Abcb1, ugt1a1 and oatp-c polymorphisms predict Irinotecan (CPT-11) toxicity

Abstract

3074 Background: Irinotecan (CPT-11), a topoisomerase I inhibitor, is approved for the use of both first- and second-line chemotherapy in metastatic colorectal cancer (CRC) patients. As of yet, only few reliable molecular markers have been identified for predicting CPT-11 toxicity. In this study, we tested specific gene polymorphisms that are known to be involved in the Irinotecan metabolic pathway: the ATP-binding cassette transporter subfamily (ABCB1, ABCG2 and ABCC2), carboxylesterase 1 (CES1), carboxylesterase 2 (CES2), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1),hepatic organic anion transport protein (OATP-C) and cytochrome P450 (CYP3A4). Methods: We ran PCR-RFLP assays using genomic DNA from the blood of 54 advanced CRC patients treated with first-line 5FU/LV and CPT-11 at USC between 1999 and 2003. Results: Our cohort was comprised of 31 men (57%) and 23 women (43%) with a median age of 56 years (range: 34–77 years). Participants represented four ethnicities: 29 Caucasian (54%), 12 Asian (22%), 10 Hispanic (19%), and 3 African-American (6%). Three patients (6%) demonstrated complete response (CR), 20 patients (38%) showed partial response (PR), 24 patients (45%) continued with stable disease (SD), and six patients (11%) were found to have progressive disease (PD). One patient was invaluable for response data. Twenty-four patients (46%) experienced Grade 0–2 toxicity, while 29 (54%) experienced Grade 3–4 toxicity. One patient was inevaluable for toxicity data. The median progression-free survival was 10.9 months (95% CI, 7.6 to 12.1 months), and the median overall survival time was 27.9 months (95% CI, 21.3 to 56.6+ months) with median follow up of 30.0 months (range: 11.2 to 59.9 months). We found that the combination of at least one OATP-C 521 wild-type T allele, at least one ABCB1 1236 C allele and at least one UGT1A1*28 variant 7 repeat demonstrated a statistically significant association with Grade 3/4 toxicities (P=0.002, Fisher’s exact test). Conclusion: This is the first study to combine three independent gene polymorphisms within the same metabolic pathway in order to explain common CPT-11 grade 3–4 toxicity. [Table: see text]