UDP-glucuronosyltransferase 1A1 Polymorphisms Research Articles

Association of UGT1A1 gene variants, expression levels, and enzyme concentrations with 2,3,7,8-TCDD exposure in individuals exposed to Agent Orange/Dioxin

Among the congener of dioxin, 2,3,7,8-TCDD is the most toxic, having a serious long-term impact on the environment and human health. UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a crucial role in the detoxification and excretion of endogenous and exogenous lipophilic compounds, primarily in the liver and gastrointestinal tract. This study aimed to investigate the association of UGT1A1 gene polymorphisms, expression levels, and enzyme concentration with Agent Orange/Dioxin exposure. The study included 100 individuals exposed to Agent Orange/Dioxin nearby Da Nang and Bien Hoa airports in Vietnam and 100 healthy controls. UGT1A1 SNP rs10929303, rs1042640 and rs8330 were determined by Sanger sequencing, mRNA expression was quantified by RT-qPCR and plasma UGT1A1 concentrations were measured by ELISA. The results showed that UGT1A1 polymorphisms at SNPs rs10929303, rs1042640 and rs8330 were associated with Agent Orange/Dioxin exposure (OR = 0.55, P = 0.018; OR = 0.55, P = 0.018 and OR = 0.57, P = 0.026, respectively). UGT1A1 mRNA expression levels and enzyme concentration were significantly elevated in individuals exposed to Agent Orange/Dioxin compared to controls (P < 0.0001). Benchmark dose (BMD) analyses showed that chronic exposure to 2,3,7,8-TCDD contamination affects the UGT1A1 mRNA and protein levels. Furthermore, UGT1A1 polymorphisms affected gene expression and enzyme concentrations in individuals exposed to Agent Orange/Dioxin. In conclusion, UGT1A1 gene polymorphisms, UGT1A gene expression levels and UGT1A1 enzyme concentrations were associated with Agent Orange/Dioxin exposure. The metabolism of 2,3,7,8-TCDD may influence UGT1A gene expression and enzyme concentrations.

Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An Exploratory Case-Control Study.

Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment. All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis. During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50-60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71-8635; p<0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86-1233; p=0.070) in the complete case analysis. Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.

Comparison of UGT1A1 Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.0–32.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.517–1.027; hazard ratio (HR), 0.729; p = 0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.410–1.008; HR, 0.643; p = 0.054), ORR (65.3% vs. 62.7%; p = 0.720), DCR (92.8% vs. 86.7%; p = 0.175), metastatectomy (36.7% vs. 29.3%; p = 0.307), and SAEs (p = 0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p > 0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.

UGT1A1 Gene Polymorphisms in Patients with Small Cell Lung Cancer Treated with Irinotecan-Platinum Doublet Chemotherapy and Their Association with Gastrointestinal Toxicity and Overall Survival.

Irinotecan (CPT11) is an important drug for small cell lung cancer (SCLC) chemotherapy (CTx). UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess prevalence of UGT1A1 polymorphisms and their association with clinical outcomes in patients with SCLC on CPT11-CTx. An observational cohort of treatment-naïve patients with SCLC was given CPT11-platinum doublet at a referral center in North India over 3 years. Clinical outcomes assessed were hematological and gastrointestinal toxicity (Common Terminology Criteria for Adverse Events, version 3.0), response rates (RECIST), and overall survival (OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation, and genomic DNA was isolated. Genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism for UGT1A1*7, UGT1A1*6, and UGT1A1*27 and by PCR-DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild-type (WT/WT), heterozygous mutant (WT/M), or homozygous mutant (M/M) for each polymorphism assessed. Of 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms (n = 111) was 89.2% for WT/WT, 8.1% for WT/M, and 2.7% for M/M. For UGT1A1*28 (n = 102), this was 41.2% for WT/WT, 43.1% for WT/M, and 15.7% for M/M. UGT1A1*6 WT/WT patients tolerated >95% predicted CPT11 dose more frequently (59.6% vs. 25.0% in WT/M-M/M combined group; p = .026). The UGT1A1*6 WT/M-M/M group also experienced severe (grade ≥3) diarrhea (41.7% vs. 17.2% in WT/WT; p = .044) and mucositis (41.7% vs. 8.1% in WT/WT; p = .005) more frequently. On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with occurrence of both mucositis (odds ratio [OR], 10.4) and severe diarrhea (OR, 4.8). UGT1A1*28 WT/M-M/M patients had better OS (320 days [95% confidence interval, 203-437] vs. 216 days [95% confidence interval, 140-292] in WT/WT group; p = .047). On multivariate Cox proportional hazards analysis, UGT1A1*28 WT/M-M/M status was independently associated with better OS (hazard ratio, 0.35), whereas lack of objective radiological response, moderate/heavy smoking, and increasing age were associated with worse OS. UGT1A1*6 and UGT1A1*28 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11-CTx. UGT1A1 gene polymorphisms are known to influence irinotecan-related toxicity. In this prospective cohort study of patients with small cell lung cancer receiving first-line irinotecan-platinum chemotherapy, the prevalence of UGT1A1*6 polymorphisms was found to be 10.8% UGT1A1*6 and 58.8% UGT1A1*28 homo/heterozygous mutant, respectively. UGT1A1*6 homo/heterozygous mutant status was associated with severe diarrhea and mucositis. UGT1A1*28 homo/heterozygous mutant status was independently associated with improved overall survival.

Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes.

Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes. Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods. Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P= .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P= .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism. UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.

Profiling of UGT1A1*6, UGT1A1*60, UGT1A1*93, and UGT1A1*28 Polymorphisms in Indonesian Neonates With Hyperbilirubinemia Using Multiplex PCR Sequencing.

Background: Single nucleotide polymorphism (SNP) variants of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene have been studied as an important factor in neonatal hyperbilirubinemia (jaundice) severity. Specific ethnicities, including Asians, have certain SNPs that appear more frequently than others.Aim: To identify the most common SNPs in Indonesian neonates and their association with the severity of neonatal hyperbilirubinemia.Methods: Eighty-eight inborn and outborn jaundiced infants from three different hospitals (Bengkulu, Jakarta, Biak Papua) across Indonesia were enrolled in this cross-sectional study and their peak total serum bilirubin (TSB) levels assessed. SNP variant analyses of the TATAA box, promoter, and exon 1 regions of UGT1A1 gene from 78 of the 88 infants were carried out using the SNaPshotR Multiplex Polymerase Chain Reaction (PCR) System followed by DNA sequencing.Results: We detected SNP variants UGT1A1*28, UGT1A1*60, UGT1A1*93, and UGT1A1*6 in our population. Mean total serum bilirubin (TSB) was 14.59 ± 5.57 mg/dL. Bivariate analyses using delivery location, gestational age, birth weight, mother's age, and ethnicity were shown to be associated with moderate-to-severe hyperbilirubinemia (p < 0.05). None of the four SNPs appeared to be associated with moderate-to-severe hyperbilirubinemia. In multivariate analysis, however, only the “other ethnic group” (e.g., Chinese, Bengkulu, Papua, Bima) category showed an association with moderate-to-severe hyperbilirubinemia, with an odds ratio of 6.49 (95% CI 1.01–41.67; p < 0.05).Conclusions: We found that the UGT1A1*60 is the most common SNP detected in neonates with hyperbilirubinemia in the Indonesian population. Interestingly, in Indonesia, UGT1A1 polymorphisms do not appear to be associated with differences in the severity of hyperbilirubinemia.

Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX.

Studies have indicated an association between UDP‐glucuronosyltransferase‐1A1 (UGT1A1) genetic polymorphisms and irinotecan‐induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 200 mg/m2, bolus 5‐fluorouracil [5‐FU] 400 mg/m2, and continuous 5‐FU 2400 mg/m2) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 200 mg/m2, and continuous 5‐FU 2400 mg/m2) as first‐line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients).In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 −/*6 than among those with UGT1A1 −/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 −/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.

Association of nephrotoxicity during platinum-etoposide doublet therapy with UGT1A1 polymorphisms in small cell lung cancer patients

