Purpose: The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT_2–4, N_x, M₀). Experimental Design: Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/β-actin in tumor)/(ERCC1/β-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained 1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P < 0.001). Conclusions: Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.

Neoadjuvant radiochemotherapy of locally advanced esophageal cancer is only effective for patients with major histopathological response. A total of 17 genes were selected to predict histopathologic tumor response to chemoradiation (cisplatin, 5-fluorouracil, 36 Gy). For gene-expression analysis quantitative TaqMan low-density arrays were applied. Expression levels in pretreatment biopsies of 41 patients (cT2-4, Nx, M0) were compared with the degree of histopathologic regression in resected specimens applying univariate, multivariate and artificial neuronal network analyses. Dihydropyrimidine dehydrogenase was identified as an independent predictor associated with major response (p < 0.002). Multivariate analysis of the marker combination provided response prediction with 75.0% sensitivity, 81.0% specificity and 78.1% accuracy. Artificial neuronal network analysis was the best predictive model for major histopathologic response (80% sensitivity, 90.5% specificity and 85.4% accuracy), representing a clinically practical system. Low-density-array RT-PCR analyzed by artificial neuronal network predicts histopathologic response to neoadjuvant chemoradiation in our patient collective, and could be used to further individualize treatment strategies in esophageal cancer.