Journal of the National Cancer Institute Advance Access originally published online on April 28, 2009
JNCI Journal of the National Cancer Institute 2009 101(9):678-686; doi:10.1093/jnci/djp061
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Four-Gene Expression Ratio Test for Survival in Patients Undergoing Surgery for Mesothelioma
Affiliations of authors: Department of Surgery, Division of Thoracic Surgery, Harvard Medical School (GJG, LD, WGR, HE, MM, RC, GM, BVO, DJS, RB) and Department of Pathology (JNG), Brigham and Women’s Hospital, Boston, MA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (BYY)
Correspondence to: Raphael Bueno, MD, Department of Surgery, Division of Thoracic Surgery, Harvard Medical School and Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (e-mail: rbueno{at}partners.org).
Background: Malignant pleural mesothelioma has few effective treatments, one being cytoreductive surgery. We previously developed a gene ratio test to predict outcome of malignant pleural mesothelioma patients undergoing surgery. In this study, we investigated the predictive value and technical assay performance of this test in patients with malignant pleural mesothelioma.
Methods: Clinical data were obtained prospectively from 120 consecutive patients with malignant pleural mesothelioma who were scheduled for debulking surgery at one institution. Specimens were obtained at surgery or by pleural biopsy examination. Expression data for four genes were collected from tumor specimens, and three ratios of gene expression (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA) were determined by quantitative reverse transcriptase–polymerase chain reaction. Patients were assigned to good or poor outcome groups by the gene ratio test. Survival was estimated by the Kaplan–Meier method and the log-rank test in univariate analyses. A multivariable Cox proportional hazards model was used to control for prognostic factors. Technical robustness was determined by using up to 30 specimens per patient, two biopsy techniques, and two performance sites. All statistical tests were two-sided.
Results: The test predicted overall survival (P < .001) and cancer-specific survival (P = .007) in univariate analysis and overall survival in multivariable analysis (hazard ratio for death = 2.09, 95% confidence interval [CI] = 1.27 to 3.45, P = .004). The test was reproducible within patients and repeatable between two determinations for specimens with widely varying tumor cell contents. Repeatability between two determinations was 88.5% (95% CI = 84.0% to 92.2%) or, when technically unacceptable test values were excluded, 91.9% (95% CI = 87.4% to 95.1%). Reproducibility between two determinations was 96.1% (95% CI = 86.5% to 99.5%). Combining the gene ratio test and other prognostic factors allowed prospective discrimination between patients at high risk (median survival = 6.9 months, 95% CI = 2.6 to 8.9 months; 3-year survival = 0%) and low risk (median survival = 31.9 months, 95% CI = 21.9 to 41.7 months; 3-year survival = 42%).
Conclusion: The gene ratio test for survival of patients with malignant pleural mesothelioma has robust predictive value and technical assay performance.
| CONTEXT AND CAVEATS Prior knowledge Malignant pleural mesothelioma has few effective treatments, except for Chemotherapy and cytoreductive surgery. Study design Clinical data were obtained before surgery from patients with malignant pleural mesothelioma. Tumor specimens were obtained at surgery or by pleural biopsy examination, and gene expression data were obtained for four genes. A gene ratio test was used to assign patients to good or poor prognosis groups, and their survival was analyzed. Robustness was determined by using many specimens per patient, two biopsy techniques, and two performance sites. Contribution The gene ratio test for survival of patients with malignant pleural mesothelioma has robust predictive value and technical assay performance. Implications The gene ratio test should be further evaluated with patient specimens collected before clinical intervention to determine whether its results can be incorporated into decision making for patient treatment. Limitations Patients had to agree to undergo aggressive surgery at enrollment and patients who did not were excluded. Consequently, the results may not apply to patients who are older or less fit. From the Editors
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Manuscript received June 10, 2008; revised January 27, 2009; accepted February 19, 2009.
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J Natl Cancer Inst 2009 101: 613.