Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome commonly characterized by the presence of inherited mutations in the tumor suppressor gene TP53. This leads to an early onset of a wide spectrum of tumors in multiple organ systems. Current surveillance protocols for early tumor detection include biochemical screening, MRI and ultrasound scans, colonoscopy and mammography (for adults). While early detection is associated with improved survival, the complexity of testing, potential to ‘misdiagnose’ tumors (false positive/negative) and requirement for multiple imaging modalities makes clinical surveillance challenging to implement and interpret. Liquid biopsies are a recently described diagnostic and prognostic tool that takes advantage of analyzing circulating tumor DNA - fragmented genomic material that are released into the blood from dying tumor cells.

In this proof-of-principle study, we use mouse xenograft tumor models to assess the dynamic relationship between tumor burden and ctDNA concentrations, as well as resolve the sensitivity of capturing the presence of lesions in their earliest stages of growth. Longitudinal analyses of ctDNA from serially collected blood were performed on mice with xenografts of rhabdomyosarcoma (Rh4 and Rh30), osteosarcoma (HOS) and non-small cell lung carcinoma (H1975) of both localized and simulated metastatic tumors. We characterized ctDNA using droplet digital PCR (ddPCR) for known gene mutations that were specific for the cancer cell lines used. We observe obvious increases in ctDNA with increased tumor burden and a complete clearance of ctDNA after tumor resection. In addition, using the metastatic model, we have conducted synchronized imaging and blood-based biopsies to determine the smallest lesion able to be detected in the blood by ctDNA.

These studies provide the foundation for early tumor detection with ctDNA in Trp53 mutant mice that develop spontaneous tumors analogous to LFS. This model will help further our understanding on the utility of ctDNA as a surveillance and diagnostic tool for LFS as well as assess its potential for clinical use.

Citation Format: Sangeetha Paramathas, Nathan Lewis, Tanya Guha, Zainab Motala, David Malkin. Assessing the utility of circulating tumor DNA as a surveillance tool for sarcomas and Li-Fraumeni syndrome using a pre-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2017-2741