What question did this study set out to answer?

This research aims to evaluate the expression of ADC targets across solid tumors using RNA profiling and IHC validation.

May 30, 2026

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

Key Points

This research aims to evaluate the expression of ADC targets across solid tumors using RNA profiling and IHC validation.
Performed transcriptome-wide RNA profiling on 1903 FFPE tumor samples using a 20,802-gene panel.
Examined RNA expression for established and emerging ADC targets like CLDN18 and ERBB2.
Validated a sub-cohort (N = 68) using IHC as the reference standard for RNA diagnostic performance.
1151 out of 1903 tumors (60.5%) showed at least one ADC-relevant target.
CLDN18 enriched in specific cancers such as gastroesophageal (45.5%) and gastric (52.9%).
In the CLDN18.2 IHC sub-cohort, RNA showed 88.2% sensitivity and 94.1% specificity.

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)

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