ObjectivesEtoposide is a key agent in the treatment of small cell lung cancer (SCLC). Uridine diphosphate (UDP)–glucuronosyltransferase 1A1 (UGT1A1) is thought to be largely responsible for the glucuronidation of etoposide as well as that of irinotecan, suggesting that polymorphisms of UGT1A1 might be predictive of etoposide toxicity. We therefore examined the relation between UGT1A1 polymorphisms and toxicity profile during platinum-etoposide doublet therapy in SCLC patients. Materials and MethodsSCLC patients who underwent platinum-etoposide doublet therapy and molecular testing for UGT1A1 genotype were reviewed for the occurrence of adverse events during treatment. ResultsA total of 41 SCLC patients received platinum-etoposide doublet therapy and were genotyped for UGT1A1*6 and UGT1A1*28 alleles. These alleles were detected in 15 (36.6%) patients, with the genotypes of *6/–, *6/*6, *28/–, *28/*28, or *6/*28 being observed in 9 (22.0%), 2 (4.9%), 2 (4.9%), 1 (2.4%), and 1 (2.4%) patients, respectively. The presence of these alleles was significantly associated with an increase in serum creatinine concentration of grade ≥2 (incidence of 66.7% for patients with the alleles versus 11.5% for those without, P < 0.001). Multivariate analysis also showed that these UGT1A1 alleles were significantly associated with therapy-induced nephrotoxicity (odds ratio of 19.30, 95% confidence interval of 2.50–149.00, P < 0.005). Although the differences did not achieve statistical significance, the incidence of other severe toxicities including febrile neutropenia was also slightly higher in patients with the UGT1A1*6 or UGT1A1*28 alleles than in those without them. ConclusionOur results reveal an association between UGT1A1 polymorphisms and toxicity of platinum-etoposide doublet therapy in SCLC patients, suggesting that close monitoring for toxicity, especially nephrotoxicity, is warranted for patients with such variant alleles receiving this treatment.

UGT1A1 polymorphisms in rectal cancer associated with the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan.

The purpose of the present study was to assess the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan against locally advanced lower rectal cancer according to UDP‐glucuronosyltransferase 1A1 (UGT1A1) polymorphisms. Between 2009 and 2016, 46 patients with resectable rectal cancer (T3‐T4, N0‐N2, M0) received preoperative chemoradiotherapy consisting of 80 mg/m2 per day tegafur/gimeracil/oteracil (S‐1; days 1‐5, 8‐12, 22‐26, and 29‐33), 60 mg/m2 per day irinotecan (days 1, 8, 22, and 29), and 45 Gy radiation (1.8 Gy/day, 5 days per week for 5 weeks). Six to eight weeks after completing chemoradiotherapy, total mesorectal excision was carried out. Patients with UGT1A1 polymorphisms were divided into WT (n = 26), heterozygous (n = 15), and homozygous (n = 5) groups, the latter including double heterozygosities. We evaluated associations between clinical characteristics, including UGT1A1 polymorphisms, and chemoradiotherapy efficacy and toxicity. Incidence rates of grade 3+ neutropenia and diarrhea were 17.0% and 30.4%, respectively. Relative dose intensity was 89.3%. Pathological complete response rate (grade 3) was 26.1%, and the good response (grade 2/3) rate was 84.8%. UGT1A1 polymorphisms were significantly associated with neutropenia and pathological good responses, but not with diarrhea. UGT1A1 polymorphism was the only predictive factor for pathological good responses. Our results indicate that UGT1A1 polymorphism is a predictive factor to determine the clinical efficacy of preoperative chemoradiotherapy and hematological toxicity induced by chemoradiotherapy using irinotecan in locally advanced rectal cancer patients.

Influence of UGT1A1 polymorphism on etoposide plus platinum-induced neutropenia in Japanese patients with small-cell lung cancer.

The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer. This retrospective analysis included patients with small-cell lung cancer who had received their first-line chemotherapy with etoposide plus cisplatin or carboplatin, between October 2008 and April 2018, at the University of Fukui Hospital. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia as well as thrombocytopenia was evaluated. A total of 55 patients were enrolled. The incidence of grade 4 neutropenia during the first cycle of etoposide-based chemotherapy was higher in patients with homozygous (hmz) polymorphisms for UGT1A1*28 and *6 (*28/*28, *6/*6, and *6/*28) than in patients with wild-type (wt) (*1/*1) and heterozygous (htz) (*1/*28 and *1/*6) polymorphisms (88% vs 43% P = 0.03). The incidence of febrile neutropenia and grade 4 thrombocytopenia, however, was not significantly different. Multivariate analysis suggested that grade 4 neutropenia associated significantly with an hmz UGT1A1 genotype [odds ratio (OR) 11.3; P = 0.04] and administration of granulocyte colony-stimulating factor (G-CSF) before the neutrophil counts dropped to < 500 cells/µL (OR; P = 0.01). UGT1A1*28 and UGT1A1*6 mutations might be regarded as predictors for etoposide-induced grade 4 neutropenia.

Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case–Control Study

Drug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH). Thirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case-control study. The frequencies and distributions of genotypes and haplotypes were compared between the groups using three genetic models (dominant, recessive, and additive) to identify associations with susceptibility to ATDH. Patients with the rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A genotypes of SLCO1B1 had a significantly lower risk of ATDH, while those carrying the rs2417957 T/T and rs4149063 T/T genotypes had an increased risk. The rs4148323 A/A genotype of UGT1A1 was found to significantly reduce the risk of ATDH. Haplotype analysis showed the TGTG, TTTC, and GTTC haplotypes of SLCO1B1 were associated with an increased ATDH risk, whereas the GACC haplotype was related to a reduced risk. The ATG haplotype of UGT1A1 reduced the risk of ATDH. Moreover, treatment outcomes in tuberculosis patients were further affected by genetic variants of SLCO1B1. Genetic polymorphisms of SLCO1B1 and UGT1A1 were found to be associated with susceptibility to ATDH. Molecular identification of susceptibility genes provides a theoretical foundation for predicting the likelihood of ATDH and predicting treatment outcomes in tuberculosis patients.

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

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.

UGT1A1 gene polymorphisms and clinical outcomes in small cell lung cancer (SCLC) patients treated with irinotecan-platinum chemotherapy: The first study from north India.

e20024 Background: Irinotecan(CPT11) is an important drug for SCLC chemotherapy(CTx). UDP-glucuronosyl-transferase1A1(UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess incidence of UGT1A1 polymorphisms and their association with clinical outcomes in SCLC patients on CPT11-CTx. Methods: Observational cohort of treatment-naïve SCLC patients given CPT11-platinum doublet at a referral centre in North India over 3-yrs(January 2013-December 2015). Clinical outcomes assessed were hematological &amp; gastrointestinal toxicity(CTC-AE v3.0), response rates by RECIST &amp; overall survival(OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation &amp; genomic DNA isolated. Genotyping was done by PCR-RFLP for UGT1A1*7, UGT1A1*6 &amp; UGT1A1*27 &amp; by PCR-DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild-type(WT/WT), heterozygous-mutant(WT/M) or homozygous-mutant(M/M) for each polymorphism assessed. Results: Of 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms(n = 111) was 89.2% WT/WT, 8.1% WT/M &amp; 2.7% M/M. For UGT1A1*28(n = 102), this was 41.2% WT/WT, 43.1% WT/M &amp; 15.7% M/M. For UGT1A1*6, 60% WT/WT patients tolerated &gt; 95% predicted CPT11 dose (vs. 25% in WT/M-M/M combined group;p = 0.026). Severe(grade≥3) diarrhea was more common in WT/M-M/M group (44.4% vs. 17.9% in WT/WT,p = 0.06) as was any grade mucositis (55.6% vs. 9.5% in WT/WT,p = 0.002). On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with(a/w) occurrence of both mucositis[OR = 10.4] &amp; severe(grade≥3) diarrhea[OR = 4.8]. UGT1A1*28 WT/M-M/M patients had better OS[338 days(95% CI = 190-486) vs. 216 days(95% CI = 136-296) in WT/WT group;p = 0.045]. On multivariate Cox proportional hazards analysis, better OS was independently a/w number of CTx cycles, UGT1A1*28 WT/M-M/M status, maximum % dose of CPT11 delivered &amp; inversely with age. Conclusions: UGT1A1*6 &amp; UGT1A1*28 polymorphisms are a/w increased toxicity &amp; improved OS respectively in North Indian SCLC patients receiving CPT11-CTx.

P17.29 UGT1A1*6 polymorphisms are predictive of high plasma concentrations of dolutegravir in Japanese individuals

