ESMO open · 2025
FGFR2-IIIc isoform detection reveals prognostic prevalence and a functional link to mesenchymal transition in gastric and gastroesophageal junction cancer.
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Hashimoto T, Iida N, Kadowaki S, Makiyama A, Machida N, Takahashi N, Boku S, Kudo T, Oki E, Ohtsubo K, Kawakami T, Okano N, Komatsu Y, Yuki S, Sakamoto N, Kuwata T, Yamashita R, Amisaki M, Shibuki T, Imai M, Fujisawa T, Nakamura Y, Bando H, Shitara K, Yoshino T
Аннотация
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.
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.