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Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

ABSTRACT: The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

SUBMITTER: Dodbiba L

PROVIDER: S-EPMC4380353 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

Dodbiba Lorin L Teichman Jennifer J Fleet Andrew A Thai Henry H Starmans Maud H W MH Navab Roya R Chen Zhuo Z Girgis Hala H Eng Lawson L Espin-Garcia Osvaldo O Shen Xiaowei X Bandarchi Bizhan B Schwock Joerg J Tsao Ming-Sound MS El-Zimaity Hala H Der Sandy D SD Xu Wei W Bristow Robert G RG Darling Gail E GE Boutros Paul C PC Ailles Laurie E LE Liu Geoffrey G

PloS one 20150331 3

The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine prim ...[more]

PMID: 25826681

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Project description:BACKGROUND AND STUDY AIMS: The HER2 status of small endoscopic biopsies is important for predicting the eligibility of patients with metastatic HER2-positive gastric cancer or gastro-esophageal junction (GEJ) cancer for anti-HER2 therapy approved by the U.S. Food and Drug Administration. The aim of this study was to identify the minimum biopsy set required to evaluate the HER2 status with confidence. PATIENTS AND METHODS: A total of 103 consecutive patients with resected gastric cancer or GEJ cancer were retrospectively selected; 2 formalin-fixed, paraffin-embedded samples of each surgical specimen and all paired endoscopic biopsies were analyzed for HER2 status with both immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) methods. A total of 10 virtual biopsies were constructed by selecting areas 2.6 mm in diameter on the luminal side of digitalized slides obtained from the surgical specimens. The results of evaluating HER2 status in virtual biopsies, slides containing complete surgical specimens, and endoscopic biopsies were compared. The resulting minimum biopsy set was applied to the endoscopic biopsy series for validation. RESULTS: A biopsy set containing a minimum of 5 samples was identified as the most accurate in predicting HER2 status (sensitivity, 92 %; specificity, 97 %). In only 3 of the 103 cases (2.9 %) did a comparison of the HER2 evaluation of virtual biopsies and that of entire slides show inconsistent results. Overall agreement between the endoscopic biopsies and surgical samples for HER2 IHC status increased from 78.4 % to 92.3 % when biopsy sets containing 4 or fewer samples were compared with biopsy sets containing 5 or more samples. CONCLUSIONS: Although the recommendations suggest that 8 to 10 biopsies are necessary, the results show that a minimum set of 5 biopsies may be sufficient for reliable HER2 assessment in gastric cancer and GEJ cancer. However, endoscopists should be aware that a smaller sample size may be less accurate in selecting patients eligible for anti-HER2 therapy.

Dataset Information

Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

Publications

Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

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