PREDICTION OF IRINOTECAN TOXICITY

GENETIC TESTING FOR THE UGT1A1*28 VARIANT TO PREDICT TOXICITY IN PATIENTS TREATED WITH IRINOTECAN BASED THERAPY

Irinotecan (CPT-11) is a topoisomerase I inhibitor primarily used for the treatment of metastatic colorectal cancer in combination with 5-fluorouracil and/or leucovorin and in combination with tyrosine kinase inhibitors (e.g. cetuximab).  Up to 36% of patients treated with irinotecan experience severe, potentially life-threatening diarrhoea and neutropenia (Fuchs et al. 2003 J Clin Oncol 21: 807-814).

SN-38 is the active metabolite of irinotecan and is metabolised through conjugation by the enzyme, uridine disphosphate glucuronosyl transferase (UGT).  The germline polymorphism UGT1A1*28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients (Innocenti and Ratain 2006 Pharmacogenomics 7: 1211-1221).

This polymorphism is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter: (TA)7TAA, instead of (TA)6TAA. More severe grades of diarrhoea and neutropenia were observed only in patients heterozygous or homozygous for the (TA)7TAA sequence (Iyer et al. 2002 Pharmacogenomics J 2: 43-7).

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.