The Efficacy of UGT1A1 Polymorphism in Chemoradiation Therapy Using Irinotecan in Patients with Locally Advanced Rectal Cancer

Abstract

Purpose: Irinotecan (CPT-11) is hydrolyzed to an active SN-38, which is further detoxicated to SN-38G through conjugation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) enzymes. There are many reports that UGT1A1 polymorphisms are associated with irinotecan related dose-limiting toxicity. The aim of the present study is to determine whether UGT1A1 polymorphisms affect individual variations of the toxicity due to and the tumor response to irinotecan via the alteration of bioavailability of SN-38 in Korean patients with locally advanced rectal cancer. Methods: Twenty patients with locally advanced rectal cancer, who had received surgery after irinotecan- containing chemoradiation from 2003 to 2006, were enrolled. We analyzed the association of UGT1A1 genotypes with toxicity and tumor response to chemoradiation therapy. A tumor response was assumed when a tumor regression grade I or II was obtained. Toxicity was graded in accordance with the NCI common toxicity criteria. Results: The frequence of -53(TA)6＞7 (UGT1A1*28), 211G＞A (UGT1A1*6), 686C＞A (UGT1A1*27), -3279T＞G (UGT1A1*60), and -3156G＞A were 25% (5/20), 25% (5/20), 0% (0/20), 55% (11/20), and 20% (4/20), respectively. There were five grade III neutropenia and one severe diarrhea. Patients with UGT1A1*28 and -3156G＞A showed higher complete tumor response rates (40% vs. 6.7%, P=0.07; 50% vs. 6.3%, P=0.08), but there was no differences in toxicity and tumor response between responders and non-responders. Patients with -3279T＞G (UGT1A1*60) showed a tendency for lower tumor response in tumor responders, but there was no statistically significant difference (P=0.07). Conclusions: This study suggested that -3279T＞G (UGT1A1*60) may be useful in predicting tumor response of irinotecan. In the future, further study is warranted using large numbers of cases to reach statistical significance.