A three-gene signature to predict survival in pediatric osteosarcoma (OS) to follow patients toward liquid biopsy: A collaborative work in OS2006 protocol.

Abstract

11014 Background: The survival of pediatric OS is stable worldwide since two decades. The management of OS is lacking new approaches to classify closely the patients and adapt thereafter the treatments. The objectives of our molecular study, using allelotyping, quantitative PCR (qPCR) and droplet digital PCR (ddPCR), were to determine the survival impact of tumor molecular profiling in the initial tumor biopsy, in the tumor resection after neoadjuvant chemotherapy and on circulating DNA at different treatment steps. The gene panel based on biomarkers of bone dedifferentiation was already identified in the large tumor cohort of the French national protocol OS94 and demonstrated a significant prognostic impact of 3 genes MET, TWIST and APC. To go further and understand its significance throughout protocols, the same study was performed in OS2006 tumors. Methods: We applied retrospectively in the cohort of OS2006 protocol (135 patients) the same molecular assessment comprising the targeting of those 3 genes with 3 techniques evaluating their rearrangement by allelotyping, their copy number variations by qPCR and ddPCR. A preliminary cohort of 20 patients with liquid biopsies at diagnosis, before tumor surgery and at the end of chemotherapy was screened by ddPCR. Results: We were able to determine frequent rearrangements in the regions containing these 3 genes and a statistically significant correlation was made between the presence of a gene rearrangement and a worst outcome. The 3-gene signature was significantly predicting the outcome of more than 85% of patients diagnosed for an OS. Furthermore, the persistence of those genes’ rearrangements in the primitive tumor after neoadjuvant chemotherapy comparatively to the initial biopsy was correlated to a higher risk of relapse. This 3-gene signature was also used for assessment of residual disease (RD) in liquid biopsies and was able to determine before tumor surgery the level of RD. Conclusions: This molecular signature seems to be clearly associated with patient outcome and was able to provide evidence that this approach is a powerful tool to be used in pediatric OS follow up to determine early relapse or progression.