Abstract 6258: Inter- and intra-tumoral heterogeneity of TNBC determined by spatial gene transcriptomics

Triple-negative breast cancer (TNBC), one of the most aggressive subtypes of breast cancer, is associated with poor prognosis and limited treatment options, particularly when diagnosed at later stages. The extensive inter- and intra-tumoral heterogeneity observed in TNBC further complicates its clinical management. Understanding the molecular difference within this TNBC is crucial for elucidating its biological characteristics and clinical behaviors, as well as for developing personalized therapeutic approaches. In this study, we employ digital spatial profiling (DSP) technology to quantitatively analyze transcript and protein abundance across spatially distinct regions of TNBC, including primary tumor cores, surrounding stroma regions, and metastatic sites. The analysis reveal marked spatial heterogeneity in gene expression profiles, cellular composition, and the immune microenvironment across these regions. Additionally, we identify distinct TNBC subtypes based on unique gene expression patterns. In primary tumor, Basal-like 1 (BL1) emerged as one of the predominant subtypes and was associated with an increased present of memory B cells. We also identified a subgroup resembling unclassified (UNS) subtypes, characterized by low macrophage levels. Moreover, tumor tissues exhibited multiple TNBC subtypes within a single tumor site. This intricate subtyping within the tumor mass underscores the challenges associated with developing effective treatment for TNBC. Our findings demonstrate the power of DSP technology in elucidating the spatial dynamics of TNBC at the molecular level. The identified molecular signatures and subtypes hold potential for improving diagnostic accuracy, enabling targeted drug development, and guiding personalized treatment approaches. Ultimately, this work underscores the utility of spatial transcriptomics for addressing the challenges posed by TNBC heterogeneity and advancing precision medicine for this aggressive cancer subtype. Citation Format: Fengyuan Huang, Deepa Bedi, Clayton Yates. Inter- and intra-tumoral heterogeneity of TNBC determined by spatial gene transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6258.