UGT1A1 Genotyping - Irinotecan

Indications for Testing

Patient who will receive irinotecan (in doses >150 mg/m²), who has a history of irinotecan sensitivity, or who experiences neutropenia while receiving irinotecan
Patient suspected to have Gilbert syndrome

Laboratory Testing

UGT1A1 (TA) polymorphism test
- Risk of irinotecan toxicity by genotype
  Risk of irinotecan toxicity by genotype*
  TA genotype
  Diarrhea risk
  Neutropenia risk
  6/6 (*1/*1)
  17%
  15%
  6/7 (*1/*28)
  33%
  27%
  7/7 (*28/*28)
  70%
  40%
  *Based on data from Br J Cancer 2004; 91:678-82.
UGT1A1 genotype does not significantly influence risk of irinotecan toxicity when low dose therapy with irinotecan (eg, 15-75 mg/m² daily for five days for two consecutive weeks) is employed

Risk of irinotecan toxicity by genotype*
TA genotype	Diarrhea risk	Neutropenia risk
6/6 (1/1)	17%	15%
6/7 (1/28)	33%	27%
7/7 (28/28)	70%	40%
*Based on data from Br J Cancer 2004; 91:678-82.

Irinotecan (CPT-11) is a common chemotherapeutic drug used for the treatment of advanced colorectal and gastric cancer. Allelic variance of UGT1A1 may be associated with increased drug toxicity and with syndromes such as Gilbert syndrome (benign familial hyperbilirubinemia) and Crigler-Najjar (rare form of nonhemolytic jaundice).

Epidemiology

Ethnicity
- Caucasian
  - (TA)6 – 61%
  - (TA)7 – 39%
- Asian
  - (TA)6 – 84%
  - (TA)7 – 16%
- African
  - (TA)6 – 47%
  - (TA)7 – 43%

Genetics

UGT1A1 is located on chromosome 2q37
The polymorphic TA repeat in the TATA element of the 5’-promoter region of UGT1A1 may consist of 5, 6, 7, or 8 repeats [(TA)5, (TA)6, (TA)7, (TA)8]
- (TA)6 (also known as UGT1A1*1) – most common number of repeats
- (TA)7 (also known as UGT1A1*28) – important genotype for risk of severe drug-induced toxicity
  - Increase in number of TA repeats may reduce transcription efficiency, lower enzyme concentrations, and lead to accumulation of SN-38 and risk for toxicities
- (TA)5 and (TA)8 alleles are rare but may also be clinically significant
  - Number of TA repeats thought to be inversely related to expression of UGT1A1 protein, such that (TA)8 would be associated with the most impaired transcription efficiency

Pathophysiology

UGT1A1 is responsible for the clearance, by glucuronidation, of drugs (eg, irinotecan) and endogenous substances (eg, bilirubin)
- >150 functional polymorphisms on UGT1A1 locus
SN-38 – primary active and toxic metabolite of irinotecan
- SN-38 is inactivated by UGT1A1 to form SN-38G, which is eliminated via bile
Variations of the TA repeat length in the UGT1A1 promoter TATA element may lead to decreased gene expression, accumulation of SN-38, and irinotecan-related toxicities
- Variations of the TA region are associated with Gilbert syndrome
Presence of UGT1A1*28 also may affect treatment with the following agents
- Raloxifene
- Raltegravir
- Indinavir
- Atazanavir
- Sorafenib

Clinical Presentation

Irinotecan toxicity-related symptoms
- Typically severe (grade 3/4) diarrhea and neutropenia
Other related symptoms
- Nausea, fever, alopecia

Tests generally appear in the order most useful for common clinical situations

Test name: UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping

ARUP #: 0051332

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

Identify patients at risk for toxicity associated with irinotecan and related drugs

Test to confirm Gilbert syndrome

Limitations:

Variations in the UGT1A1 gene, other than those targeted, will not be detected

Clinical significance of the rare (TA)5 and (TA)8 alleles on risk of irinotecan toxicities is not well established

Genetic and nongenetic factors other than UGT1A1 may contribute to irinotecan toxicity and efficacy

Guidelines

Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?. Genet Med. 2009; 11 (1) :15-20.PubMed

General

Comprehensive Review: April 2012
Last Update: January 2013

Colorectal Cancer

Pharmacogenetics