Patel_2012_J.Clin.Oncol_30_412

412 Background: Irinotecan is metabolized primarily in the liver by the carboxylesterase enzyme to the SN-38 active metabolite and is then inactivated through conjugation by the UGT1A1 enzyme, a polymorphic enzyme. Individuals genotyped with the homozygous allele have an increased risk for grade 3 and 4 neutropenia.
METHODS: A retrospective cohort analysis was conducted in the Kaiser Permanente California regions. The study period was November 1, 2005 to July 1, 2010 and included patients that were 18 years of age or older, newly initiated on irinotecan for colorectal cancer and had no previous irinotecan therapy within six months of the initiation dose. Patients were excluded if they were enrolled in clinical trials, on granulocyte-colony stimulating factor prophylaxis, and genotype tested for UGT1A1 and subsequently not treated with irinotecan. Patients tested with the UGT1A1 assay were grouped according to their genotype results: wild-type, heterozygous, or homozygous*28. The incidence of grade 3 and 4 neutropenia were compared among patients tested for UGT1A1 variant alleles by their genotype results.
RESULTS: A total of 305 (28%) patients were tested with the UGT1A1 assay with a mean age of 62 (+/- 12) years, and 52% of the population female. There were 161 (53%) wild-type, 123 (40%) heterozygous, and 21 (7%) homozygous patients. The median irinotecan dose was 150 mg/m2 (124-180 mg/m2) and median number of irinotecan cycles were 6 (3-12). The wild-type, heterozygous, homozygous*28 population had a 21% (33/161), 24% (29/123), and 48% (10/21) rate of grade 3 and 4 neutropenia. When the homozygous*28 group was compared to the heterozygous and wild-type genotype the adjusted Cox Proportional Hazard was 3.05 (95% CI, 1.55-5.99), p = 0.001. The Kaplan-Meier Log Rank Test yielded a p-value of 0.002.
CONCLUSIONS: The adjusted risk for homozygous genotyped patients was three times higher compared to the wild-type and heterozygous group for grade 3 and 4 neutropenia. Additional investigational studies examining the benefits of UGT1A1 genotyping as a prognostic test and further effect of dosage adjustments in UGT1A1*28 homozygous initiated on irinotecan therapy are needed.