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

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2019-07, Vol.22 (4), p.778-784
• Main Authors: Yamaguchi, Toshifumi, Iwasa, Satoru, Shoji, Hirokazu, Honma, Yoshitaka, Takashima, Atsuo, Kato, Ken, Hamaguchi, Tetsuya, Higuchi, Kazuhide, Boku, Narikazu
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic - therapeutic use; Biomarkers, Tumor - genetics; Cancer Research; Diarrhea; Disease control; Female; Follow-Up Studies; Gastric cancer; Gastroenterology; Gene polymorphism; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Heterozygosity; Humans; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - genetics; Intestinal Neoplasms - secondary; Irinotecan; Irinotecan - therapeutic use; Lymphatic Metastasis; Male; Medicine; Medicine & Public Health; Middle Aged; Neutropenia; Oncology; Original Article; Patients; Polymorphism; Polymorphism, Genetic; Prognosis; Retrospective Studies; Safety; Salvage Therapy; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Surgical Oncology; Survival Rate; Uridine
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-018-00917-5

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.