Lower Osteopontin Plasma Levels Are Associated With Superior Outcomes in Advanced Non–Small-Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy: SWOG Study S0003

S0003 was a phase III trial of carboplatin/paclitaxel with or without the hypoxic cytotoxin tirapazamine in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). We investigated the relationship between clinical outcomes and plasma levels of the hypoxia-associated protein osteopontin (OPN) in patients on this protocol. Baseline plasma was obtained from 172 patients. In 56 patients, sequential plasma was obtained after one or two cycles. Concentrations of OPN, as well as plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF), were measured using enzyme-linked immunosorbent assay. Tumor expression of OPN was assessed by immunohistochemistry in 61 matched archival specimens. Patients with lower OPN levels (below the median) had a significantly superior overall survival compared with patients with higher levels, regardless of treatment arm (hazard ratio [HR] = 0.60, P = .002). A similar correlation was observed for progression-free survival (HR = 0.69, P = .02). When examined as a continuous variable, OPN maintained its significant association with both progression-free (HR = 1.05, P = .01) and overall survival (HR = 1.09, P < .0001). Patients with lower plasma OPN levels were significantly more likely to have tumor response (P = .03). No differences were observed between treatment arms. Tumor OPN levels did not correlate with patient outcomes or with plasma levels. No associations were observed between patient outcomes and VEGF or PAI-1 levels; however, plasma concentrations of these markers were significantly interrelated (P < .0001) and significantly decreased after treatment (P = .0002 and P = .03, respectively). Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.