UGT1A1 mutation rates in a minority-rich comprehensive cancer center: A retrospective pharmacogenomic study.

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294 Background: Irinotecan is a widely used and effective treatment for various gastrointestinal malignancies. Its toxic metabolite, SN-38, is inactivated by UDP glucuronosyltransferase-1A1 (UGT1A1). However, variability in individual clearance of irinotecan and SN-38 can cause unpredictable toxicities. Mutations in the UGT1A1 gene reduces enzyme activity, resulting in dose-limiting neutropenia and diarrhea, hospitalizations, treatment delays, and dose reductions. The best characterized germline variant is a polymorphism in the UGT1A1*28 allele, but data in underrepresented groups remains particularly lacking. Methods: We conducted a retrospective cohort study of patients who were treated at our minority-rich academic medical center. A total of 63 patients with gastrointestinal malignancies were tested for the UGT1A1*28 polymorphism. Data for irinotecan treatment course, related toxicities, and dose reductions was available for 41 patients. Analysis was performed using Fisher’s exact test, one-way ANOVA, and Welch’s two-sample test. Results: 73% (n = 46) of patients were identified with the UGT1A1*28 polymorphism, including 63% (n = 29) with heterozygous genotype and 36.9% (n = 17) with homozygous genotype. There were significantly more patients of UGT1A1*28 polymorphisms carriers in the African American and Hispanic population as compared to the white population (p = 0.001, 0.01 respectively). The polymorphism frequency was 0.66 in the African American group [95% CI (0.49 – 0.81)], 0.48 in the Hispanic group [95% CI (0.34 – 0.62)], and 0.06 in the white group [95% CI (0.001 – 0.30)]. The frequency was significantly lower in the white population when compared to all other races (p-value = 0.0002), to African American (p- value < 0.001), and to Hispanic (p-value = 0.003) populations. There were higher rates of overall toxicities of any grade in the heterozygotes (76%) and homozygotes (64%) when compared to the wild-type group (56%). 55% (n = 6) of the homozygous and 48% (n = 10) of the heterozygous patients developed G1-G4 neutropenia, as compared to the 22% (n = 2) of the wild-type patients. Conclusions: Ethnic differences are known to exist in UGT1A1*28 polymorphism, with the prevalence being significantly higher in African and Caucasian populations. Historical data based on large-scale genotyping report allele frequencies of 0.42 in African/African American, 0.37 in Hispanic American, and 0.29 in Europeans. Our local population has a higher rate overall in both the African American and Hispanic populations with significantly higher rates than the white population. Patients with the UGT1A1*28 polymorphism experienced more toxicities and neutropenia of any grade. UGT1A1 genotyping is not routinely performed in patients initiating irinotecan treatment, however it may prove to be beneficial in certain demographics with higher rates of UGT1A1*28 polymorphisms.