A Study On Egfr Gene Amplification And Protein Expression In Chinese Esophagus Cancer Patients And Antitumor Effect Of An Egfr Inhibitor In Patient-Derived Esophagus Cancer Models

Esophagus cancer is the fifth most common malignancy and the fourth leading cause of cancer mortality in China. According to Chinese cancer registry annual report in 2012, esophagus cancer accounts for nearly 1 in 10 of all cancer deaths. Despite the fact that much progress has been made in diagnosis and systemic chemotherapy regimens, the overall prognosis of esophagus cancer is disappointing. The 5-year survival rate, all stages included, is around 15∼25%. There remains a significant unmet medical need for esophagus cancer treatment. EGFR expression was reported in 30∼90% esophagus cancers and overexpression of EGFR was found to be associated with poorer survival. Unlike colon cancer, K-ras mutation was less frequently found in esophagus cancer (5∼10%), suggesting EGFR pathway blockade might bring therapeutic benefit to those patients with EGFR activation or overexpression. In this study, as of November 2013, 35 surgical esophagus tumor samples were collected from a local hospital in Shanghai. 31 of the 35 samples were identified as squamous cell carcinoma. EGFR gene amplification, protein expression and K-ras mutation were studied. In addition, 9 patient derived esophagus cancer xenograft models (PDX) were developed and anti-tumor effect of a novel and highly potent EGFR inhibitor was evaluated in 6 PDX models. Positive EGFR protein expression was found in 66% (23/35) of esophageal cancer samples. EGFR gene amplifications were observed in 9% patients (3/35). In 9 established PDX models, 7 of them showed EGFR expression and 2 with EGFR gene amplification. No K-ras mutation was observed in the 9 models. A novel and highly potent EGFR inhibitor (EGFRi), developed by Hutchison and currently being evaluated in phase I clinical trials in China, demonstrated potent anti-tumor activity in several PDX models with tumor growth inhibition in a range of 70% to >100%. One PDX model with EGFR gene amplification and overexpression exhibited the highest sensitivity to EGFRi with remarkable tumor regression. EGFR signaling transduction was evaluated and the EGFRi inhibited phosphorylation of EGFR and downstream signaling molecules AKT and ERK. In conclusion, EGFR expression and/or gene amplification was frequently found in Chinese esophagus cancer. EGFR inhibition resulted in potent anti-tumor effect in multiple patient derived esophagus cancer models carrying EGFR amplifications or high expression, suggesting the potential benefit that anti-EGFR agents might bring to esophagus cancer patients with abnormal EGFR activation. Citation Format: Yongxin Ren, Jianming Zheng, Linfang Wang, Wei Zhang, Fang Yin, Jinghong Zhou, Xuelei Ge, Shiming Fan, Renxiang Tang, Junen Sun, Weiguo Qing, Weiguo Su. A study on EGFR gene amplification and protein expression in Chinese esophagus cancer patients and antitumor effect of an EGFR inhibitor in patient-derived esophagus cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1730. doi:10.1158/1538-7445.AM2014-1730