Spatial, Temporal, and Molecular Heterogeneity of ADC targets in High-Grade Serous Ovarian Carcinoma

BackgroundAntibody-drug conjugates (ADCs) represent a promising therapeutic approach for high-grade serous ovarian carcinoma (HGSOC). Patient selection for ADC therapy depends on tumor target expression, making it essential to characterize molecular, spatial, and temporal heterogeneity. MethodsWe analyzed two HGSOC tissue microarray cohorts: 100 genomically profiled primaries (1,565 cores) and 64 matched cases with paired primary (P), primary disseminated (PD), and recurrent (R) samples (2,395 cores). Associations between ADC target expression and molecular characteristics, sampling site, and survival were investigated. ResultsADC targets showed no significant associations with homologous recombination deficiency (HRD) or TP53 mutation status; TROP2 was modestly lower in BRCA1/2-mutated tumors. Folate receptor-alpha (FolR1) showed notable spatial heterogeneity: 25% switched therapeutic-indication groups between center and margin at P; 21.7% were reclassified between P and PD. Temporally, all markers showed [≥]20% switching, reaching 38.4% for FolR1 between P and R. High FolR1 expression in P correlated with poorer survival, a pattern not observed in PD or R samples. ConclusionsADC targets in HGSOC display limited molecular but significant spatial and temporal heterogeneity, with expression classifications varying by site and time. FolR1 expression in primary tumors associates with aggressive disease.