Evaluation of Trastuzumab Anti-Tumor Efficacy and its Correlation with HER-2 Status in Patient-Derived Gastric Adenocarcinoma Xenograft Models.
The aim of the study was to investigate trastuzumab anti-tumor efficacy and its correlation with HER-2 status in primary xenograft models derived from Chinese patients with gastric adenocarcinoma. Patient-derived gastric adenocarcinoma xenograft (PDGAX) mouse models were firstly generated by implanting gastric adenocarcinoma tissues from patients into immune deficient mice. A high degree of histological and molecular similarity between the PDGAX mouse models and their corresponding patients' gastric adenocarcinoma tissues was shown by pathological observation, HER-2 expression, HER-2 gene copy number, and mutation detection. Based on Hoffmann's criteria in gastric cancer, three models (PDGAX001, PDGAX003 and PDGAX005) were defined as HER-2 positive with fluorescence in situ hybridization (FISH) amplification or immunohistochemistry (IHC) 2+/ 3+, while two models (PDGAX002, PDGAX004) were defined as HER-2 negative. Upon trastuzumab treatment, significant tumor regression (105 % TGI) was observed in model PDGAX005 (TP53 wt), while moderate sensitivity (26 % TGI) was observed in PDGAX003, and resistance was observed in PDGAX001, 002 and 004. A significant increase in HER-2 gene copy number was only observed in PDGAX005 (TP53 wt). Interestingly, trastuzumab showed no efficacy in PDGAX001 (HER2 IHC 3+ and FISH amplification, but with mutant TP53). Consistent with this finding, phosphor-HER2 modulation by trastuzumab was observed in model PDGAX005, but not in PDGAX001.
Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Shanghai, 200127, China.
Hao
H
Chen
Qingqing
Q
Ye
Jing
J
Lv
Peng
P
Ye
Yun
Y
Sun
Shuqiong
S
Fan
Xinying
X
Su
Paul
P
Gavine
Xiaolu
X
Yin
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000068878:Trastuzumab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human