VEGFC independently predicts poor relapse-free survival in Luminal breast cancer, linked to immunosuppressive TME.
Background
Lymph node metastasis is a critical determinant of breast cancer prognosis, yet the specific microenvironmental cytokines driving this process remain elusive. Current prognostic tools often lack the precision needed to identify patients at highest risk or to guide targeted therapies effectively. Understanding the tumor microenvironment (TME) and its cytokine landscape is crucial for developing better biomarkers and therapeutic strategies. This study addresses the gap by identifying key prognostic cytokines that link nodal metastasis to TME remodeling, aiming to improve risk stratification and uncover novel therapeutic targets.
Study Design
Researchers evaluated a predefined panel of 176 microenvironmental genes using differential expression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm on the TCGA-BRCA cohort to identify optimal predictors of nodal metastasis. Prognostic value was assessed via Kaplan-Meier, subgroup, and multivariate Cox regression analyses, and validated across five independent GEO datasets. Immune infiltration and therapeutic potential were evaluated using Gene Set Enrichment Analysis (GSEA), CIBERSORT deconvolution, pharmacogenomic screening, and molecular docking simulations. The study focused on identifying a biomarker, not testing a specific intervention.
Results
Vascular Endothelial Growth Factor C (VEGFC) emerged as the top biomarker, significantly upregulated in node-positive tumors. Multivariate analysis confirmed that VEGFC acts as a robust, independent predictor of poor relapse-free survival (RFS). Notably, subgroup analyses revealed this prognostic penalty is exceptionally pronounced in hormone receptor-positive Luminal A and B subtypes. Mechanistically, elevated VEGFC is strongly associated with an immunosuppressive "cold"
TME, characterized by reduced cytotoxicCD8+ T-cellinfiltration and enrichedM2-macrophagepolarization across multiple algorithms. Furthermore, pharmacogenomic analyses and docking simulations indicated potential sensitivity toPI3K/AKTinhibitors in VEGFC-high tumors. The abstract did not provide specific numerical values for upregulation, p-values, or fold-changes.
Key Findings
- VEGFC is significantly upregulated in node-positive breast tumors.
- VEGFC independently predicts poor relapse-free survival.
- Prognostic impact of VEGFC is most pronounced in Luminal A and B breast cancer subtypes.
- High VEGFC levels correlate with an immunosuppressive TME, marked by reduced CD8+ T-cells and increased M2-macrophages.
- VEGFC-high tumors may be sensitive to PI3K/AKT inhibitors.
Why It Matters
This research identifies VEGFC as a robust, independent precision biomarker, particularly for Luminal A and B breast cancers, which could significantly refine prognostic assessment. Clinicians could use VEGFC levels to better stratify patients, identifying those at higher risk of relapse who might benefit from more aggressive or targeted interventions. The finding that high VEGFC correlates with an immune-excluded TME suggests that targeting the VEGFC axis could offer a novel strategy to reverse immune evasion, potentially enhancing the efficacy of immunotherapies. Furthermore, the indication of sensitivity to PI3K/AKT inhibitors in VEGFC-high tumors opens avenues for personalized treatment strategies, moving towards a more tailored approach for these challenging subtypes.
vegfc
breast-cancer
biomarker
prognosis
tumor-microenvironment
immune-suppression