SAN FRANCISCOA polymorphism that reduces the hepatic metabolism of irinotecan (Camptosar) and that is present in about half of patients with colorectal cancer affects their odds of response to and toxicity from regimens containing this agent, new data show. The results have implications for dose adjustments in this population, Giuseppe Toffoli, MD, PhD, said at the 2006 Gastrointestinal Cancers Symposium (abstract 222).
Individuals who have the UGT1A1*28 polymorphism have reduced expression of UGT1A1 (UDP-glucuronosyltransferase 1A1), Dr. Toffoli said (Figure 1). This enzyme is responsible for the glucuronidation of the active metabolite of irinotecan (SN-38) in hepatocytes, making it more lipophilic; the glucuronidated form (SN-38-G) is then excreted in bile (see Figure 2). Although the polymorphism leads to decreased glucuronidation of SN-38, the clinical impact of this alteration is not yet clear, he said.
Dr. Toffoli's team performed analyses in 250 patients with metastatic colorectal cancer who received the irinotecan-containing FOLFIRI regimen as first-line therapy. In all patients, the investigators undertook UGT1A1 genotyping. In a subset of 71 patients, they determined the glucuronidation ratio of SN-38 (SN-38-G AUC/SN38 AUC)a marker of enzyme activityand the biliary index for irinotecan (SN-38 AUC/SN-38-G AUC * irinotecan AUC)an indicator of pharmacokinetics. "Because biliary index is dependent on three factors, it could better describe irinotecan metabolism than a single pharmacokinetic parameter," said Dr. Toffoli, of the Centro di Riferimento Oncologico (CRO)National Cancer Institute, Aviano, Italy.
Roughly 45% of the patients had the wild-type genotype (TA6/TA6), while another 45% were heterozygous for the polymorphism (TA6/TA7) and about 10% were homozygous for the polymorphism (TA7/TA7). The glucuronidation ratio differed significantly across these groups, with a markedly lower ratio in patients homozygous for the polymorphism (4.85, 4.32, and 2.41, respectively).
The irinotecan biliary index also differed significantly across groups, Dr. Tofolli said, with a substantially higher index evident in the patients with two copies of the polymorphism (5.13, 5.79, and 9.61 µM*h, respectively).