UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer

Xu, Chengcheng; Tang, Xushan; Qu, Yanli; Keyoumu, Saifuding; Zhou, Ning; Tang, Yong

doi:10.1007/s00280-016-3057-z

Cited by 35 publications

(38 citation statements)

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“…Both UGT1A1*6 and UGT1A1*28 related to G3–4 neutropenia, rather than delayed diarrhea, which was consistent with several large-sample analysis in Asia [4–7]. Several small-sample analyses also noted that UGT1A1*28 and UGT1A1*6 could predict severe irinotecan-induced severe diarrhea [21, 22], which did not appear in the current study. A small sample analysis of Atasilp C et al, involving UGT1A1*6 and UGT1A1*28 were included in this analysis.…”

Section: Discussionsupporting

confidence: 91%

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Liú

Gao

et al. 2017

BMC Cancer

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BackgroundTo evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).MethodsThe genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.ResultsIn the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395–3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138–30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946–11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136–4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).ConclusionResults still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3406-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Liú

Gao

et al. 2017

BMC Cancer

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“…However, the UGT1A1*28 TA6/6 and TA7/7 genotypes may show an increased treatment response according to our results. In contrast to our results, Xu et al 67 observed different clinical responses in Ugyur patients with different UGT1A1*28 polymorphism genotypes, but not in the Han population. Although the reduction of irinotecan was greater in patients with the TA7/7 or TA6/7 genotypes than the TA6/6 genotype, no difference in overall or progression-free survival between the two group patients were found by Dias et al 68.…”

Section: Discussioncontrasting

confidence: 99%

Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy

Liu

Duan

et al. 2017

J. Cancer

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The UGT1A1*28 polymorphism was suggested to be significantly connected with irinotecan-induced toxicity and response to chemotherapy. However, the results of previous studies are controversial. Hence we carried out a meta-analysis to investigate the effect of UGT1A1*28 polymorphism on severe diarrhea, neutropenia, and response of patients who had undergone irinotecan-based chemotherapy. The PubMed, Web of Science, Wanfang, and CNKI databases were searched for clinical trials assessing the association of UGT1A1*28 polymorphism with severe diarrhea, neutropenia, and response to irinotecan-based chemotherapy. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship under a fixed- or random-effects model. Fifty-eight studies including 6087 patients with cancer were included. Our results showed that patients carrying the TA6/7 and TA7/7 genotypes had a greater prevalence of diarrhea and neutropenia than those with the TA6/6 genotype (TA6/7+TA7/7 vs. TA6/6: diarrhea, OR = 2.18, 95%CI = 1.68-2.83; neutropenia, OR = 2.15, 95%CI = 1.71-2.70), particularly patients with metastatic colorectal cancer. Stratified analysis showed that Asians with the TA6/7 and TA7/7 genotypes were more likely to have diarrhea and neutropenia, and Caucasians with the TA6/7 and TA7/7 genotypes were more likely to have neutropenia than other groups. However, patients with the TA6/7+TA7/7 genotypes showed a higher response than patients with TA6/6 genotype (OR = 1.20, 95%CI = 1.07-1.34), particularly Caucasians (OR = 1.23, 95%CI = 1.06-1.42) and patients with metastatic colorectal cancer (OR = 1.24, 95%CI = 1.05-1.48). Our data showed that the UGT1A1*28 polymorphism had a significant relationship with toxicity and response to irinotecan-based chemotherapy. This polymorphism may be useful as a monitoring index for cancer patients receiving irinotecan-based chemotherapy.

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“…However, Hirasawa et al26 found that UGT1A1*6 / *28 mutations are associated with an increased risk of neutropenia and delayed diarrhea at a low dose of CPT-11. In China, Xu et al3 discovered that mutant UGT1A1*6/*28 genotypes significantly increase the incidence of delayed diarrhea, and the incidence of neutropenia is significantly increased when the UGT1A1*6 and UGT1A1*28 genotypes are considered together. Further, Chinese patients with UGT1A1*6/*28 mutations are more likely to suffer delayed diarrhea than Japanese patients.…”

Section: Discussionmentioning

confidence: 99%

Relationship between <em>UGT1A16/28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

Bai

et al. 2017

OTT

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PurposeA retrospective study was performed to analyze the relationship between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) *6/*28 gene polymorphisms and adverse reactions associated with irinotecan (CPT-11)-based chemotherapy. The correlation between UGT1A1 polymorphisms and the clinical efficacy of CPT-11 was also analyzed, along with the influence of age and tumor type.Patients and methodsPatients administered a CPT-11-based regimen in the Beijing Cancer Hospital from April 2015 to September 2016 were included in our study (n=81). Blood samples for detecting UGT1A1 were collected from each patient after various administration regimens.ResultsColorectal cancer patients with the UGT1A1*6 mutant genotype had a significantly higher risk of severe delayed diarrhea than that of wild-type individuals when administered a CPT-11 dose ≥130 mg/m2 (P=0.042); the same phenomenon was observed when the UGT1A1*6 and UGT1A1*28 mutant genotypes were considered together (P=0.028). However, in lung cancer patients administered a low dose of CPT-11, UGT1A1*6/*28 variants were not significantly associated with severe neutropenia or delayed diarrhea. Furthermore, adult patients with the UGT1A1*6 mutation were more likely to develop severe delayed diarrhea than did wild-type adults (P=0.013); however, the difference was not significant in elderly patients. No significant differences in tumor response were found among the different genotypes (P>0.05).ConclusionThus, age and tumor type influence our ability to predict adverse reactions based on UGT1A1 gene polymorphisms in cancer patients. Further, UGT1A1 gene polymorphisms are not correlated with the efficacy of CPT-11-based regimens.

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UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer

Cited by 35 publications

References 40 publications

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy

Relationship between <em>UGT1A16/28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

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UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer

Cited by 35 publications

References 40 publications

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy

Relationship between <em>UGT1A1*6/*28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

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Relationship between <em>UGT1A16/28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy