Abstract Background: Tumor-associated neurogenesis has emerged as poor prognostic indicators in various solid tumors. Recent studies have suggested that neurogenesis related molecules, particularly those involved in the neuron projection guidance pathway, may promote tumor growth, metastasis, and change the tumor microenvironment of triple-negative breast cancer (TNBC). However, their clinical relevance remains to be fully understood. We hypothesized that the “neuron projection guidance score” may be associated with prognosis of TNBC patients. Methods: Transcriptomic and clinical data were obtained from the TCGA-BRCA (n = 1084) cohort, and METABRIC (n = 1980) as a validation cohort. For treatment response analysis, GSE194040 was utilized. Gene sets corresponding to the GO term neuron projection guidance were extracted from MSigDB and used to calculate a GSVA-based Neuron Projection Guidance (NPG) score. Patients were grouped into neuron projection guidance score -high and -low groups by the median score. Associations with clinicopathologic variables, prognosis, immune landscape, and treatment response were evaluated. Results: Using the xCell algorism, neuron projection guidance (NPG) score was associated with high neuron cell infiltration in TCGA. Gene set enrichment analysis (GSEA) revealed that NPG score-high TNBC was associated with pathways related to cell proliferation and migration, such as epithelial mesenchymal transition, angiogenesis, and TGF-beta signaling. Immune deconvolution using xCell revealed lower enrichment of Th1 and Th2 cells in the NPG score -high group. Consistently, CIBERSORTx showed reduced proportions of CD8+ T cells and M1 macrophages in the NPG-high group, suggesting that tumors with elevated NPG score are characterized by an immunosuppressive tumor microenvironment. Furthermore, analysis using pre-calculated scores from Thorsson et al. revealed that the NPG score-high group had a significantly lower tumor mutation burden compared to the score-low group. This finding suggests that the score-high group is associated with poor response to immune checkpoint inhibitors (ICI). To further investigate this, we extracted a subset of TNBC patients from the GSE194040 cohort who received neoadjuvant chemotherapy with ICI and evaluated the association between the NPG score and pathological complete response (pCR) to ICI therapy. pCR rates did not differ significantly between the two groups, but pCR cases tended to show lower NPG scores. In survival analysis, high NPG-scores were significantly associated with poorer overall survival in TNBC consistently in TCGA and METABRIC cohorts, while no such trend was observed in any other breast cancer subtypes. Conclusions: This study highlights the prognostic significance of neuron projection guidance score in TNBC. High scores were associated with cell proliferation-related gene sets, and an immunosuppressive tumor microenvironment. These results indicate that intratumoral neurogenesis may contribute to changes in tumor behavior and therapeutic response. Citation Format: K. Kawashima, K. Chida, T. AlRommah, M. Oshi, A. Yamada, I. Endo, K. Takabe. Neuron Projection Guidance signature associates with tumor progression and changes in the tumor microenvironment in triple-negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-03.
Kawashima et al. (Tue,) studied this question.
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