120P - Uncovering the prognostic potential of FGFR2c isoform expression in advanced gastroesophageal cancer through MONSTAR-SCREEN-2 analysis

Background

Fibroblast growth factor receptor (FGFR) isoform switching from FGFR2b to FGFR2c has been implicated in epithelial-to-mesenchymal transition (EMT) and enhanced invasive potential in various malignancies. This study aimed to investigate the prognostic impact of FGFR2c isoform expression evaluated by whole-transcriptome sequencing (WTS) and its underlying mechanism in patients with advanced gastroesophageal cancer.

Methods

Patients with advanced gastroesophageal cancer who were enrolled in MONSTAR-SCREEN-2 (UMIN000043899) with available WTS and survival data were included. FGFR2 RNA expression were assessed via WTS with Caris MI Profile, distinguishing FGFR2b and FGFR2c isoforms via splice junction detection. The FGFR2c/(2b+2c) ratio categorized patients into high and low groups using the minimum p-value approach applied to Kaplan-Meier overall survival (OS) curves. Gene Set Enrichment Analysis (GSEA) was performed using R software packages to explore molecular mechanisms related to FGFR2isoform switching.

Results

Among the 186 patients, the median value of the FGFR2c/(2b+2c) ratio was 0.10 (95% confidence interval, 0.05-0.12). The optimal cut-off value was identified as 0.35 for the FGFR2c/(2b+2c) ratio, resulting in 26 patients in the FGFR2c-high group and 160 in the FGFR2c-low group. There were no significant differences between the two groups in terms of histological subtypes and the number of metastatic sites (P=0.56 and P=0.95, respectively). FGFR2 amplification was exclusively identified in the FGFR2c-low group (N=9). FGFR2c-high group was significantly associated with shorter OS compared to the FGFR2c-low group (median OS, 7.43 months vs. not reached; hazard ratio, 2.86; 95% CI, 1.55-5.28; log-rank P<0.001). GSEA analysis revealed significantly higher enrichment scores for EMT, apical junction, and hedgehog signaling pathways in the FGFR2c-high group compared to the FGFR2c-low group (all P<0.05).

Conclusions

Our findings highlight the poor prognostic impact of FGFR2c isoform expression in patients with advanced gastroesophageal cancer, potentially due to its role in promoting EMT and enhancing tumor aggressiveness.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

This work was supported by SCRUM-Japan funds.

Disclosure

S. Kadowaki: Financial Interests, Personal, Invited Speaker: Taiho, MSD, Ono, Daiichi Sankyo, BMS, Bayer, Merck, Eisai, Otsuka; Financial Interests, Institutional, Funding: Eli Lilly, MSD, Ono, Daiichi Sankyo, Chugai, Nobelpharma, Yansen, AstraZeneca. A. Makiyama: Financial Interests, Personal, Invited Speaker: Eli Lilly, Taiho, Ono, Daiichi Sankyo, Bristol Myers Squibb. N. Machida: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Ono, Taiho, MSD, Daiichi Sankyo, Yalult, Eli Lilly Japan, Chugai, Astellas, Takeda, Merck biopharma, Nichi-iko, Nippon-Kayaku; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Ono, Daiichi Sankyo, Astellas, MSD, Amgen, ALX Oncology, Seagen. S. Boku: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol Myers Squibb, MSD Japan, Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Asahi Kasei Pharma Co.; Financial Interests, Institutional, Funding: Kyo Diagnostics Co., Ltd. N. Takahashi: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb K.K. E. Oki: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly, Bristol Myers Squibb, MSD, Takeda Pham; Financial Interests, Institutional, Research Grant: Guardant Health. N. Okano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Eli Lilly Japan, Eisai, Bayer Yakuhin, Chugai Pharma, Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, MSD, Incyte, Nihon Servier; Financial Interests, Personal, Funding: J-Pharma. T. Kawakami: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Other, honoraria: Bristol Myers Squibb, Ono Pharmaceutical, Yakult Honsha, Daiichi Sankyo, Eli Lilly, Merck Biopharma, Taiho Pharmaceutical, AstraZeneca. M. Imai-Sumida: Financial Interests, Personal, Invited Speaker: Caris Life Sciences, Sumitomo Corp. T. Fujisawa: Financial Interests, Personal, Invited Speaker: Amelieff Co Ltd. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health Pte Ltd., MSD K.K, Eisai, Zeria Pharmaceutical, Miyarisan Pharmaceutical, CareNet, Inc., Hisamitsu Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Co., Ltd., Becton Dickinson, Guardant Health Japan Corp.; Financial Interests, Personal, Advisory Board: Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda, Exact Sciences, Gilead Sciences, Guardant Health Pte Ltd.; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics, Guardant Health AMEA, Inc., Tempus; Financial Interests, Institutional, Invited Speaker: Seagen. H. Bando: Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Other, Personal, Other, Lecture fee: Ono Pharmaceutical, Taiho Pharmaceutical, Eli Lilly Japan. K. Shitara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Takeda, Ono Pharmaceutical, MSD, Novartis, Daiichi Sankyo, Amgen, Guardant Health Japan Corp, Astellas Pharma Inc., Astellas, Bayer, AstraZeneca, Zymeworks Biopharmaceuticals Inc., Alx Oncology Inc; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Janssen, AstraZeneca, Eli Lilly, Astellas, Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen, PRA Health Sciences. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd., Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., Falco Biosystems Ltd., Merus N.V., Bristol Myers Squibb K.K., Medical & Biological Laboratories Co., LTD., Takeda Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.