Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer

Nagano, Shinnosuke; Kurokawa, Yukinori; Hagi, Takaomi; Motoyama, Yuichi; Saito, Takuro; Takahashi, Tsuyoshi; Momose, Kota; Yamashita, Kotaro; Tanaka, Koji; Makino, Tomoki; Nakajima, Kiyokazu; Morii, Eiichi; Eguchi, Hidetoshi; Doki, Yuichiro

doi:https://doi.org/10.1007/s10147-026-02972-w

Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer

Nagano, Shinnosuke; Kurokawa, Yukinori; Hagi, Takaomi et al.

International Journal of Clinical Oncology, 2026

アクセス数:26件（2026-04-06 16:20 集計）

固定URL: https://hdl.handle.net/11094/104237

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タイトル	Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer
著者	著者名 Nagano, Shinnosuke
	NRID 1000010470197 1000010470197 ORCID 0000-0002-2883-0132 0000-0002-2883-0132 researchmap permalink krkw krkw Scopus Author ID 7202562410 7202562410 著者名 Kurokawa, Yukinori
	NRID 1000050804465 1000050804465 ORCID 0000-0002-4028-2714 0000-0002-4028-2714 researchmap permalink thagi thagi Scopus Author ID 57209822096 57209822096 著者名 Hagi, Takaomi
	NRID 1000060948074 1000060948074 researchmap permalink y_motoyama y_motoyama Scopus Author ID 57208337832 57208337832 著者名 Motoyama, Yuichi
	NRID 1000020646468 1000020646468 ORCID 0000-0002-1733-5064 0000-0002-1733-5064 researchmap permalink tsaito19 tsaito19 Scopus Author ID 57211629912 57211629912 著者名 Saito, Takuro
	NRID 1000050452389 1000050452389 ORCID 0000-0003-2397-1478 0000-0003-2397-1478 researchmap permalink mihogaoka13611 mihogaoka13611 Scopus Author ID 56182761100 56182761100 著者名 Takahashi, Tsuyoshi
	NRID 1000050749752 1000050749752 ORCID 0009-0004-2623-2122 0009-0004-2623-2122 researchmap permalink kom2005 kom2005 Scopus Author ID 59711925000 59711925000 著者名 Momose, Kota
	NRID 1000020747159 1000020747159 researchmap permalink k-yamashita k-yamashita Scopus Author ID 57191498316 57191498316 著者名 Yamashita, Kotaro
	NRID 1000070621019 1000070621019 ORCID 0000-0001-5178-9388 0000-0001-5178-9388 researchmap permalink koji_tanaka koji_tanaka Scopus Author ID 55628548952 55628548952 著者名 Tanaka, Koji
	NRID 1000080528620 1000080528620 ORCID 0000-0001-7918-4217 0000-0001-7918-4217 researchmap permalink _-_-_- _-_-_- Scopus Author ID 56339970700 56339970700 著者名 Makino, Tomoki
	NRID 1000030432537 1000030432537 ORCID 0000-0001-8635-7585 0000-0001-8635-7585 researchmap permalink project_engine project_engine Scopus Author ID 7404396263 7404396263 著者名 Nakajima, Kiyokazu
	NRID 1000010283772 1000010283772 ORCID 0000-0001-8490-3650 0000-0001-8490-3650 researchmap permalink read0046454 read0046454 Scopus Author ID 7003914326 7003914326 著者名 Morii, Eiichi
	NRID 1000090542118 1000090542118 ORCID 0000-0002-2318-1129 0000-0002-2318-1129 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 著者名 Eguchi, Hidetoshi
	NRID 1000020291445 1000020291445 researchmap permalink ydoki3251 ydoki3251 Scopus Author ID 7006390687 7006390687 著者名 Doki, Yuichiro
キーワード等	Claudin-18
	Gastric cancer
	Immunohistochemistry
	Intratumoral heterogeneity
	Molecular targeted therapy
内容	Nagano S., Kurokawa Y., Hagi T., et al. Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer. International Journal of Clinical Oncology (2026); https://doi.org/10.1007/s10147-026-02972-w.
抄録	Background: Claudin-18 isoform-2 (CLDN18.2) is a novel biomarker and therapeutic target for gastric cancer (GC). It may exhibit the intratumoral heterogeneity and varying expressions between biopsy and surgically resected specimens as well as pre- and post-chemotherapy, which could impact patient selection for the targeted agents. Methods: CLDN18.2 expression was immunohistochemically evaluated in pretreatment biopsy and surgically resected specimens from 183 patients with pT2-T4 GC who underwent upfront gastrectomy. The intratumoral heterogeneity was evaluated by classifying the distribution of CLDN18.2 positive cells as superficial, invasive-front, or random pattern. Furthermore, a separate cohort of 38 patients who underwent neoadjuvant chemotherapy without zolbetuximab were analyzed to compare the pre- and post-treatment CLDN18.2 status. Results: CLDN18.2 positivity was observed in 31% (56/183) of patients. Among the 93 patients with 2 + /3 + expression in ≥ 10% of the tumor cells, 81 (87%) had heterogeneous expression patterns, including superficial (n = 46), random (n = 24), and invasive-front (n = 11) patterns. The overall biopsy–surgery concordance rate was 86% (157/183), but it decreased to 73% (59/81) in patients with a heterogeneous expression pattern. Notably, the concordance rate was particularly low in the superficial pattern, at only 65% (30/46). Among the 38 patients who underwent neoadjuvant chemotherapy, only 4 of 11 initially CLDN18.2-positive cases remained positive after treatment, although the overall concordance rate was 82% (31/38). Conclusion: The CLDN18.2 expression demonstrated an acceptable concordance between biopsy and surgically resected specimens. However, high prevalence of heterogeneous expression and tendency for CLDN18.2 positivity to shift to negativity following chemotherapy existed.
