Genomic complexity in advanced gastric and esophageal adenocarcinomas: a case report of rare WDR11-AS1-FGFR2 fusions

Fibroblast growth factor receptor 2 (FGFR2) alterations represent an emerging therapeutic target in gastroesophageal adenocarcinoma (GEA). Although FGFR2 amplifications and overexpression have been associated with poor prognosis and therapeutic resistance, the clinical significant FGFR2 fusions, which are exceedingly rare, is unknown. Herein we describe two cases of advanced gastroesophageal and gastric adenocarcinomas characterized by aggressive disease course, rapid progression despite standard first-line chemoimmunotherapy, and the presence of high-level FGFR2 amplification with concurrent WDR11-AS1-FGFR2 fusion detected by circulating tumor DNA (ctDNA) analysis. These cases highlight the genomic complexity and aggressive behavior of FGFR2-driven GEA, underscored by coexisting genetic alterations. The findings emphasize the importance of comprehensive genomic profiling, including both tissue and liquid. in order to capture intratumoral heterogeneity and evolving molecular events. Further investigation of FGFR2 fusion biology and combinatorial therapeutic strategies is warranted to address the clinical challenge of biomarker overlap and treatment resistance in GEA.