Abstract 843: Assessment of high-dose radiation efficacy administered to patient-derived xenografts based on the genomic reclassification of endometrial carcinomas
Authors: Chieh-Hsiang Yang, David K. Gaffney, Elke A. Jarboe, Margit M. Janát-Amsbury
Journal: Cancer Research (2018)

Abstract Adjuvant treatment of patients with endometrial cancer (EC) is tailored to clinical-pathologic prognostic factors. Pelvic radiation therapy for stage I EC provides a highly significant improvement of local control, but without survival advantage, and the use of adjuvant radiotherapy (RT) is limited to patients with high-intermediate or high-risk factors. Due to a rising incidence rate of EC there is an immediate need to improve how adjuvant treatments are being selected. The exploration of four genomic clusters by The Cancer Genome Atlas (TCGA) Network provides molecular insights and opportunity to refine current management strategies. However, no prospective validation of the relationship between cluster-association and treatment response has been reported. In this study, we evaluated the therapeutic efficacy of high-dose rate (HDR) radiation on the basis of genomic clusters. Objectives: To evaluate treatment response of HDR radiation according to TCGA classification using a panel of endometrial cancer patient-derived xenografts (EC-PDXs). Methods: Thirty-two EC-PDXs upon histologic and genomic characterization were orthotopically transplanted and propagated. Subcutaneously grafted PDX were subjected to a PDX clinical radiation trial. Animals were placed under a lead shield for irradiation once tumors reached 150-200 mm3 and 7Gy of radiation was delivered weekly for three weeks. Two additional weeks were given to investigate potential tumor regrowth. Histologic evaluation was conducted upon necropsy. Results: The overall response rate was 78% (25/32), in which high-grade ECs exhibited increased sensitivity to radiation compared to low-grade ECs (overall response rate 89% for high-grade versus 62% for low-grade). Copy number high (CNH) EC-PDXs showed the best response rate (100%), microsatellite instable (MSI) lines responded moderately (73%), and copy number low (CNL) lines exhibited the lowest response rate (42.9%). Nonresponders were noted among CNL and MSI clusters featuring low-grade endometrioid histology. Further evaluation of the proliferation index confirmed that all responders had a &amp;gt;90% decrease on H-score compared to the nonresponders, which either showed a slight decrease or no changes at all. Conclusions: This is the first radiation treatment study selecting candidates within a PDX clinical trial based on TCGA cluster affiliation. Our findings suggest that EC-PDXs categorized as CNH or with higher histologic grade seem more sensitive to radiotherapy. Therefore, special attention and reconsideration of treatment recommendation should be given to patients harboring tumors with MSI and CNL genomic features. Further studies towards the identification of biomarkers or additional subclusters within responders and nonresponders will benefit physicians and patients to direct therapy. Citation Format: Chieh-Hsiang Yang, David K. Gaffney, Elke A. Jarboe, Margit M. Janát-Amsbury. Assessment of high-dose radiation efficacy administered to patient-derived xenografts based on the genomic reclassification of endometrial carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 843.