Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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).

Conclusion: Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.

Figures

Fig 1.

Survival by baseline osteopontin (OPN) plasma level. (A) Survival (Kaplan-Meier) plot showing patients dichotomized at greater than or less than the median plasma concentration of OPN (598 ng/mL). Patients with higher OPN levels (blue) had significantly worse overall survival compared with patients with lower levels (yellow; P = .0016). (B) Patients were subdivided into quartiles based on OPN plasma levels. Patients with increased plasma OPN concentrations performed significantly worse (P = .001).

Fig 2.

Immunohistochemical staining of tumor osteopontin (OPN). Archival tumor specimens from 61 patients were evaluated by immunohistochemistry using a manual quantitative scoring method derived from staining intensity and percent positivity (range, 0 to 400). Shown are representative samples with a (A) high and a (B) low score. The majority of tumors had sharply elevated OPN expression relative to adjacent normal tissue, with a mean score of 254.