Claudin18.2 (CLDN18.2) expression and efficacy in pancreatic ductal adenocarcinoma (PDAC): Results from a phase I dose expansion cohort evaluating IBI343","volume":"43","author":"Yu","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Li, X., Dai, R., Xu, Q., Guo, Z., Hu, C., Sun, Y., Niu, Z., Hao, J., Zhang, M., and Dai, G. (2026). Safety and preliminary efficacy results of IBI389, an anti-Claudin18.2\u00d7CD3 bispecific antibody, in patients with solid tumors and gastric or gastro-esophageal tumors: A phase 1 dose escalation and expansion study. BMC Med., 24.","DOI":"10.1186\/s12916-025-04597-8"},{"key":"ref_13","unstructured":"National Library of Medicine (US) (2026, August 24). IBI343 Combined With Chemotherapy as Neoadjuvant Therapy in Borderline Resectable Pancreatic Cancer, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07415525."},{"key":"ref_14","first-page":"e1523096","article-title":"Characterization of zolbetuximab in pancreatic cancer models","volume":"8","author":"Yamada","year":"2019","journal-title":"Onco Targets Ther. OncoImmunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102044","DOI":"10.1016\/j.tranon.2024.102044","article-title":"Extent and clinical significance of the therapy-relevant tight junction protein Claudin 18.2 in pancreatic ductal adenocarcinoma\u2014Real-world evidence","volume":"47","author":"Lyu","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.1200\/JCO.2024.42.16_suppl.4142","article-title":"FG-M108 plus nab-paclitaxel and gemcitabine (AG) as first-line (1L) treatment for patients with Claudin-18.2 (CLDN18.2)-positive locally advanced unresectable or metastatic pancreatic cancer: Preliminary results from the phase 1b study","volume":"42","author":"Jin","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2535047","DOI":"10.1080\/21688370.2025.2535047","article-title":"Concordance of claudin-18.2 expression in biopsy, resection, and recurrent specimens: Implications for zolbetuximab therapy in pancreatic ductal adenocarcinoma","volume":"14","author":"Kyuno","year":"2025","journal-title":"Tissue Barriers"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3892\/ol.2025.14886","article-title":"Claudin 18.2: An attractive marker in pancreatic ductal adenocarcinoma","volume":"29","author":"Valentini","year":"2025","journal-title":"Oncol. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Park, S., Shin, K., Kim, I.H., Hong, T., Kim, Y., Suh, J., and Lee, M. (2023). Clinicopathological Features and Prognosis of Resected Pancreatic Ductal Adenocarcinoma Patients with Claudin-18 Overexpression. J. Clin. Med., 12.","DOI":"10.20944\/preprints202306.1374.v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100712","DOI":"10.1016\/j.modpat.2025.100712","article-title":"Claudin 18.2 Expression in 1404 Digestive Tract Adenocarcinomas Including 1175 Colorectal Carcinomas: Distinct Colorectal Carcinoma Subtypes Are Claudin 18.2 Positive","volume":"38","author":"McHugh","year":"2025","journal-title":"Mod. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102362","DOI":"10.1016\/j.tranon.2025.102362","article-title":"Claudin 18 (43-14A clone) expression in pancreatic ductal adenocarcinoma: Assessment of a potential clinical biomarker for zolbetuximab therapy","volume":"55","author":"Arseneau","year":"2025","journal-title":"Transl. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Al Subhi, M., Al-Nabhani, D., Al Sarmi, M., Elrahman, A.A., AlSawafi, Y., Sirasanagandla, S.R., and Al-Mufargi, Y. (2026). Expression of Claudin-18.2 in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Front. Med., 13.","DOI":"10.3389\/fmed.2026.1809374"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1007\/s00428-025-04306-z","article-title":"The prognostic value of CLDN18.2 expression in pancreatic ductal adenocarcinoma: A systematic review and individual patient data meta-analysis","volume":"488","author":"Matheus","year":"2026","journal-title":"Virchows Arch."