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

TL;DR

This study shows that CLDN18.2 expression in gastric cancer varies within tumors and can change after chemotherapy, which may affect treatment decisions.

Contribution

The study reveals the high prevalence of CLDN18.2 heterogeneity and its alteration after chemotherapy in gastric cancer.

Findings

CLDN18.2 positivity was observed in 31% of patients, with 87% of these showing heterogeneous expression patterns.

The biopsy–surgery concordance rate for CLDN18.2 was 86%, but dropped to 73% in patients with heterogeneous expression.

Only 4 of 11 initially CLDN18.2-positive patients remained positive after chemotherapy.

Abstract

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.

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.

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).

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.

The online version contains supplementary material available at 10.1007/s10147-026-02972-w.

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