UGT1A1*6, 1A7*3, and 1A9*22 genotypes predict severe neutropenia in FOLFIRI‐treated metastatic colorectal cancer in two prospective studies in Japan. Issue 12 (27th October 2013)

• Record Type: Journal Article
• Authors: Hazama, Shoichi; Mishima, Hideyuki; Tsunedomi, Ryouichi; Okuyama, Yusuke; Kato, Takeshi; Takahashi, Ken‐ichi; Nozawa, Hiroshi; Ando, Hideaki; Kobayashi, Michiya; Takemoto, Hiroyoshi; Nagata, Naoki; Kanekiyo, Shinsuke; Inoue, Yuka; Hamamoto, Yoshihiko; Fujita, Yusuke; Hinoda, Yuji; Okayama, Naoko; Oba, Koji; Sakamoto, Jun‐ichi; Oka, Masaaki
• Is Part Of: Cancer science. Volume 104:Issue 12(2013:Dec.)
• Page Start: 1662
• Page End: 1669
• Publication Date: 2013-10-27
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12283
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" id="cas12283-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Retrospective studies have suggested that UDP‐glucuronosyltransferase <italic>(UGT)1A1</italic>, <italic>UGT1A7</italic>, and <italic>UGT1A9</italic> predict severe toxicity and efficacy of irinotecan‐containing regimens. We prospectively evaluated the impact of <italic>UGT1A</italic> genotypes and haplotypes on severe toxicity and efficacy in patients treated with fluorouracil, leucovorin, and irinotecan combination chemotherapy (FOLFIRI) for metastatic colorectal cancer (mCRC) from the two prospective multicenter phase II studies in Japan. The FLIGHT1 study was a first‐line FOLFIRI trial, and FLIGHT2 was a FOLFOX‐refractory, second‐line FOLFIRI trial. A total of 73 patients agreed to additional analysis, and were genotyped for <italic>UGT1A</italic> polymorphisms, <italic>UGT1A1*28</italic> (TA6>TA7), <italic>UGT1A1*6</italic> (211G>A), <italic>UGT1A1*27</italic> (686C>A), <italic>UGT1A1*60</italic> (−3279T>G), <italic>UGT1A1*93</italic> (−3156G>A), <italic>UGT1A7</italic> (−57T>G), <italic>UGT1A7*3</italic> (387T>G, 622T>C), and <italic>UGT1A9*22</italic> (T9>T10). Of 73 patients, 34 developed G3/4 severe hematological toxicities. The toxicities were significantly more frequent in patients with <italic>UGT1A1*6</italic> (211A), <italic>UGT1A7</italic> (387G), and <italic>UGT1A9*22</italic> reference alleles (T9). Haplotype I, which consists of all favorable alleles, was associated with a significant reduction in hematologic toxicity (<italic>P</italic> = 0.031). In contrast, haplotype II, which contains four high‐risk alleles, showed significantly higher hematologic toxicity than the other haplotypes (<italic>P</italic> = 0.010). Six out of seven patients who were homozygous for <italic>UGT1A1*28</italic> or <italic>*6</italic> experienced severe hematological toxicity despite the fact that their response rate was not impaired (42.9%). We concluded that <italic>UGT1A</italic> polymorphisms, especially <italic>UGT1A1*6</italic>, are important for the prediction of severe toxicity of FOLFIRI in northeast Asian populations. In this regard, haplotype analyses should substantially impact the prediction of severe hematological toxicities of FOLFIRI. (Clinical Trial Registration: UMIN000002388 and UMIN000002476).</p> </abstract>