Genomic characterization of a comprehensive collection of esophagogastric cancer patient-derived xenografts.

Abstract

233 Background: Large-scale sequencing has identified multiple oncogenic drivers and molecularly defined subsets in esophagogastric cancer. However, besides therapies for HER2-positive and microsatellite instability-high disease, few genomic biomarker-driven treatments are currently approved. Patient-derived xenografts (PDXs) have emerged as promising preclinical models that capture the heterogeneity and biology of human tumors. Therefore, we established a comprehensive collection of esophagogastric cancer PDXs and performed next-generation sequencing (NGS) to genomically characterize these models. Methods: Starting in 2010, we developed an ongoing program for generating esophagogastric cancer PDXs from fresh tumor specimens that are acquired from surgical resections or biopsies and implanted into NOD scid gamma (NSG) mice either subcutaneously into flanks or orthotopically into the gastric wall. We reviewed clinical and pathologic characteristics of patients from whom established PDXs were derived, including stage, histology, HER2 status and treatment history. To identify oncogenic DNA alterations, NGS was performed on PDX material using MSK-IMPACT, a capture-based NGS platform. Results: From April 2010 to August 2018, we implanted 270 tumor samples, of which 112 were successfully engrafted (41.4%) including 57 gastric adenocarcinomas, 25 gastroesophageal junction adenocarcinomas, 23 esophageal adenocarcinomas, 4 squamous cell carcinomas and 3 small cell/high-grade neuroendocrine tumors. PDXs were generated from both primary tumors (n = 67, 59.8%) and metastases (n = 45, 40.2%), with many PDXs established from patients with metastatic disease who had progressed on standard therapy (n = 50, 44.6%). In addition, a large number of PDXs were derived from patients initially diagnosed with HER2-positive esophagogastric adenocarcinoma (n = 68, 60.7%). NGS of these PDXs demonstrated frequent alterations in TP53, receptor tyrosine kinases ( ERBB2, EGFR), cell-cycle mediators ( CDK12, CCNE1, CCND3) and histone methyltransferases ( KMT2C, KMT2D), consistent with clinical sequencing. Conclusions: Comprehensive molecular profiling demonstrates that esophagogastric cancer PDXs recapitulate the genomic heterogeneity and tumor biology of patients. This panel represents one of the largest described collections of esophagogastric cancer PDXs and serves as a powerful platform to investigate mechanisms driving tumor growth and metastasis, identify predictive biomarkers for treatment responsiveness and develop novel genomically-driven therapeutic strategies.