A Phase II Study of Irinotecan and Carboplatin in Advanced Non-small Cell Lung Cancer with Pharmacogenomic Analysis: Final Report

Pillot, Giancarlo; Read, William; Hennenfent, Kristin; Marsh, Sharon; Gao, Feng; Viswanathan, Avinash; Cummings, Kristopher W.; McLeod, Howard L.; Govindan, Ramaswamy

doi:10.1016/s1556-0864(15)31629-4

Cited by 22 publications

(47 citation statements)

References 31 publications

(24 reference statements)

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“…Thirdly, three included trials were published as abstracts. Fourthly, in our analysis, grade III-IV neutropenia data were available for most studies, whereas only grade IV neutropenia information could be extracted from two studies (20,21). Fifthly, for the study of the association between UGT1A1*28 and REG of SN-38, two included trials were conducted on Asian patients.…”

Section: Discussionmentioning

confidence: 99%

“…Patients were predominantly Caucasians in 11 trials. Four trials did not clearly report the race of the participants (16,20,22,23). The patients in these four trials, however, might have been Caucasians because these trials were conducted in Europe or America and the reported frequency of the UGT1A1*28 allele was similar to that of Caucasians.…”

Section: Study Characteristics and Methodologic Quality (Association mentioning

confidence: 98%

“…Association between UGT1A1*28 and neutropenia (UGT1A1*28/*28 versus UGT1A1*1/*1 or UGT1A1*1/*28) Relevant data for the comparison of the risk of neutropenia between UGT1A1*28/*28 patients and those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype were available in 15 included trials (3)(4)(5)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Considering the individual subgroup, there was no evidence of publication bias according to either Begg's test or Egger's test (Table 3).…”

Section: Study Characteristics and Methodologic Quality (Association mentioning

confidence: 99%

“…UGT1A1*28 has been shown to be associated with decreased SN-38 glucuronidation in humans (3)(4)(5)(6)(7)(8)(9)(10)(11). The association between the UGT1A1*28 genotype and irinotecan-induced neutropenia has been extensively studied (3)(4)(5)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Seven of these studies found that UGT1A1*28/*28 patients had an elevated risk of neutropenia compared with those carrying UGT1A1*1 allele(s) (refs.…”

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confidence: 99%

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Dose-Dependent Association between UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Low Doses Also Increase Risk

Qin

Pei

et al. 2010

Clinical Cancer Research

115

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Purpose: A previous meta-analysis showed that the association between the UGT1A1*28 genotype and irinotecan-induced neutropenia was influenced by irinotecan dose and that the risk of neutropenia was similar at low doses for patients with all genotypes. However, the sample sizes for the low-and high-dose groups were small. Because additional studies have now been reported, an updated and refined metaanalysis is needed.Experimental Design: Meta-analyses were done to assess the relationship between UGT1A1*28 and neutropenia. The association between UGT1A1*28 and the relative extent of glucuronidation (REG) of SN-38 was also examined. The studies included were stratified into different dose groups.Results: A total of 1,998 patients were included for the analysis of neutropenia and 581 patients were included for REG. The risk of neutropenia at low doses was significantly higher among patients with a UGT1A1*28/*28 genotype than among those carrying the UGT1A1*1 allele(s) [relative risk (RR), 2.43; 95% confidence interval, 1.34-4.39; P = 0.003].

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Section: Discussionmentioning

confidence: 99%

Section: Study Characteristics and Methodologic Quality (Association mentioning

confidence: 98%

Section: Study Characteristics and Methodologic Quality (Association mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Dose-Dependent Association between UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Low Doses Also Increase Risk

Qin

Pei

et al. 2010

Clinical Cancer Research

115

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“…Hence, better molecular markers to identify patients at risk for complications, including severe diarrhea, as well as to predict clinical response would be helpful to patients and medical oncologists. Currently, pharmacogenetic data suggest that the UGT1A1*28/*28 genotype confers the highest risk of severe neutropenia due to increased exposure to SN-38 (Ando et al, 2000;Iyer et al, 2002;Innocenti et al, 2004;Marcuello et al, 2004;Mathijssen et al, 2004;Rouits et al, 2004;de Jong et al, 2006;Massacesi et al, 2006;McLeod et al, 2006;Pillot et al, 2006;Toffoli et al, 2006;Cote et al, 2007;Hoskins et al, 2007;Kweekel et al, 2008;Ruzzo et al, 2008;Glimelius et al, 2011). Our current study confirms that this genotype is associated with an increased risk of severe neutropenia but in univariate analyses only, whereas a more comprehensive analysis of variations at the UGT1A locus suggests that other markers in the central region of the gene and in the 39UTR region might better predict this toxicity.…”

Section: Discussionmentioning

confidence: 99%

Refining theUGT1AHaplotype Associated with Irinotecan-Induced Hematological Toxicity in Metastatic Colorectal Cancer Patients Treated with 5-Fluorouracil/Irinotecan-Based Regimens

Lévesque

Bélanger

Harvey

et al. 2013

J Pharmacol Exp Ther

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Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n 5 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 39untranscribed region (39UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) 5 2.43; P 5 0.004]. The inclusion of a 39UTR singlenucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR 5 0.55; P 5 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 39UTR SNP allowed the identification of a protective HI (OR 5 0.50; P 5 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P # 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.

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Pharmacogenomics

Wong

2009

Wiley Encyclopedia of Forensic Science

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Pharmacogenomics involves the application of genetic variation between individuals to determine whether alterations in the ability to metabolize drugs, transport drugs to active sites, or drug efficacy can explain cases of poor response or unexpected toxicity. In understanding the application of pharmacogenomics, the basic principles are introduced in this article together with the related science pharmacogenetics. Applications relevant to forensic toxicology include situations involving the use of antipsychotics, opioids, and antidepressants. Moreover, some clinical applications are provided to illustrate the wider application of pharmacogenomics. The findings from the use of pharmacogenomics in forensic toxicology can add to the understanding of adverse drug reactions, poor response to drugs, help to optimize therapy in the emerging practice of personalized medicine, and possibly add to the understanding of genetic contribution to drug therapy/behavior in the form of personalized justice.

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A Phase II Study of Irinotecan and Carboplatin in Advanced Non-small Cell Lung Cancer with Pharmacogenomic Analysis: Final Report

Cited by 22 publications

References 31 publications

Dose-Dependent Association between UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Low Doses Also Increase Risk

Dose-Dependent Association between UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Low Doses Also Increase Risk

Refining theUGT1AHaplotype Associated with Irinotecan-Induced Hematological Toxicity in Metastatic Colorectal Cancer Patients Treated with 5-Fluorouracil/Irinotecan-Based Regimens

Pharmacogenomics

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