Use of subtype-specific patterns of clinically relevant antibody–drug conjugate targets in sarcoma to guide precision oncology strategies.

11549 Background: Sarcomas are rare, biologically heterogeneous malignancies with limited targeted treatment options. Antibody–drug conjugates (ADCs) have demonstrated clinical efficacy across multiple solid tumors by exploiting tumor-associated surface antigens; however, their development in sarcoma has been limited by incomplete characterization of ADC target expression across subtypes. We evaluated expression of clinically relevant ADC targets across sarcoma histologies using bulk RNA sequencing and compared these patterns to cancer types with established ADC activity to generate a sarcoma-wide map of ADC target expression. Methods: We analyzed expression of 18 genes encoding cell-surface ADC targets that are FDA-approved or in active clinical development across more than 1,000 sarcoma samples spanning multiple histologic subtypes. Transcriptomic data were derived from The Cancer Genome Atlas (TCGA), an institutional sarcoma registry, and the Oncology Research Information Exchange Network (ORIEN). Per-sample z-scores were generated using pan-cancer distributions to enable standardized comparison. Z-score distributions were summarized using ordinal bins to define target enrichment across sarcoma subtypes. Parallel pan-cancer analyses were performed for contextual comparison. Results: Sarcomas demonstrated heterogeneous but subtype-specific expression of multiple ADC targets across datasets. Several subtypes exhibited elevated expression of select ADC targets, with z-scores comparable to or exceeding those observed in tumor types where ADCs have established clinical activity. ADC targets of particular interest included LRRC15 and CD276 (B7-H3). LRRC15, currently in investigation as an ADC in breast cancer, demonstrated enrichment in sarcoma, with 28% of undifferentiated pleomorphic sarcoma and 38% of dedifferentiated liposarcoma samples exhibiting z-scores > 2, compared to 12% in breast cancer. CD276 similarly showed subtype-specific overexpression across these sarcoma subtypes. No single target was uniformly overexpressed across all sarcomas, underscoring biologic heterogeneity. Pan-cancer comparison revealed that certain sarcoma subtypes ranked among the highest expressors for specific ADC targets. Conclusions: Across a cohort exceeding 1,000 sarcoma patients with diverse histological subtypes, we identify subtype-specific overexpression of multiple clinically relevant ADC targets. This subtype expression map provides a biologic rationale for expanding ADC development into molecularly selected sarcoma subpopulations and supports biomarker-enriched approaches to ADC trial design. Ongoing studies will validate these findings at the protein level using a sarcoma surfaceome approach, including immunohistochemistry and mass spectrometry based profiling.