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. 2025 Jul;28(4):598-608.
doi: 10.1007/s10120-025-01611-z. Epub 2025 Apr 11.

Low positivity rate of fibroblast growth factor receptor 2b is associated with heterogeneous expression in gastric cancer

Heonwoo Lee  1 , Min-Hee Ryu  2 , In-Seob Lee  3 , Ji Yong Ahn  4 , Jeong Hoon Lee  4 , Hyungeun Lee  2 , Hyung-Don Kim #  2 , Young Soo Park #  5
Affiliations

Low positivity rate of fibroblast growth factor receptor 2b is associated with heterogeneous expression in gastric cancer

Heonwoo Lee et al. Gastric Cancer. 2025 Jul.

Abstract

Background: Bemarituzumab, a monoclonal antibody targeting fibroblast growth factor receptor 2b (FGFR2b), is under evaluation in phase 3 trials of gastric cancer (GC) trials. However, data on the characteristics, prognostic significance, and heterogenous expression patterns of FGFR2b overexpression in GC remain limited. Therefore, this study aims to investigate the clinicopathologic characteristics and survival outcomes of FGFR2b-positive GC, along with the expression concordance across biopsy, surgical, and metastatic specimens.

Methods: This retrospective study included 466 patients with stages I-IV GC. Biopsy-surgical and primary-metastatic specimen pairs were available for 163 and 135 patients, respectively. FGFR2b overexpression was defined as moderate-to-strong membranous and/or cytoplasmic expression in ≥ 10% of tumor cells. FGFR2 amplification was evaluated using chromogenic in situ hybridization.

Results: FGFR2b overexpression was observed in 4.1% of patients, with 14/341 surgical specimens (4.1%), 3/284 gastric biopsies (1.1%), and 4/135 metastatic specimens (3.0%). FGFR2b overexpression correlated with deeper invasion and perineural invasion in resectable GC. However, it did not influence survival outcomes in resectable or metastatic GC. Among 163 biopsy-surgical pairs, FGFR2b overexpression was observed in only one pair (0.6%). Similarly, among 135 paired primary-metastatic specimens, FGFR2b overexpression was observed in one (0.7%). FGFR2 gene amplification occurred in 16/17 (94.1%) cases with FGFR2b overexpression.

Conclusion: Significant intratumoral and intrapatient heterogeneity is observed in FGFR2b overexpression. Given this variability in expression levels, a single endoscopic biopsy may not accurately assess FGFR2b overexpression. The FGFR2b positivity rate in gastric cancers was 4.1%, likely due to the substantial heterogeneity in its expression.

Keywords: Biomarker; FGFR2b; Gastric cancer; Heterogeneity; Targeted therapy.

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Conflict of interest statement

Declarations. Conflicts of interest: The following authors disclose potential conflicts of interest outside of study. Min-Hee Ryu received honoraria from DAEHWA Pharmaceutical, Bristol Myers Squibb, Lilly, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, Daiichi Sankyo, and AstraZeneca, received research grants from Astellas, and served as a consultant for DAEHWA Pharmaceutical, Bristol Myers Squibb, Lilly, and Ono Pharmaceutical. Hyung-Don Kim received honoraria from AstraZeneca, Bristol Myers Squibb, Ono Pharmaceuticals, Boryung Pharmaceuticals, and Boostimmune, received research grants from AstraZeneca, Amgen, and Roche/Genentech and served as a consultant for Mustbio. Heonwoo Lee, In-Seob Lee, Ji Yong Ahn, Jeong Hoon Lee, Hyungeun Lee, and Young Soo Park declare no competing interests. Financial or non-financial interest: No financial or non-financial interest are directly related to this work. Ethics approval: This study was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2023–1353) and was conducted following institutional and national ethical standards outlined in the latest Declaration of Helsinki. Informed consent: The requirement for informed consent was waived by the IRB due to the use of de-identified data.

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