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.annonc.2021.02.005","article-title":"FAST: A randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma","volume":"32","author":"Sahin","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bai, C., Xue, J., Zheng, Y., Sun, M., Ying, J., Zhou, F., Yu, Y., Sun, Y., Xing, L., and Zhang, Y. (June, January 31). A phase 1\/2 study of LM-302, an anti-claudin 18.2 (CLDN18.2) antibody\u2013drug conjugate in patients with advanced gastric\/gastroesophageal junction cancer. Proceedings of the Poster Presentation, 2024 ASCO Annual Meeting, Chicago, IL, USA.","DOI":"10.1200\/JCO.2024.42.16_suppl.3028"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"0247","DOI":"10.34133\/cbsystems.0247","article-title":"Hollow Mesoporous Carbon Nanospheres Derived from Metal-Organic Frameworks for Efficient Sono-immunotherapy against Pancreatic Cancer","volume":"6","author":"Chen","year":"2025","journal-title":"Cyborg Bionic Syst."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2203690","article-title":"Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer","volume":"387","author":"Modi","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.21873\/anticanres.17802","article-title":"High Claudin 18.2 Expression Predicts Favorable Outcomes in Pancreatic Ductal Adenocarcinoma After Curative Resection","volume":"45","author":"Cha","year":"2025","journal-title":"Anticancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1055\/a-2524-2596","article-title":"Endoscopic ultrasound-guided tissue sampling: European Society of Gastrointestinal Endoscopy (ESGE) Technical and Technology Review","volume":"57","author":"Facciorusso","year":"2025","journal-title":"Endoscopy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1055\/a-1915-5263","article-title":"Endoscopic ultrasound-guided fine-needle biopsy with or without macroscopic on-site evaluation: A randomized controlled noninferiority trial","volume":"55","author":"Mangiavillano","year":"2023","journal-title":"Endoscopy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eady7524","DOI":"10.1126\/scitranslmed.ady7524","article-title":"Spatial profiling of human pancreatic ductal adenocarcinoma reveals molecular alterations associated with venous invasion","volume":"17","author":"Bell","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/path.6398","article-title":"Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: A bottom-up approach","volume":"265","author":"Hilmi","year":"2025","journal-title":"J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zhao, W.Y., and Zhao, J.W. (2026). Pancreatic cancer immunotherapy biomarkers: From traditional markers to multimodal integration and dynamic monitoring. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1686658"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Peng, X., Liu, Z., Luo, C., Sun, R., Zhang, Y., Li, B., Zou, Y., Zhu, J., and Yuan, R. (2025). PSMD12 promotes hepatocellular carcinoma progression by stabilizing CDK1. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1581398"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yoshino, J., Blomstrand, H., Fjellander, S., Svensson, J., Halimi, A., Kesti, E., Sepp\u00e4nen, H., Vilhav, C., \u00d6hlund, D., and Haglund, C. (2026). Prognostic Value of Intratumoral Expression of Claudin 18.2 in Resected Pancreatic Cancer. Ann. Surg. Oncol.","DOI":"10.1245\/s10434-026-20191-5"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1158\/1538-7445.AM2026-1007","article-title":"Modulation of Claudin 18.2 by chemoradiotherapy in pancreatic and gastric cancer","volume":"86","author":"Heidari","year":"2026","journal-title":"Cancer Res."},{"key":"ref_37","unstructured":"National Library of Medicine (US) (2026, August 01). A Phase 1b Study of Neoadjuvant ASP2138 Monotherapy and Investigator\u2019s Choice of Adjuvant Chemotherapy in Participants With Resectable Pancreatic Ductal Adenocarcinoma Whose Tumors Have Claudin (CLDN) 18.2 Expression. Identifier NCT07024615, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07024615."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2827\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:38:40Z","timestamp":1788251920000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2827"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":37,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18172827"],"URL":"https:\/\/doi.org\/10.3390\/cancers18172827","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}