Wertigkeit der ERCC1-RNA Expression im Serum als Responsemarker auf die neoadjuvante Radio-Chemotherapie beim Ösophaguscarcinom

Abstract

Background: Only patients with locally advanced cancer of the esophagus with a major histopathological response to neadjuvant radio-chemotherapy benefit from this treatment. Unfortunately, no non-invasive molecular marker exists that can reliably predict response or non-response to neadjuvant therapy in this disease. To further improve the treatment of patients with locally advanced cancer of the esophagus, molecular predictors of response are desperately needed. The aim of this study was to determine the value of ERCC1 RNA-Expression in sera of patients with locally advanced cancer of the esophagus as a non-invasive molecular predictor of response to neoadjuvant radio-chemotherapy. Material and methods: A total of 29 patients with locally advanced cancer (cT3-T4, Nx, M0) of the esophagus were included in this study. Blood samples from each patient were drawn prior to neoadjuvant radio-chemotherapy (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 sera samples, quantitative expression analysis of ERCC1 and the internal reference gene beta-Actin was done by real-time RT-PCR (Taqman^®). 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 %) of patients showed a minor histopathological response and 10 of 29 (34.5 %) showed a major-response to neadjuvant radio-chemotherapy. ERCC1 RNA expression in sera of patients was detectable for ERCC1 in 82.8 % (24 of 29) and 100 % (29 of 29) 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 and was significantly different (p = 0.004 Mann-Whitney test). 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 histopathological response to the delivered neadjuvant therapy could be unequivocally identified. This association of dichotomized relative ERCC1 expression and histopathological response was statistically significant (P < 0.001). Conclusion: The applied method is technically feasible for the analysis of cellular ERCC1 RNA expression in sera of patients with locally advanced cancer of the esophagus. Minor-responders to the applied radiochemotherapy show a significant higher ERCC1 expression level in their sera compared to major-responders prior to therapy. ERCC1 expression levels in sera appear to be highly specific to predict minor-response to neoadjuvant radiochemotherapy in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (45 %) of patients.