Correlating Irinotecan and Capecitabine Treatment for Colorectal Cancer to Gene Expression, Polymorphisms, and Clinical Outcomes

Abstract

Colorectal cancer is the third most common type of cancer and the third most common cause of cancer-related mortality. There are three types of treatment available to patients, either individually or in combination. Treatments are radiation, chemotherapy, and surgery. In a Phase II clinical trial at IUSM, a multimodality approach was chosen. The patients with locally advanced rectal cancer received preoperative treatment with capecitabine and irinotecan (CPT-11) combination followed by chemoradiation with capecitabine and finally surgery to improve response and decrease local recurrence. Irinotecan and Capecitabine are both prodrugs activated in vivo to SN-38 and 5-FU, respectively. Identification of the molecular markers for 5-FU and Irinotecan efficacy and toxicity is important for the development of more efficient and less toxic treatment strategies for patients with colorectal cancer. The goal of this study was to determine the expression levels of the genes involved in activation and metabolism of capecitabine and irinotecan in pre and post treatment specimens from these patients. The genes quantitated by real-time PCR were carboxylesterase 1 and 2 (CES1 and CES2), thymidylate synthase (TS), β-glucoronidase (β-GUS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and topoisomerase I (Topo I). The UGT1A128 polymorphism in UDP glucuronosyltransferase 1 is associated with SN-38 toxicity. Therefore, the UGT1A128 polymorphism status in patients was determined by PCR-sequencing. Correlative analysis of gene expression and UGT1A1*28 mutation with clinical outcome in this Phase II study was completed.