# Diagnostic and therapeutic challenges in claudin 18.2-positive gastric cancer treated with zolbetuximab: Intrapatient heterogeneity or secondary loss of expression?

## TL;DR

A patient with CLDN18.2-positive gastric cancer showed differing CLDN18.2 expression in tumors and metastases, highlighting challenges in targeted therapy.

## Contribution

First documented case of CLDN18.2-positive gastric cancer identified via bone marrow biopsy and demonstrating intrapatient heterogeneity.

## Key findings

- CLDN18.2 expression was strong in the primary tumor and bone marrow but absent in a metastatic lesion.
- Disease progression occurred in lymph node metastases despite zolbetuximab treatment.
- Zolbetuximab therapy was safely administered despite severe thrombocytopenia.

## Abstract

Claudin 18.2 (CLDN18.2) has emerged as a promising therapeutic target in advanced gastric cancer (GC). Data on resistance to zolbetuximab due to secondary antigen loss or baseline intrapatient heterogeneity are sparse.

A young female patient with advanced GC and severe anemia and thrombocytopenia due to bone marrow carcinomatosis, treated with zolbetuximab-based therapy, exhibited discordant CLDN18.2 expression between primary and metastatic sites. Histological analysis of the resected Krukenberg metastasis revealed CLDN18.2 negativity, contrasting with the strong, diffuse expression in the primary tumor and bone marrow metastases. Subsequent disease progression occurred predominantly in lymph node metastases.

This case reveals the potential clinical impact of the heterogeneity of CLDN18.2 expression or secondary loss of antigen on the efficacy of CLDN18.2-targeted therapy. Reassessment of biomarkers at progression could be considered to optimize personalized treatment strategies. Furthermore, this case supports the safety of administering zolbetuximab-based therapy in the setting of bone marrow carcinomatosis, even in the presence of severe thrombocytopenia (platelet count < 50 × 109/l). To our knowledge, this represents the first documented case of CLDN18.2-positive gastric cancer identified by bone marrow biopsy worldwide.