Zhu Hanting, Wang Chunyu, Wang Jingjing, Chen Dawei, Deng Jiaying, Deng Jianyun, Fan Jianhong, Badakhshi Harun, Huang Xuesong, Zhang Likun, Cai Jie, Guo Sheng, Qian Wubin, Nie Yongzhan, Li Qixiang, Zhao Kuaile
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
J Thorac Dis. 2018 Sep;10(9):5328-5338. doi: 10.21037/jtd.2018.09.18.
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).
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.
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.
Overall, our results suggest that an ESCC subtype with EGFR amplification and overexpression benefits from cetuximab treatment, which warrants further clinical confirmation.
据报道，表皮生长因子受体（EGFR）在大多数食管肿瘤中过表达，但大多数靶向治疗在未选择的患者中未显示出疗效。本研究旨在调查一组食管鳞状细胞癌（ESCC）患者来源的异种移植瘤（PDXs）中的西妥昔单抗适应性亚组。
建立了一大组ESCC PDXs。检测了关键EGFR通路的拷贝数、mRNA表达和免疫组织化学（IHC）以及西妥昔单抗反应。对随机选择的16个ESCC PDXs队列进行了一项临床前试验，并将这些模型的基因组注释与小鼠试验的疗效读数进行了比较。
试验确定16个中有7个（43.8%）对西妥昔单抗有反应（作为反应者，ΔT/ΔC <0）。基因扩增和表达分析表明，EGFR拷贝数≥5（P = 0.035）、EGFR mRNA高表达（P = 0.001）和IHC评分为2 - 3（P = 0.034）与西妥昔单抗抑制肿瘤生长相关，表明EGFR可能作为ESCC中西妥昔单抗反应的单一预测生物标志物。
总体而言，我们的结果表明，具有EGFR扩增和过表达的ESCC亚型受益于西妥昔单抗治疗，这有待进一步的临床证实。
