Claudin-18.2 and Trop-2 as Emerging Biomarkers in Biliary Tract Cancers: Expression Analysis and Therapeutic...

Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder carcinoma, are aggressive tumors with limited treatment options and poor prognosis. Antibody-drug conjugates (ADCs) targeting membrane proteins, such as claudin-18.2 (CLDN18.2) and trophoblast cell surface antigen 2 (Trop-2), are promising targets for other epithelial cancers. However, their expression patterns and clinical relevance in BTC remain unclear.

This study aimed to evaluate CLDN18 and Trop-2 expression levels in BTC and their potential as therapeutic targets.

We retrospectively analyzed 636 patients with BTC who underwent surgical resection at Asan Medical Center between February 1998 and October 2020. Immunohistochemistry was performed using validated antibodies. CLDN18 positivity was defined as membranous staining in ≥ 75% of tumor cells with a moderate-to-strong intensity. Trop-2 expression was quantified by H-score and categorized as low (< 100), medium (100-200), or high (> 200). Associations with clinicopathologic features and survival outcomes were assessed via Kaplan-Meier and Cox regression.

CLDN18 was positive for 5.2% of patients, most frequently in perihilar cholangiocarcinoma (pCCA, 22.2%). Trop-2 high and medium expression were observed in 69.5% and 20.1% of patients, respectively; its expression was low in intrahepatic cholangiocarcinoma (iCCA, 27.3%). CLDN18 expression showed no adverse clinicopathologic features. High expression of Trop-2 was linked to higher T category and more frequent lymphovascular and perineural invasion. Neither biomarker was significantly associated with overall survival (OS) or disease-free survival (DFS).

CLDN18 was highly expressed in specific BTC subtypes, particularly perihilar cholangiocarcinoma (pCCA) and gallbladder cancer, while Trop-2 was broadly expressed. These findings supported the potential of CLDN18.2- and Trop-2-directed therapies in BTC.