Abstract 5163: A high level of circulating CXCL10 at initial diagnosis is associated with poor prognosis of osteosarcoma patients
Authors: Flores Ricardo J. , Kelly Aaron J. , Li Yiting , Nakka Manjula , Lau Ching C. , Hicks John , Man Tsz-Kwong 
Published: August 2015

Abstract
Background: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Although survival rates have reached 70% over the past few decades, the prognosis of patients with metastatic disease remains very dismal. Identification of prognostic biomarkers besides clinically detectable metastasis will facilitate risk-stratification, and identify the most appropriate treatment option to improve their outcomes. Our group has previously devised a systems biology approach and identified that chemokines pathway are associated with metastasis in OS cell line models. Additionally, we reported that the plasma levels of a group of CXC chemokines were associated with a poorer patient outcome. CXC chemokines has been identified as source of potential therapeutic targets such as the CXCL12/CXCR4 and the CXCL10/CXCR3 ligand/receptor axes, which have been targeted successfully to inhibit lung metastasis in OS mouse models. Therefore, we decided to expand our findings by employing a Luminex platform to characterize circulating levels of cytokines/chemokines in OS patients, as these represent potential prognostic biomarkers and novel therapeutic targets. Materials and Methods: In this study, we employed a Luminex platform to analyze 39 chemokines/cytokines in two cohorts comprised of totally 290 OS patients. A regressive partitioning method was used to binarize the variables in the training cohort (40 samples) and the cutoff points were examined in the validation cohort (250 samples) for significance.
Results: Twenty-two of the candidate biomarkers were significant with respect to overall survival and were tested in the validation cohort (250 samples). After Benjamini-Hochberg correction, CXCL10 significantly correlated with overall survival (p = 0.047) and remained significant after correcting for initial metastasis (CXCL10: p = 0.0037, Metastasis: p = 0.00012), indicating that CXCL10 is an independent prognostic factor. Therefore, we combined both prognostic factors to stratify the patients. Using this approach we identified three risk groups and the 5-year overall survival rate for the high-risk (high CXCL10 with initial metastasis), intermediate-risk (high CXCL10 with localized disease, or low CXCL10 with initial metastasis), and low-risk (low CXCL10 with localized disease) groups were 31%, 54%, and 71% respectively. Further, in patients with localized disease at diagnosis, which is conventionally considered to be low risk, a higher level of CXCL10 predicted a poorer outcome (p = 0.019).
Additionally, we found that the receptor for the CXCL10 ligand, CXCR3, is expressed in OS tumors and is potentially targetable. In summary, our results suggest that circulating CXCL10 can be used as non-invasive biomarker to better prognosticate osteosarcoma patients before the treatment initiation and may lead to CXCR3-targeted therapy in selected patients in future clinical trials.
Citation Format: Ricardo J. Flores, Aaron J. Kelly, Yiting Li, Manjula Nakka, Ching C. Lau, John Hicks, Tsz-Kwong Man. A high level of circulating CXCL10 at initial diagnosis is associated with poor prognosis of osteosarcoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5163. doi:10.1158/1538-7445.AM2015-5163