Trophoblast cell-surface antigen 2 expression in digestive neoplasms: a promising target for antibody-drug conjugates

Trophoblast cell-surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in multiple cancers, plays crucial roles in tumor progression and therapy resistance, yet its expression patterns and clinical significance in digestive cancers remain incompletely characterized.

This retrospective study analyzed a consecutive cohort of 2370 patients with histologically confirmed digestive cancers (804 gastric [GC], 1,384 colorectal [CRC], and 182 pancreatic cancers [PC]). Comprehensive clinicopathological data were systematically collected. Trop2 expression was quantitatively evaluated by immunohistochemistry and classified into Trop2-negative, Trop2-low, and Trop2-high based on the product of staining intensity and the proportion of positive tumor cells. Statistical analyses included univariate and multivariate logistic regression were used to identify significant clinicopathological and molecular predictors of Trop2 expression patterns. Univariate and multivariate logistic regression analyses were used to explore the relationship between Trop2 expression status (positive [Trop2 intensity ≥ 2] vs. negative) and various clinicopathological features of different tumor types.

Trop2 was widely expressed in digestive cancers, with highest prevalence in PC and GC. Multivariate analysis revealed distinct Trop2 expression patterns in gastrointestinal malignancies. At the pan-cancer level, Trop2 expression significantly correlated with tumor type, (signet ring cell carcinoma) SRCC, vascular invasion (VI) and perineural invasion. Notably, GC showed independent associations with SRCC and intestinal-type Lauren classification; CRC showed VI as the predominant factor associated with Trop2 expression; while PC demonstrated unique correlations with female sex and T1 stage. These findings highlight tumor-type specific regulation of Trop2, providing critical insights for prognostic assessment and targeted therapy.

Trop2 is a promising biomarker for tumor aggressiveness and a potential target for antibody-drug conjugates (ADCs) in digestive cancers, particularly in SRCC-rich, metastatic, and invasive subtypes. These findings provide strong rationale for stratifying patient populations in future clinical investigations of Trop2-directed ADC therapies.