Neoadjuvant Radiochemotherapy in Adenocarcinoma of the Esophagus: ERCC1 Gene Polymorphisms for Prediction of Response and Prognosis

Abstract

IntroductionNeoadjuvant radiochemotherapy (RT/CTx) regimens were primarily designed for treatment of squamous cell carcinoma of the esophagus. Own preliminary results demonstrate that also patients with locally advanced adenocarcinoma of the esophagus may achieve a major response in 30% with a 3-year survival rate of 80%. To identify these patients, ERCC1 (rs11615) gene polymorphisms were analyzed. ERCC1 is a key enzyme of the nucleotide excision and repair (NER) complex to prevent DNA inter- and intra-strand crosslinks. Patients and MethodsGenomic DNA from 217 patients with cT3/4 adenocarcinoma of the esophagus was extracted from paraffin-embedded tissues. Of these patients, 153 underwent neoadjuvant RT/CTx (CDDP, 5-FU, 36 Gy). For analysis of ERCC1 single nucleotide polymorphisms (SNPs), allelic discrimination was performed by quantitative real-time PCR. Two allele-specific TaqMan probes in competition were used for amplification of ERCC1 (rs11615). Allelic genotyping was correlated with histomorphologic tumor regression after neoadjuvant RT/CTx and survival. Major response (MaHR) was defined as <10% vital residual tumor cells (VRTC). ResultsAnalysis of tumor regression revealed a MaHR in 56/153 (36.6%) patients with a 5-year survival rate (5-YSR) of 74% (p < 0.001). ERCC1 gene polymorphisms for all patients showed the following expression pattern: ERCC1 polymorphism (rs11615) CC: n = 27 (12.4%), TT: n = 98 (45.2%), C/T: n = 92 (42.4%). ERCC1 polymorphism CT was identified as a predictor for response to the neoadjuvant RT/CTx (p < 0.001). The 5-YSR for patients with C/T genotype was 51%. Contrary to this, the 5-YSR for the group of patients with a CC/TT polymorphism decreased to 34%. ConclusionAnalysis of ERCC1 (rs11615) gene polymorphisms reveals a significant correlation with response and survival in patients with adenocarcinoma of the esophagus treated with a neoadjuvant radiochemotherapy. Single nucleotide polymorphisms of ERCC1 (rs11615) could therefore be applied to further individualize therapy in esophageal cancer.