FGFR2 amplification and fusion identified by NGS align with FGFR2b overexpression

FGFR2b is an emerging therapeutic target in HER2-negative advanced gastric cancer (AGC). However, diagnostic concordance between FGFR2b immunohistochemistry (IHC) and genomic assays has been inconsistent due to tumor heterogeneity. The clinical relevance of FGFR2 fusion also remains unclear given its low prevalence. This study assessed the diagnostic concordance and clinical significance of FGFR2b overexpression and FGFR2 genomic alterations using whole-slide surgical specimens. A total of 113 AGC gastrectomy specimens underwent FGFR2b IHC (FPR2-D antibody) and tissue-based next-generation sequencing (NGS) with the TruSight Oncology 500 assay. FGFR2b positivity followed FORTITUDE criteria (≥ 10% moderate-to-strong membranous staining). FGFR2b IHC positivity was 10.6%, and FGFR2 amplification was detected in 13.3% of cases. Surgical specimens demonstrated substantial concordance between IHC and NGS (κ = 0.62), which further improved when FGFR2 fusion was incorporated (κ = 0.67). FGFR2 fusion was relatively rare (5.3%) but associated with both amplification and FGFR2b overexpression (83% and 67%, respectively). Fusion-positive patients showed significantly worse overall survival (p = 0.02). In conclusion, adequate surgical tissue enables strong concordance between FGFR2b IHC and NGS. FGFR2b IHC is an effective frontline screen, while NGS is essential for detecting rare FGFR2 fusions that define an aggressive, poor‑prognosis subtype.