Effects of UGT1A1*6, UGT1A1*28, and ABCB1-3435C&gt;T polymorphisms on irinotecaninduced toxicity in Chinese cancer patients

Liang, Yan; Wang, Xiaofei; Wei, Luman; Nie, Yali; Liu, Jingyang; Zhang, Lirong

doi:10.5414/cp202442

Cited by 7 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recently, Salvador-Martıń et al analyzed the association between variants in ABC efflux transporter genes and irinotecan adverse effects, and found that the ABCB1 variants were significantly associated with overall toxicity (P<0.01) and with higher hematological toxicity including, but not limited to, neutropenia (P<0.01) (Salvador-Martín et al, 2018). However, other studies conducted in mCRC patients treated with irinotecan in whom ABCB1 variants were analyzed did not show significant associations with severe neutropenia (De Mattia et al, 2013;Chen et al, 2015;Teft et al, 2015;Yan et al, 2016). Our findings support these negative results as we found no associations with severe neutropenia in the 307 patients analyzed.…”

Section: Discussionsupporting

confidence: 81%

“…Few studies have analyzed ABCB1 variants as determinants of gastrointestinal toxicity in mCRC patients treated with irinotecan, and most of them produced negative results ( De Mattia et al., 2013 ; Chen et al., 2015 ; Teft et al., 2015 ; Yan et al., 2016 ; Salvador-Martín et al., 2018 ). Nevertheless, in a cohort of 56 mCRC patients receiving an irinotecan-based treatment, Cortejoso et al found that patients with the CC genotype for the rs1045642 variant had a higher probability of diarrhea than patients with CT and TT genotypes ( P =0.039) ( Cortejoso, et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

et al. 2020

View full text Add to dashboard Cite

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (Pgp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

et al. 2020

View full text Add to dashboard Cite

show abstract

“…ABCB1 c.3435C > T is associated with significantly lower AUC SN-38G levels, and homozygous ABCB1 c.3435T/T may be related to higher P-glycoprotein (MDR1) activity 34 . However, ABCB1 c.3435C > T was not associated with irinotecan induced severe neutropenia and diarrhea in Chinese cancer patients who received irinotecan chemotherapy 35 . Cote et al 36 reported that no statistically significant difference was found in ABCB1 c.3435C > T polymorphism and occurrence of severe hematologic toxicity or severe neutropenia.…”

Section: Discussionmentioning

confidence: 84%

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy

Atasilp

Chansriwong

Sirachainan

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Genetic polymorphisms in drug metabolizing enzymes and drug transporters may affect irinotecan toxicity. Although genetic polymorphisms have been shown to influence the irinotecan toxicity, data are limited in Thai population. Thus, the aim of this study was to assess the allele and genotype frequencies and the relationship between CYP3A4/5, DPYD, UGT1A1, ABCB1, and ABCC2 genetic variations and irinotecan-induced toxicity in Thai colorectal cancer patients. One hundred and thirtytwo patients were genotyped, and the effect of genetic variations on irinotecan-induced toxicity was assessed in 66 patients who received irinotecan-based chemotherapy. Allele frequencies of ABCB1 c.1236C > T, ABCB1 c.3435C > T, ABCC2 c.3972C > T, ABCG2 c.421C > A, CYP3A4*1B, CYP3A4*18, CYP3A5*3, DPYD*5, UGT1A1*28, and UGT1A1*

show abstract

“…The results were based on studies with small samples. In actual clinical practice, severe diarrhea was more closely associated with mortality than neutropenia [8], but there is still no definite biomarker that can predict severe diarrhea in Asian patients [9, 10]. Moreover, irinotecan is commonly used in combination with fluorouracil, which also induces severe neutropenia and diarrhea.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Effects of UGT1A16, UGT1A128, and ABCB1-3435C>T polymorphisms on irinotecaninduced toxicity in Chinese cancer patients

Cited by 7 publications

References 0 publications

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy

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

Contact Info

Product

Resources

About