Background Dolutegravir (DTG), an HIV integrase inhibitor, is metabolised mainly by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). Several UGT1A1 polymorphisms have been correlated with UGT1A1 expression level or enzymatic activity. We compared the effect of two polymorphic alleles in this gene, UGT1A1*6 and UGT1A1*28, on plasma DTG concentrations in Japanese HIV-1-infected patients. Methods The plasma trough DTG concentration was measured in 69 HIV-1 patients taking DTG at Osaka National Hospital, and UGT1A1 genetic screening (*6 and *28) was performed. UGT1A1 was genotyped using the sequence method. Plasma was sampled immediately before taking DTG, and plasma DTG concentrations were determined using a liquid chromatography-mass spectrometry. Results In the 69 patients who received DTG, the frequencies of UGT1A1*6 and UGT1A1*28 were 23% and 13%, respectively. The plasma trough concentrations of DTG in patients homozygous for UGT1A1*6 (n = 7, median: 1.4 µg/mL) were significantly higher those in the patients carrying the normal allele (n = 32, median: 0.89 µg/mL; p = 0.011). The plasma trough concentrations of DTG in patients homozygous for UGT1A1*28 (n = 3, median: 1.2 µg/mL), compound heterozygous for UGT1A1*6 and UGT1A1*28 (n = 2, 0.98 and 1.2 µg/mL, respectively), and heterozygous for UGT1A1*6 and UGT1A1*28 (n = 15 and 10, median: 1.1 and 1.0 µg/mL, respectively) were not significantly different from those in the patients homozygous for the normal allele. Conclusion The plasma trough concentration of DTG was significantly higher in patients who were homozygous for UGT1A1*6 than in those with the normal allele. This finding suggests that the presence of UGT1A1*6 influences the plasma DTG concentration. Disclosure of interest statement Authors do not have any commercial or other association that might pose a conflict of interest.

Correlation between UGT1A1 polymorphisms and raltegravir plasma trough concentrations in Japanese HIV-1-infected patients.

Raltegravir (RAL), an HIV integrase inhibitor, is metabolized mainly by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in UGT1A1 may cause alterations in the pharmacodynamics of RAL, which is taken twice daily with no dietary restrictions. We compared the effect of two polymorphic alleles in this gene, UGT1A1*6 and UGT1A1*28 on plasma RAL concentrations in Japanese HIV-1-infected patients. Of 114 Japanese HIV-1-infected patients who received RAL, the frequencies of UGT1A1*6 and UGT1A1*28 were 18% and 13%, respectively. The percentage of homozygotes for UGT1A1*6 and UGT1A1*28 was 6% and 4%, respectively, the percentage of compound heterozygotes for UGT1A1*6 and UGT1A1*28 was 2%, and that of heterozygotes for UGT1A1*6 and UGT1A1*28 was 22% and 17%, respectively. RAL plasma trough concentrations were compared for each polymorphism. Significantly higher levels of RAL were observed with patients who were homozygous for UGT1A1*6 (median: 1.0 μg/mL) than for the normal allele (median: 0.11 μg/mL; p = 0.021). Multivariate logistic regression analysis showed that the presence of one or two alleles of UGT1A1*6 or two alleles of UGT1A1*28 were independent factors associated with high RAL plasma trough concentrations (≥ 0.17 μg/mL). These results indicated that UGT1A1*6 and UGT1A1*28 are both factors influencing the RAL plasma trough concentrations in Japanese HIV-1-infected patients.

Association of Neonatal Hyperbilirubinemia with UGT1A1 Gene Polymorphisms: A Meta-Analysis.

BackgroundThe results of studies on association between the polymorphisms in the coding region and the promoter of uridine diphosphateglucuronosyl transferase 1A1 (UGT1A1) and neonatal hyperbilirubinemia are controversial. This study aimed to determine whether the UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter were significant risk factors associated with neonatal hyperbilirubinemia.Material/MethodsThe PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity.ResultsA total of 32 eligible studies and 6520 participants were identified. Among them, 24 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, and a significant difference was found for the comparison of AA vs. AG+GG (OR=3.47, 95% CI=2.29–5.28, P<0.0001). We included 19 studies on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphism, which also found a statistically significant difference between 7/7 and 6/7 + 6/6 (OR=2.24, 95% CI=1.29–3.92, P=0.004).ConclusionsThis meta-analysis demonstrated that UGT1A1 polymorphisms (Gly71Arg and TATA promoter) significantly increase the risk of neonatal hyperbilirubinemia.

A multicenter exploratory study of irinotecan-based chemotherapy on UGT1A1 polymorphisms for patients with colorectal cancer.

