Association of Pretherapeutic Expression of Chemotherapy-Related Genes with Response to Neoadjuvant Chemotherapy in

Purpose: We analyzed pretherapeutic gene expression patterns of patients with locally advanced adenocarcinomas of the esophagus with regard to response to neoadjuvant chemo- therapy. Experimental Design: Pretherapeutic, paraffin-embedded, formalin-fixed endoscopic esoph- ageal tumor biopsies of 38 patients with locally advanced esophageal adenocarcinomas (Barrett adenocarcinoma) were included. All patients underwent two cycles of cisplatin and 5-fluorouracil (5-FU) therapy with or without additional paclitaxel followed by abdominothor- acal esophagectomy. RNA expression levels of 5-FU metabolism-associated genes thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, methylenetetrahydrofo- late reductase, MAP7 ,a ndELF3, of platinum- and taxane-related genes caldesmon, ERCC1, ERCC4, HER-2/neu ,a ndGADD45 , and of multidrug resistance gene MRP1 were determined using real-time reverse transcriptase-PCR. Expression levels were correlated with response to chemotherapy, histopathologically assessed in surgically resected specimens. Results: Responding patients showed significantly higher pretherapeutic expression levels of MTHFR (P =0 .012 ),caldesmon (P =0 .016), andMRP1 (P = 0.007). In addition, patients with high pretherapeutic MTHFR and MRP1 levels had a survival benefit after surgery (P =0 .013 and P = 0.015, respectively). Additionally, investigation of intratumoral heterogeneity of gene expres- sion of relevant genes (MTHFR, caldesmon, HER-2/neu, ERCC4 ,a ndMRP1), verified in nine untreated Barrett adenocarcinomas by examination of five distinct tumor areas, revealed no signif- icant heterogeneity in gene expression indicating that expression profiles obtained from biopsy material may yield a representative genetic expression profile of total tumor tissue. Conclusions: Our results indicate that determination of mRNA levels of few genes may be useful for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced Barrett adenocarcinoma. Multimodal treatment protocols are being increasingly employed to improve the survival of patients with locally advanced adenocarcinoma of the esophagus. Neoadjuvant chemotherapy, mainly based on 5-fluorouracil (5-FU) and cisplatin, has been shown to induce tumor remission, and there seems to be a survival advantage for patients who respond to preoperative therapy compared with surgical treatment alone. However, in the majority of the patients, no objective response is achieved and the prognosis for