UGT1A1 Genotype and Irinotecan Toxicity

Irinotecan-based chemotherapy was approved by FDA as the 1st line (with 5-FU and leucovorin) and 2nd line therapy for metastatic colon/rectal cancer. The test detects polymorphic variants of UGT1A1 that cause increase toxicity associated with Irinotecan. 

FDA Guidance. Studies have identified a genetic variant of the UGT1A1 gene that is commonly associated with severe toxicity in cancer patients undergoing Irinotecan-based therapy. In 2005 FDA cleared a test for UGT1A1 that detects this genetic variant, helping physicians determine the appropriate dosage of the drug with minimum adverse effects.

UGT1A1*28-associated risk of neutropenia:

Functional roles of UGT1A1. Uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) is an enzyme that catalyzes the glucuronidation of various compounds, including steroid hormones, bilirubin, as well as xenobiotics, such as irinotecan. This process converts these substances to more water-soluble compounds that can be eliminated from the body.¹ A polymorphic variation in the promoter of UGT1A1 leads to decreased expression of UGT1A1, resulting in reduced glucuronidation of SN-38, the active metabolite of irinotecan.² Patients with a (TA)7 repeat (UGT1A1*28) have a 12-50% increased risk of Grade 4 neutropenia or severe diarrhea.^3,4 Individuals that are homozygous for UGT1A1*28 mutation, that is have two alleles with 7 TA repeats (7/7 homozygous) also known as a Gilbert’s syndrome, will have the most severe toxicity to irinotecan.⁵

Reporting. This assay tests for two polymorphic variations in the promoter region of UGT1A1: UGT1A1*1 (TA)6  and UGT1A1*28 (TA)7.

Interpretation. Patients in the HIGH RISK and MODERATE RISK groups carry a 50% and 12.5% risk of severe (Grade 4) neutropenia, respectively. A dose reduction of irinotecan should be considered.

Reimbursement. Irinotecan Toxicity Predictive test is reimbursed by major insurance carriers.

Other names for irinotecan drugs: Camptosar^®, CPT-11

References

1. Rouits et al., Clin Cancer Res. 2004; 10:5151-5159
2. Iyer et al., J Clin Invest. 1998; 101:847-854
3. Proceedings from FDA Clinical Pharmacology Subcommittee, November 3-4, 2004. (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4079B1_03_Topic1-TabA.pdf)
4. Innocenti et al., J Clin Oncol. 2004; 22:1382-1388
5. Beutler et al., Proc Natl Acad Sci USA. 1998; 95:8170-8174