Transcriptome-wide profiling of antibody–drug conjugate (ADC) targets across solid tumors with IHC validation in a sub-cohort.

Abstract

e15177 Background: The expanding use of ADCs and other expression-driven therapies requires biomarker assessment beyond DNA alterations. Transcriptome-wide RNA expression profiling enables quantitative, multi-target assessment, with immunohistochemistry validation supporting clinical use. Methods: Transcriptome-wide RNA profiling was performed on 1903 FFPE tumor samples using a 20,802-gene panel (Exacta). Elevated RNA expression (log₂ fold-change > 2) was assessed for established and emerging ADC targets, including cell-surface antigens ( CLDN18, TROP2 , Nectin-4), receptor tyrosine kinases ( ERBB2, ERBB3, EGFR, MET ), and lineage-associated markers ( DLL3 matched CLDN18 .2 IHC was available in a sub-cohort (N = 68) and served as the reference standard for RNA diagnostic performance. Results: Expression patterns demonstrated both pan-tumor distribution and expected organ-specific enrichment, with CLDN18 enriched in gastroesophageal, gastric, pancreatic, and esophageal cancers; ERBB2 in breast and upper gastrointestinal tumors; and MET in lung and gastric cancers. Several targets, including TROP2 and ERBB3 , showed broad cross-tumor expression, supporting tumor-agnostic ADC strategies. Co-expression of multiple actionable targets was frequently observed. Overall, at least one ADC-relevant target was identified in 60.5% (1151/1903) of tumors, while 23.4% (446/1903) harbored ≥2 potential ADC targets. In the CLDN18 .2 IHC sub-cohort (N = 68), 25% of cases were IHC positive. Using IHC as the reference, RNA expression demonstrated strong concordance, with sensitivity 88.2%, specificity 94.1%, PPV 83.3%, NPV 96.0%, and overall accuracy 92.6%. Conclusions: Transcriptome-wide RNA expression profiling complements DNA-based comprehensive genomic profiling by enabling expression-driven ADC biomarker assessment. Concordance with CLDN18 .2 IHC supports analytical validity, while limited tumor-specific cohorts and single-marker IHC highlight the need for broader multi-marker validation studies. Prevalence of ADC-relevant therapeutic targets identified by transcriptome-wide RNA expression profiling. ADC Target Overall Incidence (%, N=1903) Organ-Specific Incidence (%; n/N) CLDN18 9.3 Gastroesophageal 45.5% (56/123),Gastric 52.9% (36/68),Esophageal 22% (9/41),Pancreatic 38.4% (33/86) MET 10.8 Lung 30.6% (30/98),Gastric 25% (17/68) ERBB2 22.1 Breast 15.3% (55/360),Gastric 27.9% (19/68),Gastroesophageal 26.8% (33/123) DLL3 10.4 Neuroendocrine 42.3% (11/26) TROP2 17.9 Prostate 57% (20/35),Urothelial 50% (7/14),Ovary 34.1% (71/208),Lung 10.2% (10/98),Pancreatic 4.7% (4/86),Breast TNBC 2.7% (3/112) Nectin-4 8.1 Urothelial 14.3% (2/14),Breast 13.9% (50/360),Lung 9.2% (9/98) ERBB3 12.7 Lung 27.6% (27/98) EGFR 5.6 Lung 8.2% (8/98)