563 Background: Recent pharmacogenetic studies have revealed a significant association between uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6 and toxicities such as severe diarrhea and neutropenia under treatment with irinotecan. Moreover, the latter of these two polymorphisms is specifically detected in East Asian populations. We performed a prospective study to determine the optimal dose of this drug depending on which polymorphism is present in order to maximize the effectiveness of therapy while avoiding side effects. Methods: 59 patients from 11 institutions were enrolled in this study. Patients were assigned to one of the following three groups: wild type (*1/*1), heterozygous (*28/*1, *6/*1), or homozygous (*28/*28, *6/*6*, *28/*6*). The double heterozygous state (*28/*6) was included within the homozygous group. Second-line FOLFIRI was administered, with the dose of irinotecan at 150 mg/m2, in the wild type and heterozygous groups and at 100 mg/m2 in the homozygous group. The incidences of severe toxicities according to UGT1A1 gene type, response rate, and progression-free survival were investigated. Results: 26 (44.1%) were assigned to the wild type group, 28 (47.4%) to the heterozygous group, and 5 (8.5%) to the homozygous group. Grade 3 or higher severe toxicities were observed in 8 patients (30.8%) in the wild type group, 5 (17.9%) in the heterozygous group, and 1 (20.0%) in the homozygous group. No significant difference was observed among the three groups. The most frequently observed severe toxicities were neutropenia, nausea, vomiting, and diarrhea. The overall response rate (complete response + partial response) was 2 patients (7.7%) in the wild type group, 2 (7.1%) in the heterozygous group, and none (0.0%) in the homozygous group. Conclusions: In terms of tolerability and safety, the present results suggest that irinotecan should be administered at a dose of 150mg/m2 in heterozygous patients and 100 mg/m2 in homozygous patients receiving second-line FOLFIRI.

Comprehensive analysis of UGT1A1 polymorphisms through high-resolution melting analysis and DNA sequencing.

Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) is a key conjugating enzyme of bilirubin and the anti-tumor medication irinotecan. Comprehensive analysis of UGT1A1 gene polymorphisms may provide benefit by predicting pharmacokinetics and outcomes of treatment with irinotecan and certain antiviral medications. A high-resolution melting (HRM) analysis was designed to characterize the UGT1A1 gene. Genomic DNA from 110 healthy subjects was extracted from peripheral blood samples. The promoter and 11 exons from UGT1A1 were screened by HRM, and all results were subsequently confirmed by direct DNA sequencing. HRM analysis readily identified UGT1A1 gene mutations. We identified 5 different known variants of UGT1A1 including c.211 G > A; G71R, c.686 C > A; P229Q, c.1091 C > T; c.-3279 T > G; and c.-3156 G > A in 110 normal Taiwanese individuals. We also identified 8 new sequence variants, namely, c.-3296 C > T; c.43 C > A; c.45 G > A; c.234 G > A; c.577 G > A; c.614 C > T; c.1011 T > C; and c.1352 C > T. Each UGT1A1 variant was easily identifiable by differences in curves plotted from HRM data. HRM analysis was rapid, accurate, and economical for screening UGT1A1 gene mutations.

Phase II clinical trial of metronomic chemotherapy with combined irinotecan and tegafur–gimeracil–oteracil potassium in metastatic and recurrent breast cancer

We investigated the efficacy and safety of metronomic chemotherapy with combined irinotecan and tegafur-gimeracil-oteracil potassium (TS-1) in patients with metastatic and recurrent breast cancer (MRBC), and the association between irinotecan metabolizing enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms and adverse events. The study group comprised 40 patients aged 35-79 years. Irinotecan (60 mg/m(2) in 5 % dextrose) was administered by 120-min infusion on days 1, 8, and 15 every 4 weeks. TS-1 (prescribed in a standard quantity) was administered at 80 mg/m(2)/day orally on days 3-7, 10-14, and 17-21 every 4 weeks. Tumor response data were available for 34 patients. Median follow-up was 12 months (range 1-45 months). Response rate was 47 % (one complete and 15 partial responses). Stable disease was observed in 17 patients (50 %). One patient had disease progression (3 %). Median progression-free survival was 14 months [95 % confidence interval (CI), 10-26]. Median overall survival was 26 months (95 % CI not calculable owing to sample size), and 79.3 % of patients survived for 1 year. The most common grade 3 or 4 adverse events were neutropenia (15 %), leukopenia (12.5 %), diarrhea (7.5 %), and anemia (2.5 %). All other adverse events were grade 1 or 2. Treatment-related toxicity was generally modest and manageable. No significant correlation was observed between UGT1A1 polymorphisms and hematological or non-hematological toxicities. Metronomic chemotherapy with combined irinotecan and TS-1 was effective in MRBC patients. Adverse effects were mild and the regimen was safely administered without identifying UGT1A1 polymorphisms.

Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia

Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML. Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28. All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3). These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.