Trastuzumab: A New Treatment Option for HER2-Positive Metastatic Gastric and Gastroesophageal Junction Cancer

Lordick, Florian

doi:10.2217/fon.10.178

Cited by 23 publications

(12 citation statements)

References 58 publications

(67 reference statements)

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“…The percentage of patients with gastric cancer who have FGFR2 amplification is low at 5% to 7%, and hence identification of this cohort will present a significant challenge to the clinical development and treatment strategy. However, recent examples such as crizotinib in lung cancer (39) and trastuzumab in both breast and gastric cancer (40), show that in common cancers niche patients can be identified and successfully treated by highly targeted drugs. Two approaches were used to functionally inhibit FGFR2 in gastric cancer cell lines and patient-derived xenograft models; pharmacologic modulation with the small-molecule inhibitor AZD4547, and specific shRNA knockdown of the FGFR2 gene.…”

Section: Discussionmentioning

confidence: 99%

FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547

Xie

Zhang

et al. 2013

Clinical Cancer Research

203

173

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Purpose: FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ATPcompetitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR)1-3, in patients with FGFR2-amplified gastric cancer.Experimental Design: Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2.Results: Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI 50 values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents.Conclusion: FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification. Clin Cancer Res; 19(9); 2572-83. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547

Xie

Zhang

et al. 2013

Clinical Cancer Research

203

173

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“…Differences in HER2 dysregulation in primary solid tumors and metastases may, at least partially, explain HER2-targeted therapeutic inconsistencies. Trastuzumab has been approved for the treatment of advanced gastric cancer (GC) and GEJAC (6–9). While, HER2 is overexpressed in a number of cancers, the rate of HER2 amplification is variable in esophageal cancer (10) and few studies have investigated the different features of HER2 gene amplification among ESCC, GEJAC and GC.…”

Section: Introductionmentioning

confidence: 99%

HER2 gene amplification in esophageal squamous cell carcinoma is less than in gastroesophageal junction and gastric adenocarcinoma

et al. 2013

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The aim of the present study was to detect the amplification of the human epidermal growth factor receptor 2 (HER2) gene in esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJAC) and gastric cancer (GC), as well as to understand the pathological meaning of HER2 gene amplification with regard to clinico-pathological parameters in these types of cancer. HER2 gene amplification was evaluated by fluorescence in situ hybridization (FISH) in surgically obtained specimens from 76 cases of ESCC, 50 of GEJAC and 48 of GC, as well as 21 specimens of tumor-adjacent normal epithelium as a control group. The HER2 gene amplification rates in ESCC, GEJAC and GC were 3.9 (3/76), 24.0 (12/50) and 18.8% (9/48), respectively. The rates of HER2 gene amplification in GEJAC and GC were significantly higher compared with ESCC (χ2=11.563, P<0.001 and χ2=7.375, P<0.007, respectively). HER2 gene amplification was not detected in the normal esophageal or gastric mucosa samples. In ESCC, HER2 gene amplification was correlated with the invasion of the ESCC cells, vascular invasion and lymph node metastasis (χ2=4.789, 3.858 and 5.354, respectively; all P<0.05). However, in GEJAC and GC, no correlations were observed between HER2 amplification and the gender, age, degree of differentiation, invasion, vascular invasion and lymph node metastases of the patients (all P>0.05). The rate of HER-2 gene amplification was low in ESCC, although the amplification of HER-2 was correlated with tumor metastasis in these patients. The rates of HER-2 gene amplification in GEJAC and GC were higher compared with ESCC. Therefore, compared with ESCC, GEJAC may be more similar to GC with regard to HER-2 gene amplification features.

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“…However, a fundamental step toward improving the survival of patients with lymph node-positive gastric cancer lies in the increased understanding of the tumor biological behavior and searching for the possible targets for individual therapy [10], [11]. For example, the human epidermal growth factor receptor 2 (HER2) has become now a new marker of gastric cancer following evidence-based principles [12].Adding trastuzumab to standard chemotherapy could change the poor survival of patients with HER2-positive metastatic gastric cancer [13]–[15].…”

Section: Introductionmentioning

confidence: 99%

Beclin-1 Expression Is a Significant Predictor of Survival in Patients with Lymph Node-Positive Gastric Cancer

Geng

et al. 2012

PLoS ONE

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BackgroundBeclin 1 is a main actor of autophagy. The expression of Beclin 1 and its prognostic role in gastric cancer is largely unexplored. The purpose of the present study is to investigate the expression of beclin 1 in gastric cancer cells, tissues and its relationship with prognosis.MethodsThe expression of Beclin 1 was detected in 271 specimens of lymph-node positive gastric cancer patients by immunohistochemistry. The correlation of Beclin 1 expression to clinicopathologic features and survival of gastric cancer was studied. Beclin-1 expression in gastric cancer cell lines and clinical specimens is also detected using reverse transcription-PCR and Western blotting.ResultsBeclin 1 is up-regulated at both mRNA and protein levels in six gastric cancer cell lines compared with those in normal gastric mucosa cell line (GES-1). The expression of Beclin-1 in gastric clinical specimens is also higher than those in the adjacent noncancerous tissues. Of the 271 patients, 229 (84.5%) were Beclin 1 high expression tumors by immunohistochemistry. Beclin 1 expression is closely associated with intravascular embolus. Kaplan-Meier analysis showed high beclin 1 expression was associated with longer overall survival. Both univariate analysis and multivariate analysis revealed that Beclin 1 expression were independent prognostic factors in the patients with node-positive gastric cancer.ConclusionsOur findings strongly suggest that Beclin 1 has a potential role in tumorigenesis of gastric cancer and could be a promising biomarker for predicting the prognosis of patients with lymph node-positive gastric cancer. It might also serve as a novel therapeutic target for gastric cancer treatment.

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Trastuzumab: A New Treatment Option for HER2-Positive Metastatic Gastric and Gastroesophageal Junction Cancer

Cited by 23 publications

References 58 publications

FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547

FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547

HER2 gene amplification in esophageal squamous cell carcinoma is less than in gastroesophageal junction and gastric adenocarcinoma

Beclin-1 Expression Is a Significant Predictor of Survival in Patients with Lymph Node-Positive Gastric Cancer

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