Abstract 3815: Genomic predictors of response to preoperative chemotherapy in patients with pediatric osteosarcoma.
Authors: Iwata Shintaro , Ohira Miki , Yonemoto Tsukasa , Ishii Takeshi , Kamoda Hiroto , Nakagawara Akira 
Published: August 2014

Purpose: It is generally accepted that sensitivity of preoperative chemotherapy, evaluated by a histological analysis using resected tumor tissue, is the most important prognostic factor for Osteosarcoma (OS). Methotrexate, doxorubicin, cisplatin (MAP regimen), and ifosfamide (IFO) are recognized as key drugs for OS, although it is still debatable whether addition of IFO for all OS patient is beneficial or not. There have been few analyses documenting molecular markers that predict the response to each regimen used in the preoperative chemotherapy of OS patients. The aim of this study is to identify possible genomic markers for the prediction of sensitivity of preoperative chemotherapy for pediatric OS patients.

Methods: Pre-therapeutic biopsy tumor samples of 22 pediatric conventional OS patients treated in Chiba Cancer Center who had homogeneous clinicopathological- and therapeutic- background were analyzed. In our study, all patients were divided into 3 groups according to the histological response; group A includes 8 patients who demonstrated a good histological response to MAP regimen, group B includes 6 patients who were resistant to MAP regimen but showed good response to IFO regimen, and group C includes 8 patients who did not respond to neither MAP nor IFO regimen. Genomic DNAs were prepared from frozen biopsy samples and used for aCGH analysis with Agilent 44k DNA microarray.

Results: Survival analysis revealed that patients in group A and B exhibited significantly better outcomes than in group C concerning both overall and event-free survivals. According to the results of comparative analysis of copy number variation (CNV) patterns in each group, 2 CNV regions that separated group A from group B and C (sensitivity 100%, specificity 92.9%) and 6 CNV regions that separated group C from group A and B (sensitivity 100%, specificity 100%) were identified. CNV regions specifically identified in Group C contained several genes previously reported as OS-related genes, such as CDKN2A/B, PTEN, and CDK4. Based on these CNV profiles, we established a scoring system that clearly classify the tumors into these 3 groups Re-sequencing of known cancer-related genes in these OS tumors is also underway to integrate genomic alterations into the system.

Conclusion: Our results indicated that copy number changes in OS biopsy samples could be good predictors of response to preoperative chemotherapy. These signatures may be useful for the future genomics-based personalized chemotherapy for OS patients.

Citation Format: Shintaro Iwata, Miki Ohira, Tsukasa Yonemoto, Takeshi Ishii, Hiroto Kamoda, Akira Nakagawara. Genomic predictors of response to preoperative chemotherapy in patients with pediatric osteosarcoma. [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 3815. doi:10.1158/1538-7445.AM2013-3815