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Prognostic Factors in Resected Stage I Non–Small-Cell Lung Cancer: A Multivariate Analysis of Six Molecular Markers

From the Departments of Thoracic/Head and Neck Medical Oncology, Clinical Cancer Prevention, Pathology, and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Institut Gustave Roussy, Villejuif, France; and Winship Cancer Institute, Emory University, Atlanta, GA

Address reprint requests to Charles Lu, MD, SM, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030-4009; e-mail: clu{at}mdanderson.org

PURPOSE: To analyze the prognostic significance of six molecular biomarkers (death-associated protein kinase [DAPK] promoter methylation, interleukin-10 [IL-10] protein expression, cyclooxygenase-2 [COX-2] mRNA expression, human telomerase reverse transcriptase catalytic subunit [hTERT] mRNA expression, retinoic acid receptor-beta [RAR-ß] mRNA expression, and K-ras mutational status) in stage I non–small-cell lung cancer (NSCLC) patients.

PATIENTS AND METHODS: Biomarker analyses were performed on tumors from 94 patients with stage I NSCLC who underwent surgical resection at our institution. A minimum follow-up period of 5 years was required. DAPK methylation was assessed by methylation-specific polymerase chain reaction (PCR). RAR-ß, COX-2, and hTERT mRNA levels were determined by in situ hybridization with digoxigenin-labeled antisense riboprobes. K-ras mutation status was determined by the PCR–primer introduced restriction with enrichment for mutant alleles method. IL-10 protein expression was analyzed by immunohistochemistry using a polyclonal antihuman IL-10 antibody. Cancer-specific survival was analyzed with a Cox proportional hazards model. To identify independent prognostic factors, a stepwise selection method was used.

RESULTS: DAPK methylation, IL-10 lack of expression, COX-2 expression, hTERT expression, RAR-ß expression, and K-ras mutations were observed in 46.8%, 29.8%, 59.6%, 34.0%, 23.4%, and 34.0% of patients, respectively. In the final model, DAPK methylation and IL-10 lack of expression were significant negative prognostic factors for cancer-specific survival, whereas COX-2 expression was of borderline significance.

CONCLUSION: In this cohort of resected stage I NSCLC patients, molecular markers that independently predict cancer-specific survival have been identified. The prognostic roles of DAPK methylation, IL-10, and other biomarkers in NSCLC merit further investigation.

Supported in part by National Cancer Institute grant No. K12 CA088084 and the Department of Defense, Biology, Education, Screening, Chemoprevention, and Treatment of Lung Cancer grant No. DAMD17-01-1-0689 and Translational Approaches for the Reversal, Genetic, Evaluation and Treatment of Lung Cancer grant No. DAMD17-02-1-0706.

Presented in part at the 93rd Annual Meeting of the American Association for Cancer Research, San Francisco, CA, April 6–10, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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