Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma

Abstract

BackgroundFibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma.Patients and MethodsA total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined.ResultsBased on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK.ConclusionsFGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.

FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib

“…Furthermore, it is almost a general principle that cancer cells that undergo EMT are resistant to molecular-targeted drugs partially due to dysregulation of apoptosis. In KRAS-mutant NSCLC cell line SW1573 with an EMT phenotype, marked apoptosis cannot be induced with combinational treatment of BGJ398 and trametinib unless the Bcl-2/Bcl-xL inhibitor ABT263 is added (24). In the present study, although two powerful targeted drugs were utilized, the inhibitory effects on ESCC cells were only moderate.…”

“…High copy numbers of FGFR1 correlated with a significantly higher risk of recurrence in patients with ESCC compared to patients with low copy number expansions (10). Overexpression of FGFR2 was associated with tumor growth and patient outcomes in esophagogastric junction adenocarcinoma (24). Notably, the level of phosphorylation plays a key role in enhancing the activity of the FGFRs.…”

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

“…For example, Su et al [17] reported 7.4% of FGFR2 amplification in a UK GC cohort, while TCGA consortium [18] described a maximum of 9% for specific GC molecular subtypes. Nagatsuma et al reported that 31.1% of GCs presented FGFR2 protein overexpression, while Tokunaga et al extended this observation to 61% in a cohort of esophagogastric junction adenocarcinoma [15,19]. These and other studies triggered several clinical trials using different FGFR2-targeting antibodies in unselected GC patients, but with no survival benefit [12,20] (e.g., clinical trial #NCT01719549).…”

Prognostic role of fibroblast growth factor receptor 2 in human solid tumors: A systematic review and meta-analysis

“…An intensity score ≥2 and the proportion of positively stained cells was greater than 10% were regarded as FGFR2 positive expression Jia et al 13 GC 49/94 IHC, the intensity of staining was scored as 0 (no staining), 1 (weak staining), 2 (moderate staining), or 3 (strong staining). An intensity score ≥3 was regarded as FGFR2 positive expression Tokunaga et al 24 EC 108/68 IHC, the intensity of staining was scored as 0 (no staining), 1 (weak staining, incomplete membranous staining), 2 (moderate staining, complete membranous staining), or 3 (strong staining). An intensity score ≥2 was regarded as FGFR2 positive expression FGFR2: fibroblast growth factor receptors 2; BC: breast cancer; CEP10: chromosome enumeration probe 10; CRC: colorectal cancer; EC: esophageal cancer; FISH: fluorescence in situ hybridization; GC: gastric cancer; HCC: hepatocellular carcinoma; IHC: immunohistochemistry; no.…”