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Clinical Significance of Insulin-like Growth Factor-binding Protein-3 Expression in Stage I Non-Small Cell Lung Cancer¹

Department of Thoracic/Head and Neck Medical Oncology [Y. S. C., S. S., F. R. K., W. K. H., H-Y. L.], Biostatistics [D. L.], and Pathology [A. K. E-N.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Breast Cancer Center at Baylor College of Medicine, Houston, Texas 77030 [K. G.]

The activities of insulin-like growth factors (IGFs), including mitogenic and antiapoptotic properties, are modulated by a family of high-affinity insulin-like growth factor-binding proteins (IGFBPs), of which IGFBP-3 is the major serum carrier protein. Even though it is well known that IGFBP-3 plays an important role in cell proliferation, the expression of IGFBP-3 and its significance in primary non-small cell lung cancer (NSCLC) samples are unknown. This study explored IGFBP-3 expression in tumor samples from 74 patients with a diagnosis of pathological stage I NSCLC to determine if the expression status of IFGBP-3 influences the prognosis of patients with NSCLC. Two-sided statistical analyses were performed to correlate the clinical parameters and the prognostic effect with the IGFBP-3 expression level in this cohort. Reduced IGFBP-3 expression was found in 42 (56.8%) of 74 samples, and it was more frequent in large cell carcinoma than in squamous cell carcinoma and adenocarcinoma, although this difference was not statistically significant. This phenomenon was not associated with the other clinicopathological parameters tested, such as age, sex, histological grade, and smoking history. Significant statistical correlation between IGFBP-3 expression and disease-specific survival was noted (P = 0.019 by log-rank test). Although statistically nonsignificant, patients with decreased IGFBP-3 expression had shorter overall, disease-free, and event-free survival rates than did patients with normal IGFBP-3 expression. In a multivariate analysis using IGFBP-3 expression and other clinicopathological parameters, the level of IGFBP-3 expression remained as an independent factor for predicting a shorter disease-specific survival probability (P = 0.020). Our work demonstrates that down-regulation of IGFBP-3 is a frequent event in stage I NSCLC and correlates with the disease-specific survival probability of patients with stage I NSCLC. These results suggest that IGFBP-3 functions as a tumor suppressor and plays an important role in determining biological aggressiveness in early NSCLC.

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