FGFR2-IIIc isoform detection reveals prognostic prevalence and a functional link to mesenchymal transition in gastric and gastroesophageal junction cancer.

[BACKGROUND] Fibroblast growth factor receptor 2 (FGFR2), a therapeutic target for advanced gastric and gastroesophageal junction cancers (GC/GEJCs), exists as two functionally distinct isoforms: FGFR2-IIIb and FGFR2-IIIc. We investigated the clinical significance of FGFR2 splice variant distribution in advanced GC/GEJCs and its implications for therapeutic targeting.

[PATIENTS AND METHODS] Whole-transcriptome sequencing was carried out on 235 patients with advanced GC/GEJCs enrolled in MONSTAR-SCREEN-2 (UMIN000043899). FGFR2-IIIc proportion was quantified using splice junction analysis, and its association with clinical outcomes was evaluated through survival analysis, comprehensive molecular profiling, and longitudinal assessment of treatment-induced isoform dynamics.

[RESULTS] Among 209 patients with detectable FGFR2 expression, high-proportion FGFR2-IIIc (>0.28) was associated with significantly shorter overall survival compared with low-proportion FGFR2-IIIc (median 9.59 versus 16.0 months, hazard ratio 2.08, 95% confidence interval 1.33-3.26, P < 0.001). Multivariable Cox regression confirmed FGFR2-IIIc proportion as an independent predictor of poor prognosis (P = 0.008), superior to total FGFR2 expression levels. Longitudinal analysis of 33 paired pre- and post-treatment samples revealed treatment-induced increases in FGFR2-IIIc proportion (P = 0.0085), suggesting adaptive isoform switching. Notably, all tumors with elevated FGFR2 expression exclusively belonged to the low-IIIc group, indicating that current FGFR2-targeted therapies primarily benefit patients with FGFR2-IIIb-dominant expression profiles. High-proportion FGFR2-IIIc was significantly associated with epithelial-to-mesenchymal transition and myogenesis pathway activation. Differential splicing analysis identified coordinated alternative splicing events in ESRP1-regulated targets, suggesting potential broader splicing dysregulation and providing mechanistic insights into the aggressive phenotype.

[CONCLUSIONS] FGFR2-IIIc proportion represents a clinically relevant prognostic biomarker in advanced GC/GEJCs. Treatment-induced isoform switching toward FGFR2-IIIc suggests a novel resistance mechanism requiring targeted therapeutic approaches. These findings underscore the importance of developing isoform-specific therapeutic strategies and implementing FGFR2-IIIc assessment in precision oncology approaches for GC/GEJCs.