FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study

Su, Xinying; Zhan, Ping; Gavine, Paul R.; Morgan, Shethah; Womack, Chris; Ni, Xiaoqing; Shen, Danhong; Bang, Yung‐Jue; Im, Sungbin; Kim, W. Ho; Jung, Eujene; Grabsch, Heike; Kilgour, Elaine

doi:10.1038/bjc.2013.802

Cited by 166 publications

(146 citation statements)

References 44 publications

(72 reference statements)

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“…13,18 In this large-scale study with 1974 gastric cancer patients, FGFR2 amplification and FGFR2b overexpression were more commonly identified in poorly differentiated tumors with diffuse histology, which is different from other reports. 4,15 Diffuse histology was found in most tumors with high 15 In this study, although FGFR2 amplification itself was not associated with overall survival, FGFR2b overexpression with high H-score showed strong prognostic value for survival.…”

Section: Discussioncontrasting

confidence: 75%

“…4,15 Diffuse histology was found in most tumors with high 15 In this study, although FGFR2 amplification itself was not associated with overall survival, FGFR2b overexpression with high H-score showed strong prognostic value for survival. Considering the controversial clinical significance and high intratumoral heterogeneity of FGFR2 amplification in gastric cancer, 13,18 the extent of FGFR2b overexpression, rather than the presence of FGFR2 amplification itself, may be a better predictor of patient survival. Because FGFR2 FISH assays traditionally only examine a small portion of the tumor, whereas immunohistochemistry assays provide data on the entire tumor section, immunohistochemistry may be a better assay to cover intratumoral heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

“…11 In previous studies, the frequency of FGFR2 amplification varied from 3 to 9% depending on the testing methods. 4,5,[12][13][14][15][16][17][18] The prevalence rates also varied between countries-7% in the United Kingdom, 5% in China, and 4% in Korea-using the same FISH test analyzed in one core laboratory. 18 Nevertheless, the frequency of FGFR2 overexpression detection by immunohistochemistry ranged from 31% up to 51%-which were considerably higher than the incidence of FGFR2 amplifica tions.…”

mentioning

confidence: 99%

“…4,5,[12][13][14][15][16][17][18] The prevalence rates also varied between countries-7% in the United Kingdom, 5% in China, and 4% in Korea-using the same FISH test analyzed in one core laboratory. 18 Nevertheless, the frequency of FGFR2 overexpression detection by immunohistochemistry ranged from 31% up to 51%-which were considerably higher than the incidence of FGFR2 amplifica tions. [19][20][21][22] In this large-scale study comprising of+1900 gastric cancer patients, we have used a sensitive and specific monoclonal antibody against the b-isoform of FGFR2, a known driver of gastric cancer.…”

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confidence: 99%

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FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

et al. 2016

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FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoformspecific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r = 0.79) and FISH (r = 1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; Po0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P = 0.01) and higher N stage (P = 0.006). FGFR2b overexpression with H-score ≥ 150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034-3.261; P = 0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors. Gastric cancer is the second most common cause of cancer-related deaths worldwide, and the prognosis of advanced gastric cancer is still poor. 1 Several large-scaled clinical trials have failed to demonstrate survival benefits of targeted therapeutic agents in patients with metastatic gastric cancer. Nevertheless, the REGARD trial demonstrated significantly longer progression-free survival of gastric cancer patients treated with ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2, compared with that of patients in the placebo group. 2 This was the first trial to demonstrate a meaningful benefit for a monotherapy in metastatic gastric cancer. The RAINBOW trial, which compared the efficacy of paclitaxel with or without ramucirumab in second-line chemotherapy, showed prolonged

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Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

et al. 2016

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“…In another study it as been reported that FGFR1 is an independent negative prognostic factor in surgically resected SCCL and is associated with cigarette smoking (Kim et al, 2016a;Kim et al, 2016b). In gastric cancer, FGFR2 amplification was detected in 4.2-7.4% of cases and has been correlated with poor prognosis and lymphatic invasion (Su et al, 2014). Recently a study screened 312 gastric cancer patients demonstrating that FGFR2 amplification is correlated with a metastatic status at the diagnosis and a poor prognosis .…”

Section: Fgfr In Cancermentioning

confidence: 97%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

et al. 2018

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Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of fibroblast growth factor receptor 2 (FGFR2) was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose‐dependent manner and selectively in FGFR2‐amplified cells. Regorafenib induced G1 arrest (SNU‐16, KATO‐III) and apoptosis (NCI‐H716); however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU‐16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2‐amplified gastric and colorectal cancer and, therefore, might be considered for integration into treatment in patients with FGFR2‐amplified gastric and colorectal cancers.

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FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study

Cited by 166 publications

References 44 publications

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

FGFR a promising druggable target in cancer: Molecular biology and new drugs

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

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