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The Role of ERCC1 RNA Expression in Blood As a Non-Invasive Predictor of Response to Neadjuvant Radio-Chemotherapy in Patients with Locally Advanced Cancer of the Esophagus
Jan Brabender*1, Daniel VallböHmer1, Frederike C. Ling1, Andreas C. Hoffmann1, Georg Lurje1, Elfriede Bollschweiler1, Arnulf H. HöLscher1, Paul M. Schneider2, Ralf Metzger1
1Department of Surgery, University of Cologne, Cologne, Germany; 2Department of Surgery, University of zuerich, Zuerich, Switzerland
Background: Only patients with locally advanced cancer of the esophagus with a major response to neadjuvant radio-chemotherapy do benefit from this treatment. Unfortunately, no non-invasive molecular marker exists that can reliably predict response to neadjuvant therapy in this disease. To improve the treatment of patients with cancer of the esophagus, molecular predictors of response are desperately needed. Aim of this study was to determine the value of ERCC1 RNA-Expression in peripheral blood of patients with cancer of the esophagus as a non-invasive molecular predictor of response to neoadjuvant therapy.
Material and methods: A total of 29 patients with locally advanced cancer of the esophagus were included in this study. Blood samples were drawn from each patient prior to neoadjuvant therapy (cis-Platin, 5-FU, 36Gy). Transthoracic en-bloc esophagectomy was performed in all patients following completion of neadjuvant therapy. After extraction of cellular tumor-RNA from blood samples, quantitative expression analysis of ERCC1 and the internal reference gene beta-Actin was done by real-time RT-PCR. Histomorphological regression was defined as major response when resected specimen contained <10% of residual vital tumor cells, and minor response with >10% of vital residual tumor cells.
Results: Nineteen of 29 (65.5%) patients showed a minor histopathological response and 10(34.5%) showed a major-response to neadjuvant therapy. ERCC1 RNA expression in blood of patients was detectable for ERCC1 in 82.8% and 100% for beta-Actin. The median ERCC1 expression was 0.62 (min.: 0.00, max.: 2.48) in minor-responders and 0.24 (min.: 0.00, max.: 0.45) in major-responders (p=0.004). No significant associations were detected between ERCC1 expression levels and patients clinical variables (histology, tumor stage, gender etc.). Relative ERCC1 expression levels above 0.452 were not associated with major histopathological response (sensitivity: 68.4; specificity: 100%) and 13 of 19 patients with minor response to the delivered neadjuvant therapy could be unequivocally identified.
Conclusion: The applied method is technically feasable for the analysis of cellular ERCC1 RNA expression in blood of patients with cancer of the esophagus. Minor-responders to the applied therapy show a significant higher ERCC1 expression level in their blood compared to major-resonders prior to therapy. ERCC1 expression levels in blood appear to be highly specific to predict minor-response to neoadjuvant radiochemotherapy in patients with esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (45%) of patients.
