title: Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models.
abstract: BACKGROUND
  Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models.
  
  
  METHODS
  PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC) tissues into immunodeficient (SCID/nude) mice. HER-2 gene copy number (GCN) and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group). Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient's ESCC tissues. Similarity between the PDECX models and their corresponding patient's ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation.
  
  
  RESULTS
  None of the PDECX models (or their corresponding patient's ESCC tissues) harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+) in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+). A second HER-2 positive (IHC 2+) model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model.
  
  
  CONCLUSIONS
  This study demonstrates Trastuzumab-induced tumor regressions in HER-2 positive tumors, and highlights PIK3CA mutation as a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models.
authors.affiliation: Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wu
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Ruheng
authors.initials: R
authors.lastname: Zhen
authors.forename: Jing
authors.initials: J
authors.lastname: Lv
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.forename: Songtao
authors.initials: S
authors.lastname: Xu
authors.forename: Shaohua
authors.initials: S
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.forename: Yalan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Tan
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yin
authors.forename: Deming
authors.initials: D
authors.lastname: He
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
authors.forename: Yingyong
authors.initials: Y
authors.lastname: Hou
authors.forename: Di
authors.initials: D
authors.lastname: Ge
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D017931:DNA Primers; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D017931:DNA Primers; D000068878:Trastuzumab