Abstract
Background
FGFR2b is an emerging therapeutic target in gastric and gastroesophageal junction adenocarcinoma (G/GEJ), although expression heterogeneity may compromise biomarker assessment and patient selection.Methods
This retrospective study evaluated FGFR2b heterogeneity in 169 patients with paired primary and metastatic G/GEJ specimens, comprising 369 samples. Immunohistochemistry was performed for FGFR2b, HER2, PD-L1, CLDN18.2, and MMR proteins, and FGFR2 gene amplification was assessed by fluorescence in situ hybridization (FISH).Results
Using the any 2+/3+ cutoff, FGFR2b positivity was observed in 24 primary tumors (14.2%) and 16 metastatic lesions (9.5%). Using the ≥10% 2+/3+ cutoff, 12 primary tumors (7.1%) and 12 metastatic lesions (7.1%) were FGFR2b-positive. FGFR2b status was not significantly associated with major clinicopathologic variables. Spatial analysis showed significantly fewer FGFR2b-positive tumor cells in superficial than in deeper regions. Marked discordance was observed between primary and metastatic lesions, mainly due to positive-to-negative conversion: 58.3% of primary tumors with FGFR2b any 2+/3+ expression became 0/1+ in metastatic lesions, and 25.0% of primary tumors with FGFR2b ≥10% 2+/3+ expression became Conclusion
These findings highlight the importance of considering expression heterogeneity in FGFR2b-targeted trial design and patient selection. Despite its low prevalence, FGFR2b may represent an independent therapeutic target for a distinct subset of patients.