Abstract
BACKGROUND: Osteosarcoma (OS) is the most common malignant pediatric bone tumor. The identification of novel biomarkers for early prognostication will facilitate risk-based stratification and therapy. This study investigated the significance of circulating cytokines/chemokines for predicting the prognosis at the initial diagnosis. METHODS: Luminex assays were used to measure cytokine/chemokine concentrations in blood samples from a discovery cohort of OS patients from Texas Children's Hospital (n = 37) and an independent validation cohort obtained from the Children's Oncology Group (n = 233). After the validation of the biomarkers, a multivariate model was constructed to stratify the patients into risk groups. RESULTS: The circulating concentrations of C-X-C motif chemokine ligand 10 (CXCL10), Fms-related tyrosine kinase 3 ligand (FLT3LG), interferon γ (IFNG), and C-C motif chemokine ligand 4 (CCL4) were significantly associated with overall survival in both cohorts. Among these candidates, CXCL10 and FLT3LG were independent of the existing prognostic factor, metastasis at diagnosis, and CCL4 further discriminated cancer cases from controls. CXCL10, FLT3LG, and the metastatic status at diagnosis were combined to develop a multivariate model that significantly stratified the patients into 4 distinct risk groups (P = 1.6 × 10(-8) ). The survival analysis showed that the 5-year overall survival rates for the low-, intermediate-, high-, and very high-risk groups were 77%, 54%, 47%, and 10%, respectively, whereas the 5-year event-free survival rates were 64%, 47%, 27%, and 0%, respectively. Neither CXCL10 nor FLT3LG tumor expression was significantly associated with survival. CONCLUSIONS: High circulating levels of CXCL10 and FLT3LG predicted worse survival for patients with OS. Because both CXCL10 and FL3LG axes are potentially targetable, further study may lead to novel risk-based stratification and therapy for OS. Cancer 2017;144-154. © 2016 American Cancer Society.