FGFR4 and HER2 co-expression is associated with the proinflammatory tumor microenvironment in HR + breast cancer.

[BACKGROUND] Dysregulated FGFR4 signaling has been associated with aggressive subtypes of breast cancers, characterized by HER2 enrichment or endocrine resistance. However, the biological functions of FGFR4 across breast cancer subtypes remain unclear. This study investigated the molecular characteristics of FGFR4-high tumors to inform potential therapeutic strategies.

[METHODS] This study analyzed clinicopathological characteristics and gene expression profile of 53 hormone receptor-positive (HR) and 41 HR-negative (HR) patients using the AmoyDx Master Panel. The results were validated using The Cancer Genome Atlas (TCGA) and single-cell RNA-seq datasets.

[RESULTS] The patients in the PUMCH cohort (n = 94) were stratified by HER2 and HR statuses and further stratified according to FGFR4 expression. FGFR4-high tumors showed no genomic differences but enriched immune activation pathways, specifically in HRHER2-low/positive subgroups. HR tumors with co-expression of FGFR4 and HER2 exhibited increased immune infiltration (T cells, NK cells, M1 macrophages) and upregulated checkpoints (BTLA, CTLA4, HAVCR2, LAG3). Single-cell data confirmed elevated T-cell abundance in HRHER2-high FGFR4-high cases. TCGA analysis linked high FGFR4 to prolonged disease-free survival (DFS) in HRHER2-positive patients but reduced DFS in HRHER2-zero patients.

[CONCLUSIONS] Co-expression of FGFR4 and HER2 is associated with a proinflammatory tumor microenvironment in HR breast cancer, suggesting immunotherapy potential. Further studies should explore therapeutic strategies to reshape the tumor immune microenvironment.