ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients

Chen, Sylvia; Villeneuve, Lyne; Jonker, Derek J.; Couture, Félix; Laverdière, Isabelle; Cecchin, Erika; Innocenti, Federico; Toffoli, Giuseppe; Lévesque, Éric; Guillemette, Chantal

doi:10.1097/fpc.0000000000000168

Cited by 33 publications

(24 citation statements)

References 41 publications

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“…This protective effect was observed in Caucasian patients with the ABCC2*2 haplotype (including six ABCC2 variants without any UGT1A1*28 alleles). Although their role in irinotecan efflux has not yet been established, ABCC5 and ABCG1 could also be involved in this process since several SNPs in these transporters are correlated with severe diarrhea [ 272 ].…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

et al. 2018

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Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.

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Section: Pharmacogeneticsmentioning

confidence: 99%

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

et al. 2018

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“…22 Além disso, na última década, diversos estudos têm revelado que o polimorfismo genético tem sido determinante na ocorrência das toxicidades gastrointestinais graves. [23][24][25][26] Nessa perspectiva, a identificação de biomarcadores, a associação de terapias alvo moleculares com os esquemas mFOLFOX6 e FOLFIRI, assim como variações/modificações desses esquemas, vêm sendo investigadas e sugeridas com o intuito de minimizar as reações gastrointestinais severas. 16,27,28 Outra estratégia apontada na literatura, para diminuição das toxicidades gastrointestinais, é a personalização da dose de 5-FU, nos esquemas empregados para o CCR, com base no monitoramento plasmático do medicamento.…”

Section: Discussionunclassified

Adverse drug reaction: a comparative analysis of protocols used for treatment of colorectal cancer

Melo¹,

Cardoso²,

Silva³

2017

Medicina (Ribeirão Preto)

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Modelo do estudo: Estudo de coorte. Objetivo: Analisar as reações adversas ocorridas em pacientes brasileiros com câncer colorretal submetidos ao tratamento quimioterápico com dois protocolos distintos, visando identificar os tipos e a severidade das alterações mais frequentes. Método: Foram avaliados 63 pacientes, que iniciaram tratamento entre junho de 2014 a maio de 2015 em uma instituição do Rio de Janeiro, subdivididos em dois grupos: protocolo mFOLFOX6 (esquema contendo oxaliplatina 85mg/m2, ácido folínico 400mg/m2 e 5-fluorouracil em infusão em bolus 400mg/m2 e contínua 2.400mg/ m2, n= 40) e protocolo FOLFIRI (esquema contendo irinotecano 180mg/m2, ácido folínico 400mg/m2 e 5-fluorouracil em infusão em bolus 400mg/m2 e contínua 2.400mg/m2, n= 23). Foram coletados do prontuário dados relacionados ao perfil demográfico e clínico dos pacientes, além de informações do tratamento realizado e das toxicidades manifestadas. As toxicidades foram classificadas quanto à gravidade (graus 1, 2, 3 e 4) e causalidade (definida, provável, possível e duvidosa). Resultados: Foi observada alta frequência de toxicidades em ambos os grupos, atingindo 92,5% dos pacientes com protocolo mFOLFOX6 e 95,6% com protocolo FOLFIRI. As toxicidades gastrointestinais e neurológicas foram as mais frequentes, independente do grupo. Ao comparar a ocorrência das reações intergrupos, houve diferença apenas para as toxicidades gastrointestinais (p=0,035). Em 17,5% dos pacientes do grupo mFOLFOX6 (n= 7) e em 8,7% do grupo FOLFIRI (n= 2) se observou toxicidades dos tipos 3 e 4, sendo estas classificadas como provável reação adversa aos medicamentos. Conclusão: As toxicidades foram mais variadas e frequentes no grupo mFOLFOX6 em comparação ao grupo FOLFIRI. Entretanto, não se observou diferença na severidade e na causalidade das reações ocorridas em ambos os grupos.

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“…Associations with response rate and severe toxicities (neutropenia and diarrhea) were assessed by logistic regression. HRs and odds ratios (ORs) were adjusted for covariates including age, and co-treatment for the Canadian cohort and adjusted for gender, age, cancer primary site, stage at diagnosis, radical surgery and adjuvant chemotherapy in the Italian cohort, as performed in previous reports ( Toffoli et al, 2006 ; Cecchin et al, 2009 ; Levesque et al, 2013 ; Chen et al, 2015a , b ). Additive, dominant and recessive models were fitted independently.…”

Section: Methodsmentioning

confidence: 99%

Improved Progression-Free Survival in Irinotecan-Treated Metastatic Colorectal Cancer Patients Carrying the HNF1A Coding Variant p.I27L

et al. 2017

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Hepatocyte nuclear factor 1-alpha (HNF1A) is a liver-enriched transcription factor that plays a key role in many aspects of hepatic functions including detoxification processes. We examined whether HNF1A polymorphisms are associated with clinical outcomes in two independent cohorts combining 417 European ancestry patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based chemotherapy. The intronic rs2244608A>G marker was predictive of an improved progression-free survival with a trend in the Canadian cohort and reaching significance in the Italian cohort, with hazard ratios (HR) of 0.74 and 0.72, P = 0.076 and 0.038, respectively. A strong association between rs2244608A>G and improved PFS was found in the combined analysis of both cohorts (HR = 0.72; P = 0.002). Consistent with an altered HNF1A function, mCRC carriers of the rs2244608G minor allele displayed enhanced drug exposure by 45% (P = 0.032) compared to non-carriers. In Caucasians, rs2244608A>G is in strong linkage with the coding variant rs1169288c.79A>C (HNF1A p.I27L). In healthy donors, we observed an altered hepatic (ABCC1, P = 0.009, ABCC2, P = 0.048 and CYP3A5, P = 0.001; n = 89) and intestinal (TOP1, P = 0.004; n = 75) gene expression associated with the rs1169288C allele. In addition, the rs1169288C polymorphism could significantly increase the ABCC1 promoter activity by 27% (P = 0.008) and 15% (P = 0.041) in the human kidney HEK293 and the human liver HepG2 cell lines, respectively. Our findings suggest that the HNF1A rs2244608, or the tightly linked functional coding variant p.I27L, might be a potential prognostic marker with irinotecan-based regimens.

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ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients

Abstract: This combination of predictive genetic markers could potentially lead to better risk assessment and may thus improve personalized treatment.

Cited by 33 publications

References 41 publications

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

Adverse drug reaction: a comparative analysis of protocols used for treatment of colorectal cancer

Improved Progression-Free Survival in Irinotecan-Treated Metastatic Colorectal Cancer Patients Carrying the HNF1A Coding Variant p.I27L

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