Taiwan 2000 Is UGT1A1*28 homozygosity the strongest predictor for severe hematotoxicity in patients treated with 5- fluorouracil (5-FU)-irinotecan (IRI)?

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Taiwan 2000 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 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

Irinotecan PathwayCPT-11 CPT-11 APC NPC CYP3A4 CYP3A5 SN-38G UGT1A1 CES 2 CES2 SN-38 SN-38 TOP I death SN-38 ABCB1 P-gp CPT-11 ABCB1 P-gp

UGT1A1 ASCO 2008  UGT1A1 mediates the glucuronidation of bilirubin and other endogenous 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) Function of UGT1A1

UGT1A1 ASCO 2008 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)

UGT1A1 ASCO 2008 Author n/N (%) Est. Odds Ratio**95% CI 7/76/6 + 6/7 Carlini a 0/6 (0%) 21/58 (36%)-- Innocenti3/6 (50%)3/53 (6%) – Marcuello b 1/10 (10%)2/85 (2%) – 56.0 Rouits4/7 (57%)10/66 (15%) – 38.5 Ando c 4/7 (57%) 22/111 (20%) – 25.9 NCCTG 9741* 2/11 (18.2%)9/98 (8.8%) a Gr 3 or 4 diarrhea or neutropenia b Gr 4 values from personal communication. Published values are 3+. C Gr 4 leukopenia and/or Gr 3+ diarrhea. * ASCO 2006 #3520, IFL regimen **Unadjusted Odds Ratio Published Data on UGT1A1 & Grade 4 Neutropenia

UGT1A1 ASCO 2008 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

UGT1A1 ASCO 2008 Methods DNA was extracted with phenol/chloroform from 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

UGT1A1 ASCO 2008 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

UGT1A1 ASCO 2008 UGT1A1 Genotype frequency Genotypes Patient number Proportion A6/A % A6/A % A7/A % A5/A650.37% A5/A730.22% A6/A820.15% A7/A820.15% 1335 of 1405 samples (95%) with a result

UGT1A1 ASCO 2008 Neutropenia grade 4 per arm (cycles 1-3) Arm A (CPT-11) Patient #, (%) Arm B (Control) Patient #, (%) 6/6-6/7 237/540 (6.8%)13/546 (2.4%) 7/7 13/86 (15.1%)1/74 (1.3%) Arm A: p<0.009 (chi-square Test), Odds Ratio: 2.42 (95%CI: ) Arm B: p=1.0 (Fisher’s Exact Test)

UGT1A1 ASCO 2008 Febrile Neutropenia per arm (cycles 1-3) Arm A (CPT-11) Patient #, (%) Arm B (Control) Patient #, (%) 6/6-6/7 23/546 (4.2%)9/546 (1.6%) 7/7 10/86 (11.7%)2/74 (2.7%) Arm A: p<0.009 (Fisher’s Exact Test), Odds Ratio: 2.99 (95%CI: ) Arm B: p=0.63 (Fisher’s Exact Test)

UGT1A1 ASCO 2008 Grade 4 neutropenia (cycles 1-3): Multivariate logistic regression analysis and Odds Ratio Estimates Effect Wald Chi- Square Pr > Chi-Sq. OR Estimate (95% CI) Bilirubin ( ) Body surface area ( ) Age +/- 60y ( ) Sex ( ) Performance status ( ) UGT1A1 7/ ( )

UGT1A1 ASCO 2008 Grade 4 neutropenia (cycles 1): Multivariate logistic regression analysis and Odds Ratio Estimates Effect Wald Chi- Square Pr > Chi-Sq. OR Estimate (95% CI) Bilirubin ( ) Body surface area ( ) Age +/- 60y ( ) Sex ( ) Performance status ( ) UGT1A1 7/ ( )

UGT1A1 ASCO 2008 Probabilities to develop grade 4 neutropenia according to sex and UGT1A1 status (From the logistic regression model) Probabilities (95% CI) Cycle 1 Probabilities (95% CI) Cycles 1-3 Male not 7/ ( )0.036 ( ) Male, 7/ ( )0.101 ( ) Female not 7/ ( )0.107 ( ) Female, 7/ ( )0.259 ( )

UGT1A1 ASCO 2008 Dose reductions (cycle 1) Multivariate logistic regression analysis Summary of Backward Elimination Effect Wald Chi-Square Pr > Chi-Sq. Bilirubin Body surface area Age +/- 60y Sex < Performance status UGT1A1 7/

UGT1A1 ASCO 2008 Dose reductions (cycles 1-3) Multivariate logistic regression analysis Summary of Backward Elimination Effect Wald Chi-Square Pr > Chi-Sq. Bilirubin Body surface area Age +/- 60y Sex < Performance status UGT1A1 7/

UGT1A1 ASCO 2008 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.

UGT1A1 ASCO 2008 Conclusion Female sex is a stronger predictor of grade 4 neutropenia than UGT1A1 7/7