Spatial heterogeneity of antibody-drug conjugate targets in pancreatic ductal adenocarcinoma.

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.