Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the third-line treatment for advanced gastric cancer

Abstract

Background While uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme in the metabolism of irinotecan, relationship between UGT1A1 genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer is not clarified. Methods Efficacy and safety in advanced gastric cancer patients, who were tested for UGT1A1*6 and *28 genotype and treated with irinotecan monotherapy as third-line treatment from 2009 to 2014, were evaluated according to the UGT1A1*6 and *28 genotypes. Results Among 74 patients of the subjects, the genotypes of UGT1A1 were wild-type (WT) in 37 patients (50%), single heterozygosity (SH) in 27 (36.5%) and double heterozygosity or homozygosity (Homo/DH) in 10 (13.5%). The initial dose of irinotecan was reduced in 10 patients (27%) with WT, in 9 (33%) with SH, and in 7 (70%) with Homo/DH. Median overall survival was 6.9 months, 6.3 months, and 2.8 months in the WT, SH and Homo/DH genotypes, associated with median time to treatment failure of 2.4 months, 2.3 months, and 1.3 months, respectively. Among 36 patients with measurable lesion, disease control rates were 47.6%, 41.7% and 33.3% in the WT, SH and Homo/DH genotypes. Grade 3 or higher adverse events of special interest were neutropenia (13%, 22%, and 64% for the WT, SH and Homo/DH genotypes), febrile neutropenia (2%, 7%, and 50%) and diarrhea (6%, 5%, and 21%). Conclusions The UGT1A1 polymorphism may be related to the clinical outcomes of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.

Impact of single-heterozygous UGT1A1 on the clinical outcomes of irinotecan monotherapy after fluoropyrimidine and platinum-based combination therapy for gastric cancer: a multicenter retrospective study

“…This trend was also shown regardless of treatment line and use of taxanes. Non-hematological toxicity such as diarrhea did not significantly differ according to UGT1A1 status, consistent with the findings of previous studies [13,23,24]. To date, few studies and guidelines have mentioned the impact of However, clinicians should be aware that not only double heterozygous or homozygous UGT1A1, but also SH is a significant risk factor for severe hematological AEs.…”

“…Nishimura et al [23] reported a higher incidence rate of hematological toxicity in irinotecan monotherapy as third-line treatment for AGC refractory to fluoropyrimidines, platinum, and taxanes. Yamaguchi et al [13] reported a similar rate of toxicity in third-line irinotecan monotherapy between UGT1A1 WT and SH patients. The discrepancy may be explained by the different rates of initial dose reduction of irinotecan.…”

“…This multicenter retrospective study showed that among AGC patients treated with irinotecan monotherapy as second-or later-line treatment the incidence of hematological AEs was higher in UGT1A1 SH patients than UGT1A1 WT patients. Several studies have indicated that UGT1A1 polymorphism is associated with toxicity in irinotecan monotherapy [11,12,13,19] and combination therapy [10,12,[19][20][21]. Racial differences in UGT1A1 polymorphism have also been reported.…”

“…Homozygous or double-heterozygous UGT1A1*6 or *28 is associated with higher incidence of severe neutropenia but not diarrhea [10,11]. Yamaguchi et al [13] reported that gastric cancer patients who have double heterozygous or homozygous UGT1A1 tend to have severe neutropenia. However, the association of single-heterozygous and wild type UGT1A1 with hematological toxicity is unclear.…”

“…SN-38 is inactivated by the liver enzyme UGT1A1 [9] to SN-38 glucuronide (SN-38G). Several studies showed that UGT1A1 polymorphisms (homozygous or double heterozygous UGT1A1*6/*28) is associated with delayed metabolism of SN-38, and this leads to enhanced irinotecan-induced toxicity in various tumors including gastric cancer [10][11][12][13]. Ethnic differences in the frequency of the UGT1A1*6 variant have been reported, with higher frequency in Asians than in Caucasians (13-17% vs. < 0.1%) [14][15][16][17].…”