出版者	Springer
収録物名	International Journal of Clinical Oncology
刊行年月	2026-01-28
言語	英語
ハンドルURL	https://hdl.handle.net/11094/104237
PISSN	13419625
eISSN	14377772
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1007/s10147-026-02972-w
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	International Journal of Clinical Oncology. 2026
DC.title	Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer
DC.creator	Nagano, Shinnosuke
	Kurokawa, Yukinori
	Hagi, Takaomi
	Motoyama, Yuichi
	Saito, Takuro
	Takahashi, Tsuyoshi
	Momose, Kota
	Yamashita, Kotaro
	Tanaka, Koji
	Makino, Tomoki
	Nakajima, Kiyokazu
	Morii, Eiichi
	Eguchi, Hidetoshi
	Doki, Yuichiro
DC.publisher	Springer
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2026-01-28
DC.identifier	https://doi.org/10.1007/s10147-026-02972-w
DC.subject	Claudin-18
	Gastric cancer
	Immunohistochemistry
	Intratumoral heterogeneity
	Molecular targeted therapy
DC.description	Nagano S., Kurokawa Y., Hagi T., et al. Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer. International Journal of Clinical Oncology (2026); https://doi.org/10.1007/s10147-026-02972-w.
DCTERMS.abstract	Background: Claudin-18 isoform-2 (CLDN18.2) is a novel biomarker and therapeutic target for gastric cancer (GC). It may exhibit the intratumoral heterogeneity and varying expressions between biopsy and surgically resected specimens as well as pre- and post-chemotherapy, which could impact patient selection for the targeted agents. Methods: CLDN18.2 expression was immunohistochemically evaluated in pretreatment biopsy and surgically resected specimens from 183 patients with pT2-T4 GC who underwent upfront gastrectomy. The intratumoral heterogeneity was evaluated by classifying the distribution of CLDN18.2 positive cells as superficial, invasive-front, or random pattern. Furthermore, a separate cohort of 38 patients who underwent neoadjuvant chemotherapy without zolbetuximab were analyzed to compare the pre- and post-treatment CLDN18.2 status. Results: CLDN18.2 positivity was observed in 31% (56/183) of patients. Among the 93 patients with 2 + /3 + expression in ≥ 10% of the tumor cells, 81 (87%) had heterogeneous expression patterns, including superficial (n = 46), random (n = 24), and invasive-front (n = 11) patterns. The overall biopsy–surgery concordance rate was 86% (157/183), but it decreased to 73% (59/81) in patients with a heterogeneous expression pattern. Notably, the concordance rate was particularly low in the superficial pattern, at only 65% (30/46). Among the 38 patients who underwent neoadjuvant chemotherapy, only 4 of 11 initially CLDN18.2-positive cases remained positive after treatment, although the overall concordance rate was 82% (31/38). Conclusion: The CLDN18.2 expression demonstrated an acceptable concordance between biopsy and surgically resected specimens. However, high prevalence of heterogeneous expression and tendency for CLDN18.2 positivity to shift to negativity following chemotherapy existed.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	104237
citation_title	Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer
citation_author	Nagano, Shinnosuke
	Kurokawa, Yukinori
	Hagi, Takaomi
	Motoyama, Yuichi
	Saito, Takuro
	Takahashi, Tsuyoshi
	Momose, Kota
	Yamashita, Kotaro
	Tanaka, Koji
	Makino, Tomoki
	Nakajima, Kiyokazu
	Morii, Eiichi
	Eguchi, Hidetoshi
	Doki, Yuichiro
citation_publisher	Springer
citation_language	英語
citation_date	2026-01-28
citation_journal_title	International Journal of Clinical Oncology
citation_doi	https://doi.org/10.1007/s10147-026-02972-w
citation_public_url	https://hdl.handle.net/11094/104237

Intratumoral heterogeneity and chemotherapy-induced alteration of CLDN18.2 expression in resectable gastric cancer

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