Abstract 2701: Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

Abstract

Abstract Purpose: Metastatic colorectal cancer is frequently treated with Irinotecan (CPT-11), a topoisomerase-I inhibitor. Irinotecan toxicity is relatively commonly observed. The gene UGT1A1 encodes an enzyme that catalyzes the glucuronidation of the active irinotecan metabolite SN-38 which is eliminated in the liver by metabolic alteration to an inactive form SN-38G. We retrospectively evaluated the association between UGT1A1 genetic variation, prevalence of severe toxicity and colorectal survival. Patients and Methods: In the Molecular Epidemiology of Colorectal Cancer (MECC) Study we identified 213 patients with metastatic colorectal cancer treated by irinotecan-based chemotherapy (FOLFIRI, IFL). DNA extracted from blood was used for genotyping either by simple determination of TATA box sequence in patient DNA or by implementation of fragment analysis that detects the difference in the number of nucleotides in the specific region analyzed. The polymorphism UGT1A1*28 is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Data on side effects and survival were extracted from full follow-up oncology records. Results: UGT1A1*28 genotypes 6/6, 6/7, 7/7 were detected in 41.8%, 46.5%, and 11.7% of the patients respectively. Observed grade 3-4 toxicity included: diarrhea 22.4%, leucopenia 9.3%, neutropenia 8.9%, neutropenic fever 3.7%, and mucositis 4%. No significant difference was observed in the rate of diarrhea in patients with UGT1A1*28 7/7 genotype (20%) as compared to these with the 6/6 genotype (27.5%). Hematological toxicity was significantly more common in patients with the 7/7 genotype. Neutropenic fever was observed in 24% of the 7/7 genotype but only in 2% of the 6/7 genotype and 0% of the 6/6 genotype. Oncological hospitalization rate was very high among the 7/7 group (45.8%) and significantly higher than among the 6/6 group (14.4%). The Median overall survival of patients with 7/7 was significantly lower (2.10 years) than that of patients with the 6/6 variant (4.13 years, p=0.002). Conclusion: UGT1A1*28 7/7 genotype is strongly associated with severe toxicity (mainly neutropenic fever) and oncological hospitalizations and with lower survival. These data support the FDA recommendation and product labeling to tailor treatment plans for colorectal cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2701.