Elevated osteopontin (OPN) plasma levels are highly prognostic in advanced non-small cell lung cancer (NSCLC): Analysis of SWOG S0003

Abstract

7198 Background: OPN is a secreted glycoprotein with a diverse array of functions, including induction of uPA & increased cell migration. OPN has been shown to be elevated in a number of tumor types, & its downregulation reduces tumorigenicity & metastasis in tumor models. High levels have also been associated with tumor hypoxia/angiogenesis, as are vascular endothelial growth factor (VEGF) & plasminogen activator inhibitor (PAI-1). We hypothesized that secreted levels of these biomarkers would correlate with clinical outcome after treatment. Methods: Plasma concentrations of OPN, VEGF & PAI-1 were measured by ELISA in 160 NSCLC patients enrolled on the Southwest Oncology Group (SWOG) trial S0003 (paclitaxel/carboplatin ± the hypoxic cytotoxin tirapazamine). Post-treatment plasma samples were available in 56 patients. Results: Baseline OPN plasma levels correlated significantly with patient overall survival (OS). High interpatient variability was observed, with levels ranging from undetectable to 2560 ng/ml, (median: 606.5 ng/ml). When dichotomized, median OS was 11 months for patients below median OPN levels & 7 months for those above (p = 0.004). Survival decreases with increasing OPN concentration. Furthermore, OPN levels correlated with response rate (RR) (median responders: 497; median non-responders: 698 ng/ml. Wilcoxon rank-sum p = 0.03). No association between baseline levels of either VEGF or PAI-1 with RR or OS was observed. However, plasma levels of both PAI-1 & VEGF were significantly inter-related & trended together (p < 0.0001), & both decreased significantly after treatment (p = 0.0004 & 0.04, respectively). Median decrease: OPN: 17%, PAI: 44%, VEGF: 42%. No significant differences were observed between study arms, suggesting that OPN is prognostic in NSCLC, but not predictive for response to tirapazamine. Conclusions: 1) There is a great need for development of tumor biomarkers which can be serially assessed pre- & post-therapy. 2) High OPN plasma levels were significantly associated with reduced RR & OS for patients on this trial. OPN is a strong candidate for inclusion in a panel of prognostic (& perhaps predictive) markers for NSCLC. Supported by the Hope Foundation & R01-CA107228. No significant financial relationships to disclose.