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An Evaluation of Tumor Oxygenation and Gene Expression in Patients with Early Stage Non–Small Cell Lung Cancers

Authors' Affiliations: Departments of ¹ Radiation Oncology, ² Pathology, ³ Cardiothoracic Surgery, ⁴ Medicine, and ⁵ Biostatistics, Stanford University Medical Center, Stanford, California; ⁶ Department of Surgery, University of Colorado School of Medicine, Denver, Colorado; ⁷ Departments of Oncology, Pathology, and Epidemiology, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; and ⁸ Department of Medical Oncology, St. James' Hospital, Dublin, Ireland

Requests for reprints: Quynh-Thu Le, Stanford University, 875 Blake Wilbur Drive, MC 5847, Stanford, CA 94305-5847. Phone: 650-498-5032; Fax: 650-725-8231; E-mail: qle{at}stanford.edu.

Background: To directly assess tumor oxygenation in resectable non–small cell lung cancers (NSCLC) and to correlate tumor pO₂ and the selected gene and protein expression to treatment outcomes.

Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO₂ were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO₂ was correlated with CA IX staining, osteopontin levels, and treatment outcomes.

Results: The median tumor pO₂ ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO₂ in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO₂ as a reflection of tumor oxygenation. The median T/L pO₂ was 0.13. T/L pO₂ correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO₂ (P = 0.04), and osteopontin levels (P = 0.001).

Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

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