Indispensability of UGT1A1*6 genotyping in Japanese cancer patients treated with irinotecan

Abstract

We would like to congratulate Onoue and colleagues [1] for their excellent article on investigation of the relationship between severe neutropenia and UGT1A1 and SLCO1B1 polymorphisms. In the article, they suggested that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients. The significance was observed in not only UGT1A1*6 ?/? patients but also UGT1A1*6 ?/cases. Odds ratios were surprisingly high; 5.19 in UGT1A1*6 ?/cases and 7.63 in UGT1A1*6 ?/? cases. A metaanalysis of nine Euro-American studies revealed that frequency of grades III and IV hematologic toxicities increased in the patients with UGT1A1*28 ?/? genotype at a high doses of irinotecan [2]. At lower doses (B150 mg/m), the risk of hematologic toxicity in patients with UGT1A1*28 ?/? genotype was not statistically significantly different from that among patients with UGT1A1*28 ?/or UGT1A1*28 -/genotype [2]. Taking account of the results, it seems appropriate that genotyping of UGT1A1*28 could be omitted for the patients treated at a low dose of irinotecan in western countries. On the other hand, the significant contribution of UGT1A1*6 ?/to grades III and IV neutropenia and diarrhea was also clearly observed in Japanese prospective multi-institutional analysis for gynecologic patients treated with a low dose of irinotecan (60 mg/m, 3 weeks on and 1 week off) and cisplatin [3]. The UGT1A1*6 ?/genotype was identified as an independent risk factor for grades III and IV neutropenia (hazard ratio = 6.54), and grades III and IV diarrhea (hazard ratio = 7.45). We are so surprised to see almost the same odds ratio for severe neutropenia in heterogeneously treated cohort with irinotecan [1] as in our homogeneously treated cases [3]. It is noteworthy that severe toxicities in UGT1A1*6 ?/cases were observed in two separate studies, even at a low dose of irinotecan. Recently in Japan, genotyping of UGT1A1*28 and *6 has been approved by the Japanese Organization of the Ministry of Health, Labor and Welfare; however, there exists an argument against routine use of UGT1A1 genotype testing for the patients who will be treated with irinotecan. It is true that UGT1A1 genotyping is not a magic tool to certify no toxicities caused by irinotecan, as there are some cases that experience severe toxicities in UGT1A1 wild-type cases. We would emphasize that one half of the cases who experienced grade III–IV neutropenia were treated at a lower dose of irinotecan and increasing doses of irinotecan were not related with increase toxicities in the analysis by Onoue and colleagues [1]. On the contrary, a report on a Japanese population suggested the metabolic ratios were variable according to administrated dose of irinotecan in patients with homozygosity of UGT1A1*6 or heterozygosity of UGT1A1*6 [4]. Thus, dose matters of irinotecan have been unresolved in Japanese patients with different frequency of UGT1A1*28 and *6 from western patients. Together, the utility of M. Takano (&) M. Kato T. Yoshikawa T. Goto K. Furuya Department of Obstetrics and Gynecology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan e-mail: mastkn@ndmc.ac.jp