Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: Implications for claudin 18.2 monoclonal antibody therapy.

AIMS Claudin-18 (CLDN18) is a member of the CLDN family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells and is frequently expressed at high levels in gastric adenocarcinoma. Based on this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastroesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of HER2 inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs. METHODS AND RESULTS We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients and compared the expression profile with a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 and CLDN18.2 expression was validated by reverse transcription-PCR in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CAC cases and in 5% (3/56) of sporadic CRCs (P=0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% vs 36%; P=0.017). CLDN18 expression was significantly associated with MUC5AC expression (P<0.001) and loss of SATB2 expression (P=0.005) in CACs. CLDN18.2 was expressed in CRCs immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2 and no differences were identified in sporadic CRCs. CONCLUSIONS These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.