ctDNA quantification improves estimation of outcomes in patients with high-grade osteosarcoma: a translational study from the OS2006 trial

Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification. Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before su...

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Bibliographic Details
Published in:	Annals of oncology Vol. 35; no. 6; p. 559
Main Authors:	Audinot, B, Drubay, D, Gaspar, N, Mohr, A, Cordero, C, Marec-Bérard, P, Lervat, C, Piperno-Neumann, S, Jimenez, M, Mansuy, L, Castex, M-P, Revon-Riviere, G, Marie-Cardine, A, Berger, C, Piguet, C, Massau, K, Job, B, Moquin-Beaudry, G, Le Deley, M-C, Tabone, M-D, Berlanga, P, Brugières, L, Crompton, B D, Marchais, A, Abbou, S
Format:	Journal Article
Language:	English
Published:	England 01-06-2024
Subjects:	Adolescent Adult Biomarkers, Tumor - blood Biomarkers, Tumor - genetics Bone Neoplasms - blood Bone Neoplasms - genetics Bone Neoplasms - mortality Bone Neoplasms - pathology Bone Neoplasms - surgery Child Circulating Tumor DNA - blood Circulating Tumor DNA - genetics DNA Copy Number Variations Female Humans Male Middle Aged Neoplasm Grading Osteosarcoma - blood Osteosarcoma - diagnosis Osteosarcoma - genetics Osteosarcoma - mortality Osteosarcoma - pathology Osteosarcoma - surgery Prognosis Progression-Free Survival Prospective Studies Whole Genome Sequencing Young Adult prognostic score stratification ctDNA osteosarcoma
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Summary:	Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification. Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event. ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression. The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway.
ISSN:	1569-8041
DOI:	10.1016/j.annonc.2023.12.006