Differential FGFR1 copy number status displays unique tumour immune microenvironment in triple-negative breast cancer

Fibroblast growth factor receptor 1 (FGFR1) amplification, a significant cancer alteration with both prognostic and therapeutic relevance, lacks a standardized definition. The relationship between FGFR1 copy number (CN) variations and tumour microenvironment (TME) characteristics also remains poorly understood. This study defined FGFR1 amplification and investigated TME features across FGFR1 CN subtypes in triple-negative breast cancer (TNBC) to guide precise treatment. We analysed 182 TNBC tumour specimens. FGFR1 CN status was assessed using fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) was performed on 88 samples to explore biological differences. Immunohistochemical (IHC) results for CD3, CD4, and CD8 along with clinical data were analysed. Samples were categorized into four groups based on the FGFR1/CEN8 ratio and the mean FGFR1 signals per cell. Groups 1 (ratio ≥ 2.0, signals ≥ 4.0) and 2 (ratio ≥ 2.0, signals < 4.0) exhibited robust tumour proliferation, increased FGFR signalling, and an immunosuppressive TME. Conversely, group 4 (ratio < 2.0, signals < 4.0) showed significantly enhanced immune cell infiltration (e.g. CD8⁺ T cells, NK cells), supported by elevated CD3⁺/CD8⁺ T-cell densities. Group 3 (ratio < 2.0, signals ≥ 4.0) was heterogeneous: tumours with FGFR1 CN ≥ 5 resembled groups 1/2, while those with CN < 5 mirrored group 4. Thus, FGFR1 amplification (FGFR1-Amp) was defined as FGFR1/CEN8 ratio ≥ 2.0 or CN ≥ 5.0 (14.29% prevalence, 26/182). Remaining cases were FGFR1-neutral (FGFR1-Neu). Immune profiling revealed that FGFR1-Amp & HER2-low TNBC had reduced immune cell infiltration but heightened oncogenic signalling (including epithelial-mesenchymal transition, angiogenesis) compared with other subgroups. In contrast, FGFR1-Neu tumours, especially HER2-zero, displayed increased immune cell infiltration (NK cells, effector cells), MHC I/II molecules, activation markers, and elevated immune checkpoint expression (e.g. PD-L1, CTLA4, LAG3). This study defines FGFR1 amplification in TNBC and characterizes its TME. FGFR1-Amp in HER2-low TNBC correlates with an immunosuppressive environment, potentially hindering HER2-ADC efficacy and suggesting combined FGFR inhibition. Conversely, FGFR1-Neu & HER2-zero tumours with immune activation may respond better to immunotherapy. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.