Revealing the Angiogenic Signature of FH-Deficient Breast Cancer: Genomic Profiling and Clinical Implications

<b>Background</b>: Fumarate hydratase (<i>FH</i>) deficiency is a rare metabolic alteration in breast cancer that may drive tumor progression through angiogenic remodeling. However, its role in shaping the tumor microenvironment remains poorly defined, limiting our understanding of metabolism-driven angiogenesis and its therapeutic significance. <b>Methods</b>: We analyzed genomic and transcriptomic profiles from thousands of breast cancer samples, including the TCGA cohort, to identify <i>FH</i> mutations and copy number alterations. Differential expression, pathway enrichment, and weighted gene co-expression network analysis (WGCNA) were performed to characterize metabolic and signaling changes. Clinical relevance was examined in a triple-negative breast cancer patient with an <i>FH</i> mutation treated with bevacizumab. <b>Results</b>: <i>FH</i> alterations were enriched in larger, primary tumors and in older patients. <i>FH</i>-deficient tumors displayed metabolic reprogramming, with reduced oxidative phosphorylation and TCA cycle activity, accompanied by upregulation of angiogenesis, VEGF signaling, and epithelial-mesenchymal transition pathways. WGCNA identified 11 hub genes (including CDH5, CLDN5, VWF, and PECAM1) linked to a pro-angiogenic microenvironment. A clinical case illustrated a durable and exceptional response to bevacizumab-based therapy in an <i>FH</i>-mutant patient. <b>Conclusions</b>: <i>FH</i> deficiency promotes an angiogenic tumor microenvironment and may serve as a predictive biomarker for VEGF-targeted therapies. These findings underscore the therapeutic potential of exploiting metabolic vulnerabilities to inform precision oncology.