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UGT1A1 ASCO 2008

Is UGT1A1*28 homozygosity the strongest predictor for severe hematotoxicity in patients treated with 5-fluorouracil (5-FU)-irinotecan (IRI)? Results of the PETACC 3 - EORTC 40993 -SAKK 60/00 trial comparing IRI / 5-FU/folinic acid (FA) to 5-FU/FA in stage II-III colon cancer (COC) patients.

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UGT1A1 ASCO 2008

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  1. Is UGT1A1*28 homozygosity the strongest predictor for severe hematotoxicity in patients treated with 5-fluorouracil (5-FU)-irinotecan (IRI)? Results of the PETACC 3 - EORTC 40993 -SAKK 60/00 trial comparing IRI / 5-FU/folinic acid (FA) to 5-FU/FA in stage II-III colon cancer (COC) patients A.D. Roth, P. Yan, D. Dietrich, R. Fiocca, G. Bodoky, R. Labianca, D. Cunningham, E. Van Cutsem, F. Bosman, S. Tejpar UGT1A1 ASCO 2008

  2. P-gp CPT-11 ABCB1 CES2 CES2 APC CYP3A4 CPT-11 CYP3A5 NPC UGT1A1 SN-38G ABCB1 P-gp death CPT-11 TOPI SN-38 SN-38 SN-38 Irinotecan Pathway

  3. Function of UGT1A1 • UGT1A1 mediates the glucuronidation of bilirubin and otherendogenous compounds (estradiol, arachidonic acid metabolites) • Moderate decrease in UGT1A1 activity => Gilbert’s syndrome • Severe decrease in UGT1A1 activity => Crigler-Najjar syndrome • UGT1A1 and other UGTs (1A6, 1A7, 1A9 and 1A10) are involved in the glucuronidation of SN-38 • UGT1A1 also involved in the glucuronidation of many xenobiotics (codeine, acetaminophen, tolbutamide and several statins)

  4. UGT1A Gene Cluster TATATATATA=(TA)5 TATATATATATA=(TA)6= *1 (WT) TATATATATATATA=(TA)7=*28 TATATATATATATATA=(TA)8 …(TA)n… UGT1A: 17 alleles (different Exon 1’s)

  5. Published Data on UGT1A1 & Grade 4 Neutropenia

  6. Objectives • To assess the impact of UGT1A1 7/7 genotype compared to the 6/6 and 6/7 genotypes on the occurrence of severe toxicity attributable to FOLFIRI in a large population of colon cancer patients

  7. Methods • DNA was extracted with phenol/chloroformfrom normal and tumoral tissues after microdissection of formol fixed paraffin embeded sections • UGT1A1 genotype was assessed by PCR and fragment sizing on Normal DNA • Patients were all treated by FOLFIRI for up to 24 weeks divided in 4 cycles of 6 weeks

  8. Statistics • Frequency of toxicity according to UGT1A1 genotype status (6/6,6/7 or 7/7) was assessed by chi-square or Fisher’s exact tests • Frequency trends of toxicity over 6/6, 6/7 and 7/7 were examined by Cochran-Armitage trend tests • Multiple logistic regression was used to test the impact of other variables on toxicity outcomes • Associations between two categorical variables were examined by chi-square or Fisher’s exact tests • Multiple logistic regression was used to test the impact of other variables on toxicity outcomes and on occurence of dose reductions

  9. UGT1A1 Genotype frequency 1335 of 1405 samples (95%) with a result

  10. Neutropenia grade 4 per arm (cycles 1-3) Arm A: p<0.009(chi-square Test), Odds Ratio: 2.42 (95%CI: 1.23-4.77) Arm B: p=1.0 (Fisher’s Exact Test)

  11. Febrile Neutropenia per arm (cycles 1-3) Arm A: p<0.009(Fisher’s Exact Test), Odds Ratio: 2.99 (95%CI: 1.37-6.52) Arm B: p=0.63 (Fisher’s Exact Test)

  12. Grade 4 neutropenia (cycles 1-3): Multivariate logistic regression analysis and Odds Ratio Estimates

  13. Grade 4 neutropenia (cycles 1): Multivariate logistic regression analysis and Odds Ratio Estimates

  14. Probabilities to develop grade 4 neutropenia according to sex and UGT1A1 status(From the logistic regression model)

  15. Dose reductions (cycle 1)Multivariate logistic regression analysisSummary of Backward Elimination

  16. Dose reductions (cycles 1-3)Multivariate logistic regression analysisSummary of Backward Elimination

  17. Discussion • UGT1A1 7/7 increases the incidence of grade 4 neutropenia and febrile neutropenia of FOLFIRI • In multivariate LR analysis, sex is a much stronger predictor of grade 4 neutropenia than UGT1A1 during the first cycle of treatment and stays as a significant factor despite of dose reductions when 3 cycles of treatment were considered • In multivariate analysis, female sex was strongly associated to dose reductions while UGT1A1 was not.

  18. Conclusion • Female sex is a stronger predictor of grade 4 neutropenia than UGT1A1 7/7

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