Abstract 1220: Spatial transcriptomics revealed potential resistance and response factors of sacituzumab govitecan in metastatic breast cancer.

Abstract Background: Sacituzumab govitecan (SG) is a TROP2-targeting antibody-drug conjugated that is approved in metastatic and locally advanced hormone-receptor positive HER2 negative and triple negative breast cancer. Its clinical trials showed significant improvement in clinical benefits, but the reported objective response rates were about 30%. Biomarkers associated with response or resistance to SG are poorly understood. Methods: GeoMx® DSP was performed on tissue transfer arrays generated from 17 biopsies of SG-treated metastatic breast cancer patients. Patients with long time-on-treatment (≥ 10 cycles) were considered responders (N = 7) whereas patients with short time-on-treatment (≤ 4 cycles) were considered non-responders (N = 10). Expression of the whole human transcriptome represented by over 18,000 genes were profiled within the cytokeratin labeled tumor segments and stroma segments. Differentially expressed genes between responders and non-responders were calculated using the linear mixed model with Benjamini-Hochberg procedure. Gene set enrichment analysis (GSEA) was performed using the Reactome pathway database. Results: Over 10,000 gene targets in 117 segments passed the quality control pipeline and therefore used for analysis. In the tumor segments, 7 genes were upregulated in responders including immunoglobin heavy chain genes IGHG2, IGHG3, and IGHG4. 25 genes were upregulated in non-responders, including genes encoding for extracellular matrix (ECM) proteins (TNC, MMP11, MMP14, COL1A, FKBP10, and POSTN). GSEA indicated that ECM organization and proteoglycan regulating pathways are highly expressed in non-responders whereas eukaryotic translation termination pathways, regulation of ornithine decarboxylase, and mitotic G1 phase and G1/S phase transition pathways are upregulated in responders. In the stroma segments, 6 genes were upregulated in the responders including immune related genes (C7, IGHG2, IGHG3, and IGHG4) and lipid metabolism regulating gene APOC1. 11 genes were upregulated in the non-responders, including ECM protein encoding genes (MMP11, COL11A1, COL12A1, and CA2) and immune related genes (HLA-DQA1, PIP, and TSPAN1). GSEA also showed that ECM organization pathways and elastic fiber formation pathways are upregulated in non-responders whereas eukaryotic translation termination, interferon α/β signaling, B cell related signaling, and plasma lipoprotein assembly, remodeling and clearance pathways are upregulated in responders in the stroma segments. Conclusions: Our study identified differential expressed genes between SG-responding and -resistance tumors. Specifically, the upregulation of immune-related genes is associated with response and upregulation of ECM organizations and remodeling are associated with resistance. Validation of these observations is underway. Citation Format: Mengni He, Charles J. Robbins, Julia Benanto, Thazin Nwe Aung, Yalai Bai, Ian E. Krop, David L. Rimm. Spatial transcriptomics revealed potential resistance and response factors of sacituzumab govitecan in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1220.