Hanting Zhu1,2, Chunyu Wang1,2, Jingjing Wang3, Dawei Chen3, Jiaying Deng1,2, Jianyun Deng3, Jianhong Fan4, Harun Badakhshi5, Xuesong Huang3, Likun Zhang3, Jie Cai3, Sheng Guo3, Wubin Qian3, Yongzhan Nie6, Qixiang Li3,7, Kuaile Zhao1,2. 1. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China. 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 3. Crown Bioscience, Inc., San Diego, CA, USA. 4. Department of Gynaecology, Renhe Hospital, Shanghai 200431, China. 5. Department of Radiation Oncology, Charité School of Medicine and Centre for Cancer Medicine, Berlin, Germany. 6. State Key Laboratory of Cancer Biology & Xijing Hospital of Digest Diseases, Fourth Military Medical University, Xi'an 710032, China. 7. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Abstract
BACKGROUND: Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal tumors, but most targeted therapies showed no efficacy in non-selected patients. This study aims at investigating the adaptive cetuximab subset in a cohort of esophageal squamous cell carcinoma (ESCC) patient-derived xenografts (PDXs). METHODS: A large panel of ESCC PDXs has been established. The copy number, mRNA expression and immunohistochemistry (IHC) of key EGFR pathways have been examined along with cetuximab response. A preclinical trial on a randomly selected cohort of 16 ESCC PDXs was conducted, and the genomic annotations of these models were compared against the efficacy readout of the mouse trial. RESULTS: The trial identified that 7 of 16 (43.8%) responded to cetuximab (ΔT/ΔC <0 as responders). The gene amplification and expression analysis indicated that EGFR copy number ≥5 (P=0.035), high EGFR mRNA expression (P=0.001) and IHC score of 2-3 (P=0.034) are associated with tumor growth inhibition by cetuximab, suggesting EGFR may function as a single predictive biomarker for cetuximab response in ESCC. CONCLUSIONS: Overall, our results suggest that an ESCC subtype with EGFR amplification and overexpression benefits from cetuximab treatment, which warrants further clinical confirmation.
BACKGROUND: Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal tumors, but most targeted therapies showed no efficacy in non-selected patients. This study aims at investigating the adaptive cetuximab subset in a cohort of esophageal squamous cell carcinoma (ESCC) patient-derived xenografts (PDXs). METHODS: A large panel of ESCC PDXs has been established. The copy number, mRNA expression and immunohistochemistry (IHC) of key EGFR pathways have been examined along with cetuximab response. A preclinical trial on a randomly selected cohort of 16 ESCC PDXs was conducted, and the genomic annotations of these models were compared against the efficacy readout of the mouse trial. RESULTS: The trial identified that 7 of 16 (43.8%) responded to cetuximab (ΔT/ΔC <0 as responders). The gene amplification and expression analysis indicated that EGFR copy number ≥5 (P=0.035), high EGFR mRNA expression (P=0.001) and IHC score of 2-3 (P=0.034) are associated with tumor growth inhibition by cetuximab, suggesting EGFR may function as a single predictive biomarker for cetuximab response in ESCC. CONCLUSIONS: Overall, our results suggest that an ESCC subtype with EGFR amplification and overexpression benefits from cetuximab treatment, which warrants further clinical confirmation.
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