Claudin 18.2 Expression in 1,404 Digestive Tract Adenocarcinomas including 1,175 Colorectal Carcinomas: Distinct Colorectal Carcinoma Subtypes are Claudin 18.2 Positive.

Abstract

Claudin 18.2 (CLDN18.2) immunohistochemical expression can be used to select patients with gastric/gastroesophageal junction adenocarcinomas for zolbetuximab (IMAB362) therapy, a monoclonal antibody targeting CLDN18.2. The aim of this study was to correlate immunohistochemical expression of CLDN18.2 with clinicopathologic and molecular features in a large series of digestive tract cancers. Immunohistochemistry (IHC) for CLDN18.2 was performed on tissue microarrays from 1404 adenocarcinomas including 155 gastric/gastroesophageal, 74 pancreatic ductal, 1175 colorectal (576 in initial test cohort; 599 in subsequent validation cohort), and correlated with HER2 and mismatch repair (MMR) status. Cases were scored as CLDN18.2 positive or negative, with positivity defined as moderate to strong membranous staining in >75% of tumor cells. CLDN18.2 expression was correlated with clinicopathologic and molecular features for all colorectal adenocarcinomas. CLDN18.2 was positive in 39% (61/155) of gastric/gastroesophageal adenocarcinomas, 38% (28/74) of pancreatic ductal adenocarcinomas, and 3.4% (40/1175) of colorectal adenocarcinomas (p<0.001). For gastric/gastroesophageal and pancreatic ductal adenocarcinoma, there was no correlation between CLDN18.2 expression and either HER2 or MMR status. In contrast, CLDN18.2-positive colorectal adenocarcinomas had distinct clinicopathologic and molecular features. CLDN18.2-positive colorectal adenocarcinomas were more frequently proximally located and were more often MMR deficient and BRAF V600E positive (all with p<0.05). Quantitative pathologic analysis using the digital pathology biomarker QuantCRC demonstrated marked differences in histologic features between CLDN18.2-positive and negative colorectal adenocarcinomas, with CLDN18.2-positive tumors having increased tumor:stroma ratio and %mucin but decreased %immature stroma in both the test and validation cohorts (all with p<0.05). In conclusion, CLDN18.2-positive colorectal adenocarcinomas are frequently MMR deficient, BRAF V600E mutated, and demonstrate distinct histologic features. Future studies addressing the efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.