Abstract 648: Integrated genomic characterization of endometrial cancer tumor grafts: a step toward genomic-guided treatment

Abstract

Abstract Endometrial cancer (EC) is the fourth most frequently diagnosed gynecological cancer among American Women. Steady increased numbers of newly diagnosed cases and deaths necessitates an added attention. Despite survival rates between 60-80% for localized, early stage disease, only marginal advances have been made in the treatment of distant (16%) and recurrent (15% of early stage) EC over the past two decades. New treatment strategies, guided by more predictive preclinical disease models incorporating molecular characteristics are crucial. Recent findings from The Cancer Genome Atlas (TCGA) Research Network suggested that the current histo-pathologically-guided classification of EC may not suffice to direct treatment recommendations, and introduced the potential adequacy of genomic profiling for reclassifying EC. However, these findings are hampered by the lack of appropriate in vivo models, which adequately facilitate obtaining the necessary preclinical evidence before translating findings to genome-guided clinical trials. Objectives: To establish patient derived orthotopic endometrial tumor grafts recapitulating histology, metastasis, and molecular characteristics of the original tumor specimen, and integrating TCGA genomic characterization to facilitate the development of genomic-guided treatment. Methods: Patient derived EC tissues were orthotopically transplanted to murine uteri and propagated over multiple generations. Generated tumor grafts were characterized for metastases, histopathology, and molecular profiles to ensure grafts resemblance of the original tumor samples. Tumor grafts were then further categorized into the four reported TCGA clusters on the basis of mutation frequency, somatic copy number alterations, microsatellite instability, and POLE mutation. Results: Twenty EC tumor grafts were successfully generated. Histological features, including tumor grade and hormone receptor status, as well as genomic profiles were maintained for up to 7 generations. Xenografts were capable to form metastasis closely parallel to clinical relevant sites. Results from a survival study demonstrated that the established tumor grafts reflected clinical stage-, and grade-based disease progression, and recapitulate TCGA cluster-based survival findings. Conclusions: This study reports the first successful generation of orthotopic EC patient-derived tumor grafts, which retain crucial histo-pathological characteristics, the capacity to form distant metastasis following known clinical patterns, as well as recapitulating molecular features of the original human tumor specimen. Additionally, our model can indeed be used as a tool to investigate the need for reclassifying EC into four clusters rather than two simplified disease subtypes and feasibility in directing genomic-guided treatment based on TCGA recommendations. Citation Format: Chieh-Hsiang Yang, Elke A. Jarboe, Jason Gertz, Katherine E. Varley, C. Matthew Peterson, Margit M. Janát-Amsbury. Integrated genomic characterization of endometrial cancer tumor grafts: a step toward genomic-guided treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 648.