Role of UGT1A1, MTHFR AND TS gene polymorphisms in the prediction of irinotecan (CPT11) and raltitrexed (TOM) gastrointestinal toxicity in pre-treated patients (pts) with metastatic colorectal cancer (CRC)

Abstract

2064 Background: In this phase II study we evaluated the association of genetic variants of uridine diphosphate glucuronosyl transferase (UGT1A1), thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) with toxicity following CPT11 and TOM administration, in pre-treated pts with metastatic CRC. Methods: Fifty-six pre-treated pts received CPT11 (80 mg/m2 days 1, 8, 15, 22 q5wks), combined with TOM (3 mg/m2 q3wks). Genotyping for MTHFR C677T polymorphism, TATA box region in UGT1A1 promoter and tandem repeats in TS promoter was assessed on genomic DNA extracted from blood samples. Results: Characteristics of pts were: M/F 29/27; median age 64 (42–78); refractory disease in 32 pts. Previous chemotherapy for advanced disease: Folfox-4, infusional 5FU, Folfiri, bolus 5FU, and TOM/l-OHP in 64%, 30%, 21%, 14%, and 13% of the patients respectively. Genotypic distribution for each polymorphism was in Hardy-Weinberg equilibrium. Pts evaluable for response were 53: PR in 19% of pts, SD in 51% (median duration 4.8 mo), and PD in 30%. NCI-CTC toxicities were evaluated in 154 cycles: G3–4 leuco-neutropenia in 7% of cycles; G2–4 Nausea 19%; G2–4 vomit 10%; G2–4 hepatic 27%; G2–4 diarrhea 17%, G2–3 asthenia 11%. Many variables related to pts, disease and treatment characteristics, together with genotypes, were included in a logistic regression model to evaluate association with main toxicities. Homozygosis for six TA repeats (6/6) in the promoter region of UGT1A1 gene was the main protective factor for diarrhea (p<.00005), emesis (p=.0001), and asthenia (p=.006). Homozygosis for two tandem repeats in TS promoter (2/2) was associated with less incidence of asthenia (p=.04). No differences in toxicity were observed with regard to MTHFR C677T polymorphism. Conclusions: CPT11/TOM regimen has shown acceptable toxicity profile and good antitumor activity in pre-treated metastatic CRC pts. Screening for UGT1A1 promoter polymorphism is clinically useful to identify patients with greater susceptibility to CPT11-induced gastrointestinal toxicity. No significant financial relationships to disclose.