1 / 18

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.

hamilton-whitehead
Télécharger la présentation

UGT1A1 ASCO 2008

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related