Smad4 is predictive for response in neoadjuvant treated esophageal squamous cell carcinoma

Abstract

4591 Background: The evaluation of the prevalence of TGF-β1-pathway gene expressions (TGF-β1, Smad7 and Smad4) and its predictive value for histopathological response in patients with esophageal squamous cell carcinoma and neoadjuvant radiochemotherapy. Methods: RNA was prepared from pretherapeutic taken formalin-fixed and paraffin-embedded biopsies of 98 patients with histological proven locally advanced ESCC (cT3, cN0/+, cM0), who underwent preoperative combined simultaneous RTx/CTx with consecutive esophagectomy. All tumor biopsies underwent tumor-cell-microdissection, RNA-extraction and real-time TaqMan reverse transcriptase- polymerase chain reaction. RT-PCR-measurements were made by doublet measuring. Quantitative mRNA expression of TGFβ1 and its downstream effectors Smad4 and Smad7 was correlated with histopathological response by the percentage of residual tumor cells. Analysis was performed by dichotomized calculation and for determination of a cut-off by ROC-analysis. Results: Dichotomized analysis revealed the following median values: Smad4=0.098± 0.7 (CI: 0.024–0.396), Smad7=1.9250±1.7 (CI: 0.4–16.1) and TGFβ1=6.427±4.86 (CI: 0- 25.7). Cross-tabs-analysis for histopathological response disclosed the following correlations: TGFβ1 (p=0.671), Smad7 (p=0.672) and Smad4 (p=0.038). ROC-analysis revealed a Smad4-cut-off of 0.0635 by an area-under-curve of 6280 (p=0.038). Consecutive re-cross-tabs-analysis of histopathological response revealed a sensitivity of 80% (p=0.013). The pretherapeutic predictive value of Smad4 was 73%. Medians in survival was not reached during follow-up, whether TGFβ1 (p=0.519), Smad7 (p=0.5728) nor Smad4 (p=0.552). Histopathological responders showed a significant better survival compared to nonresponders (p<0.0001). Conclusions: High levels of Smad4 gene expression are significantly correlated with histopathological response. ROC-Analysis identified a cut-off of Smad4 with a sensitivity of 80% and a predictive value of 73%. No significant financial relationships to disclose.