Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma

Abstract

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.

Figure 1

Overall survival of patients with malignant pleural mesothelioma and predictions from the gene ratio test. A) Entire cohort. B) Subgroups of patients as classified by the gene ratio test. Hash marks = censored patients; N = number of patients at risk; S = Kaplan–Meier survival point estimate as percent; 95% CI = 95% confidence interval for the survival estimate.

Figure 2

Overall survival of patients with malignant pleural mesothelioma after surgery from combined prediction models (as defined in Table 4). A) Model for four subgroups of patients. B) Model for three subgroups of patients. Hash marks = censored patients; N = number of patients at risk; S = Kaplan – Meier survival point estimate as percent; 95% CI  =  95% confidence interval for the survival estimate.