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| Gene Expression Profiles in Esophageal Adenocarcinoma Predict Survival Following Resection |
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Arjun Pennathur1, Liqiang Xi3, Virginia R. Litle2, William E. Gooding1, Rodney J. Landreneau1, Tony Godfrey2, James D. Luketich1; 1The Heart,Lung and Esophageal Surgery Institute, University of Pittsburgh Medical Center, PITTSBURGH, PA; 2University of Rochester Medical Center, Rochester, NY; 3National Cancer Institute, Rockville, MD Objective: Esophageal adenocarcinoma(EC) is rapidly rising in the western population. Despite aggressive treatment,the survival after esophagectomy is suboptimal.The current TNM classification has also been imprecise in prediction of survival in these patients.We hypothesized that gene expression pattern of EC will predict survival after surgical resection. Methods: We conducted a prospective NIH/NCI funded study to evaluate the prognostic significance of gene expression in patients with EC. Esophageal cancer tissues were stored at -80°C until analysis. All tissues were evaluated by a pathologist to ensure >70% tumor representation. Gene expression was analyzed with U-133 plus 2.0 arrays (Affymetrix) and data was filtered to exclude probesets with low variance in expression values. Patients were followed up in the thoracic surgery clinic. The association of gene expression and overall survival was analyzed using the tail-strength statistic and Cox regression analysis.Semi-supervised methods using principal components were used to construct a gene signature.Leave-one-out cross-validation was used to develop a prognostic classifier. Results: We evaluated the results of 69 patients(N1: 34) who underwent esophagectomy for EC.During follow-up(median 34 months),31 patients are alive.The median overall survival was 27 months(95% CI 22 - NR). After filtering, 17716 probesets were used for survival analysis. The tail strength statistic for these probesets was 0.23(95%CI:0.22 -0.24) indicating a significant association of the dataset as a whole with overall survival. Ninety-nine probesets were individually associated with overall survival(P< .001).We applied the semi-supervised methods to 71 of the 99 probesets, representing 70 genes using 3 principal components. Patients were classified into high and low risk groups, based on the gene signature, by leave-one-out crossvalidation. High risk patients had a predicted median survival of 13 months while the median was not reached for the low risk groups(Figure,P=0.000001). We are currently working on refining this gene signature. Conclusion: In this prospective study of gene expression in EC,global gene expression levels are significantly associated with overall survival after esophagectomy.Furthermore, individual genes can be successfully combined into a strongly predictive internally cross-validated gene signature.If further validated, these results may help direct further clinical trials in neoadjuvant and adjuvant therapies for Esophageal Adenocarcinoma.  Kaplan-Meier Plot of overall survival stratified by gene signature of esophageal cancer into high risk and low risk groups. Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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