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

B Audinot; D Drubay; N Gaspar; A Mohr; C Cordero; P Marec-Bérard; C Lervat; S Piperno-Neumann; M Jimenez; L Mansuy; M-P Castex; G Revon-Riviere; A Marie-Cardine; C Berger; C Piguet; K Massau; B Job; G Moquin-Beaudry; M-C Le Deley; M-D Tabone; P Berlanga; L Brugières; B D Crompton; A Marchais; S Abbou

doi:10.1016/j.annonc.2023.12.006

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

Ann Oncol. 2023 Dec 22:S0923-7534(23)05113-X. doi: 10.1016/j.annonc.2023.12.006. Online ahead of print.

Authors

B Audinot¹, D Drubay², N Gaspar³, A Mohr¹, C Cordero⁴, P Marec-Bérard⁵, C Lervat⁶, S Piperno-Neumann⁷, M Jimenez⁸, L Mansuy⁹, M-P Castex¹⁰, G Revon-Riviere¹¹, A Marie-Cardine¹², C Berger¹³, C Piguet¹⁴, K Massau¹, B Job¹⁵, G Moquin-Beaudry¹, M-C Le Deley¹⁶, M-D Tabone¹⁷, P Berlanga¹⁸, L Brugières¹⁸, B D Crompton¹⁹, A Marchais¹, S Abbou²⁰

Affiliations

¹ National Institute for Health and Medical Research (INSERM) U1015, Gustave Roussy, Villejuif.
² Gustave Roussy, Office of Biostatistics and Epidemiology, Université Paris-Saclay, Villejuif; Inserm, Université Paris-Saclay, CESP U1018, Oncostat, labeled Ligue Contre le Cancer, Villejuif.
³ National Institute for Health and Medical Research (INSERM) U1015, Gustave Roussy, Villejuif; Gustave Roussy Cancer Campus, Children and Adolescent Oncology Department, Villejuif; French Cancer Society (SFCE), Bordeaux.
⁴ Pediatric Department, Institut Curie, Paris; French Cancer Society (SFCE), Bordeaux.
⁵ Department of Oncology for Child and Adolescent, Centre Léon Bérard, Pediatric Oncology and Hematology Institute (IHOPe), Lyon; French Cancer Society (SFCE), Bordeaux.
⁶ Department of Pediatric Oncology, Adolescents and Young Adults, Centre Oscar Lambret, Lille; French Cancer Society (SFCE), Bordeaux.
⁷ Medical Oncology Department, Institut Curie, Paris.
⁸ Research and Development Department, Unicancer, Paris.
⁹ Department of Pediatric Hematology and Oncology, Nancy University Hospital, Vandœuvre-lès-Nancy; French Cancer Society (SFCE), Bordeaux.
¹⁰ Pediatric Oncology Immunology Hematology Unit, Children's University Hospital, Toulouse; French Cancer Society (SFCE), Bordeaux.
¹¹ Department of Pediatric Hematology and Oncology, La Timone Children's Hospital, Marseille; French Cancer Society (SFCE), Bordeaux.
¹² Department of Pediatric Hematology and Oncology, Rouen University Hospital, Rouen; French Cancer Society (SFCE), Bordeaux.
¹³ Department of Pediatric Oncology, North Hospital, University Hospital of Saint Etienne, Saint Etienne; French Cancer Society (SFCE), Bordeaux.
¹⁴ Pediatric Oncology Hematology Unit, Limoges University Hospital, Limoges; French Cancer Society (SFCE), Bordeaux.
¹⁵ National Institute for Health and Medical Research (INSERM) US23, Gustave Roussy, Villejuif.
¹⁶ Gustave Roussy, Office of Biostatistics and Epidemiology, Université Paris-Saclay, Villejuif; Clinical Research Department, Centre Oscar Lambret, Lille.
¹⁷ Pediatric Hematology Department, Trousseau Hospital, Sorbonne Université, Paris, France; French Cancer Society (SFCE), Bordeaux.
¹⁸ Gustave Roussy Cancer Campus, Children and Adolescent Oncology Department, Villejuif; French Cancer Society (SFCE), Bordeaux.
¹⁹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston; Broad Institute of Harvard and MIT, Cambridge, USA.
²⁰ National Institute for Health and Medical Research (INSERM) U1015, Gustave Roussy, Villejuif; Gustave Roussy Cancer Campus, Children and Adolescent Oncology Department, Villejuif; French Cancer Society (SFCE), Bordeaux. Electronic address: Samuel.abbou@gustaveroussy.fr.

PMID: 38142939
DOI: 10.1016/j.annonc.2023.12.006

Abstract

Background: Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification.

Patients and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: ctDNA; osteosarcoma; prognostic score; stratification.