Spatial heterogeneity of antibody–drug conjugate targets in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, with limited therapeutic options, few patients showing targetable molecular changes. New therapeutic strategies are necessary. Antibody–drug conjugates (ADCs) have emerged as alternative therapeutic strategies across various cancer types. Herein, we analyze the expression and spatial heterogeneity (six cores per patients) of three ADC targets (c‐MET, NECTIN4, and TROP‐2) in a cohort of 62 PDAC patients (1,116 tissue cores) and associate their levels with clinicopathological and genomic parameters, and the expression of immune checkpoints. c‐MET exhibited significantly higher expression at the tumor front versus tumor center, along with notable intratumoral heterogeneity. In contrast, NECTIN4 and TROP‐2 displayed homogeneous expression patterns, with NECTIN4 being absent in approximately two‐thirds of cases, while TROP‐2 showed consistently strong positivity across tumor regions (98% 3+). By simulating sampling sufficiency for reliable scoring, we observed that, for c‐MET, two tumor samples were sufficient to achieve a maximum score of 1+, while for higher scores (2+ and 3+), four samples were required. For NECTIN4, four samples were necessary to detect scores of 1+ and 2+. For TROP‐2, for a 3+ score, just two samples were sufficient to reach the maximum score. c‐MET or TROP‐2 expression scores were not associated with any clinicopathological parameters. In contrast, NECTIN4 expression showed an association with tumor grade. Correlations with immune checkpoints revealed that high TROP‐2 expression was inversely correlated with PD‐L1 expression. For all three markers no significant differences in expression were found between SMAD4 wild‐type and SMAD4 ‐mutated tumors, nor between TP53 wild‐type and TP53 ‐mutated tumors. Furthermore, analysis of lymph node and distant (liver and peritoneal) metastases revealed significantly higher c‐MET and NECTIN4 expression in the metastatic setting. In conclusion, TROP‐2 is highly expressed in most PDACs, independent of clinicopathological and genomic parameters, and inversely correlating with PD‐L1, making TROP‐2 an ideal ADC target.