Multidimensional analysis of B7 homolog 3 (B7-H3) RNA expression in small-cell lung cancer (SCLC) molecular subtypes.

8088 Background: SCLC is an aggressive cancer with a poor prognosis. B7-H3, a transmembrane protein showing low expression in normal tissues but overexpression in SCLC and other tumors, is a promising target for antibody–drug conjugates. We performed a multidimensional analysis of B7-H3/ CD276 expression in SCLC molecular subtypes (SCLC-A, -N, -P, and -I) and its relationship with expression of other immune-related genes. Methods: Clinical and molecular data for a cohort of patients (pts) with SCLC were derived from a real-world database (Caris Life Sciences, Irving, TX, USA). Tumor RNA expression was used to assign the SCLC molecular subtype derived from non-negative matrix factorization. Programmed death ligand-1 (PD-L1) protein expression was assessed by immunohistochemistry (IHC; antibody 22c3; positive cut-off: tumor proportion score >1%). Demographic, clinical, and molecular data were summarized by SCLC subtype or B7-H3 expression quartile (Q). Spearman’s r evaluated correlations between expression of B7-H3 and other immune-related genes/signatures. Results: The cohort included 1721 pts (52.5% female; 98.9% [434/439] smokers; median age, 67 years [range, 18–90+]). Across the subtypes, B7-H3 expression was high and remarkably consistent ( q>0.05; Table). Other biomarker genes, including DLL3 (q<0.05), had lower and more variable expression. Median (range) B7-H3 expression across all samples was 16.75 (0–68.2) transcripts per million (TPM). Across B7-H3 expression Qs, the proportion of PD-L1-positive pts by IHC was similar (Q1, 39.8%; Q2, 46.5%; Q3, 40.7%; Q4, 39.2%). Median (95% confidence interval) B7-H3 expression was similar between pts with prior immunotherapy ( n=24; 14.43 [11.64–21.17] TPM) and pts without ( n=208; 14.20 [13.00–15.91] TPM); treatment information was not available for the remaining samples in this cohort. B7-H3 expression was not strongly correlated with any other immune-related genes/signatures, although several had moderate correlation ( HAVCR2/ TIM3, r=0.59; PDCD1LG2/ PD-L2, r=0.56; M2 macrophages, r=0.56; CD86, r=0.56). Conclusions: In pts with SCLC, B7-H3 showed high and consistent expression across subgroups defined by molecular subtype or prior immunotherapy. The relative expression of B7-H3 was higher and less variable among molecular subtypes than for other key molecular targets in this tumor type, including DLL3. B7-H3 expression had limited association with PD-L1 expression, supporting a role as a distinct therapeutic target. [Table: see text]