Abstract 2774: The molecular determinants of sensitivity to HER2 targeted therapy in Patient Derived Xenograft gastric tumor models from Caucasian and Eastern Asian patients.
Authors: Vuaroqueaux Vincent , Ackermann Andreas , Guo Jianing , Peille Anne-Lise , Krumbach Rebekka , Foucault Frederic , Metz Thomas , Fiebig Heinz-Herbert 
Published: August 2014

Introduction: Gastric cancer is common in Asia and Eastern Asia where more than half of the world's cases arise. As is the case for Caucasian patients, amplification and overexpression of the HER2 gene is a critical event in the tumorigenesis of gastric cancer and is present in 10 to 20% of Asian patients. Trastuzumab has been approved for treatment of HER2-positive gastric cancer. However, primary and secondary resistance to Trastuzumab is a significant problem and new strategies to overcome resistance are needed. Models which recapitulate this differential response aid the development of new therapies targeting HER2. We recently enlarged our collection of gastric cancer Patient Derived Xenografts (PDX), which in the past focused on Caucasian patients, by developing PDX from Eastern Asian patients. In this study we investigated whether the newly developed PDX collection is reflective of the clinical situation and contains HER2 amplified/overexpressing tumors. We evaluated the sensitivity to Trastuzumab treatment of gastric cancer PDX which are HER2 amplified/overexpressing and searched for possible additional molecular determinants of sensitivity.

Material and Methods: Gastric tumors were xenografted in nude mice and were characterized by Affymetrix SNP V6.0 array and qPCR for gene copy number variation, Sanger sequencing and Sequenom MassARRAY OncoCarta panels 1, 2 and 3 for mutations, Affymetrix HGU133 plus 2.0 arrays for gene expression and using immunohistochemistry (IHC) for protein expression. Response to HER2-targeted therapy was assessed in vivo by treating gastric PDX with Trastuzumab 10 mg/kg/day at days 7, 14, and 21.

Results: A total of 29 gastric cancer PDX were established (7 PDX of Caucasian and 22 of Eastern Asian origin). Among these 29 PDX, 1 PDX from a Caucasian patient and 4 from Eastern Asian patients expressed high amounts of HER2 mRNA due to gene amplification that ranged from 10 to &gt;50 copies. IHC in situ analyses revealed that the HER2 amplification/mRNA overexpression correlated with strong HER2 protein expression (score 3+). Ongoing analyses investigating these HER2-amplified/overexpressing PDX for sensitivity to Trastuzumab revealed one PDX sensitive and one PDX resistant to treatment. We will present analyses of key biomarkers such as NRAS/KRAS/BRAF mutations, PIK3CA/PTEN status, HER2 integrity, gene expression profiles and their correlation with sensitivity/resistance to trastuzumab.

Conclusion: In agreement with what is observed in clinical practice, we identified Caucasian and Eastern Asian gastric tumors amplified and overexpressing HER2. The PDX from these tumors allowed the investigation of response to therapy targeting HER2. These PDX will aid in testing new HER2 targeted treatments and in identifying potential molecular determinants of resistance to Trastuzumab and other HER2 targeting agents.

Citation Format: Vincent Vuaroqueaux, Andreas Ackermann, Jianing Guo, Anne-Lise Peille, Rebekka Krumbach, Frederic Foucault, Thomas Metz, Heinz-Herbert Fiebig. The molecular determinants of sensitivity to HER2 targeted therapy in Patient Derived Xenograft gastric tumor models from Caucasian and Eastern Asian patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2774. doi:10.1158/1538-7445.AM2013-2774