Therapy Related Markers and Response Prediction Towards Multimodal Treatment of Carcinomas of the Upper Gastrointestinal Tract

Gisela      Keller; Rupert      Langer; Heinz      Hofler

Abstract

Adenocarcinomas of the upper gastrointestinal tract are characterized by a high mortality rate. Various multimodal therapy regimens are used to improve the patients prognosis, but the majority of patients does not respond to treatment. Thus, the identification of biomarkers that could predict response is highly demanding. The chemotherapeutic regimens most commonly used for the treatment of adenocarcinomas of the upper gastrointestinal tract are mainly based on 5-fluorouracil (5FU), cisplatin and taxan derivates. Molecular markers related to the efficiency of these components have been analyzed in various studies. One example is thymidylate synthase (TS) the major target of 5FU. Expression of TS in tumors of the upper gastrointestinal tract has been found to correlate with the outcome of the patient in some studies, but the results are inconsistent. Polymorphisms in the promotor region of the gene have been reported, which influence the expression of the protein and a correlation of the genoytpes with patients survival has been demonstrated. Markers related to the efficiency of cisplatin, encompass the DNA-repair genes. One example is the nucleotide excisison repair gene ERCC1, for which gene expression in upper gastrointestinal tumors as well as polymorphisms in the gene have been analyzed in relation to the patients outcome. Genome wide screening methods, as cDNA-microarrays or differential qualitative and quantitative protein expression analysis recently have been reported to give promising results for the pretherapeutic discrimination of therapy responders and nonresponders. In this review we will summarize the current state on genetic alterations in upper gastrointestinal malignancies and on the role of polymorphisms and their implications for response prediction, with a focus on parameters in therapy related genes in the group of patients treated in the neoadjuvant setting.

Keywords: Chemotherapy, upper gastrointestinal malignancies, gastric cancer, esophageal adenocarcinoma, response prediction, biomarkers, cisplatin, 5-fluorouracil, DNA polymorphisms