Faculty, Staff and Student Publications
Language
English
Publication Date
8-14-2025
Journal
Clinical Cancer Research
DOI
10.1158/1078-0432.CCR-24-3981
PMID
40553459
PMCID
PMC12351277
PubMedCentral® Posted Date
6-24-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.
Experimental design: Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor proportion score ≥1%).
Results: The predominant molecular subtype was SCLC-A in 848 (49.3%), SCLC-N in 202 (11.7%), SCLC-P in 142 (8.3%), SCLC-I in 291 (16.9%), and equivocal in 238 (13.8%) samples. B7-H3 expression was high and consistent among subtypes (q > 0.05), whereas DLL3 and SEZ6 expression each differed significantly (both q < 0.0001). PD-L1 positivity was similar across B7-H3 expression quartiles (range, 39.2%-46.5%). Median (95% confidence interval) B7-H3 expression was comparable between patients with and without prior immunotherapy [18.7 (16.5-21.2) and 17.3 (16.4-18.1) transcripts per million, respectively]. B7-H3 was not correlated with a T-cell signature but showed a strong correlation with HAVCR2/TIM3, CD86, PDCD1LG2/PD-L2, and M2 macrophages.
Conclusions: B7-H3 showed consistent, high expression across SCLC molecular subtypes, whereas DLL3 and SEZ6 expression varied significantly. These data suggest that B7-H3-targeting antibody-drug conjugates may be active across SCLC subtypes, consistent with the high reported response rates.
Keywords
Humans, Small Cell Lung Carcinoma, B7 Antigens, Lung Neoplasms, Male, Female, Biomarkers, Tumor, B7-H1 Antigen, Gene Expression Regulation, Neoplastic, Middle Aged, Aged, Mutation, Membrane Proteins, Intracellular Signaling Peptides and Proteins
Published Open-Access
yes
Recommended Citation
Gay, Carl M; Owonikoko, Taofeek K; Byers, Lauren A; et al., "Multidimensional Analysis of B7 Homolog 3 RNA Expression in Small Cell Lung Cancer Molecular Subtypes" (2025). Faculty, Staff and Student Publications. 5414.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5414
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