Irinotecan Toxicity and UGT1A


Irinotecan is a topoisomerase I inhibitor used to treat several solid tumor types, especially in combination with other chemotherapeutic agents in the treatment of colorectal cancer. Inhibition of topoisomerase I by irinotecan and its active metabolite, SN-38, prevents re-ligation of single-stranded DNA breaks induced during the DNA synthesis phase of cellular replication. Because the ensuing double-stranded DNA damage is not repaired efficiently, cell death ultimately occurs. [123456]

Adverse effects of irinotecan treatment include severe diarrhea, myelosuppression, and neutropenia. These effects are likely induced by inefficient metabolism and excretion of SN-38, which undergoes glucuronidation primarily in the liver by UGT1A prior to excretion through the kidneys. [17]

The UGT1A locus is alternatively spliced to produce 9 isoenzymes. These isoenzymes are responsible for the phase II metabolism of numerous endogenous and exogenous compounds by glucuronidation, which solubilizes compounds for excretion through the kidneys. The UGT1A1 isoform is solely responsible for the metabolism of bilirubin, numerous endogenous hormones, and numerous pharmacologic compounds, including irinotecan. Thus, genetic variation in UGT1A correlates with adverse events caused by irinotecan toxicity. [2]

Many UGT1A1 variants have been described, a few of which can have a significant impact on irinotecan metabolism and toxicity. UGT1A1*28, the most well-characterized variant, is a TA repeat expansion in the promoter of UGT1A1, most commonly increasing the number of TA dinucleotides from 6 to 7 repeats. This variant causes reduced levels of UGT1A1 gene expression. UGT1A1*28 occurs at high frequency in white and African populations (26% to 31% and 42 to 56%, respectively) and at lower but appreciable frequency in Asian populations (9% to 16%). [89Two other promoter variants known to lower UGT1A1 levels include UGT1A1*60 and UGT1A1*93. These variants occur at significant frequency in many populations (>10%). Both variants occur at a frequency of greater than 30% in white populations, and UGT1A1*60 occurs at an estimated frequency of 83% in Japanese populations. [1011]

UGT1A1*6 G71R, a nonsynonymous variant also known to reduce UGT1A1 activity, occurs at a frequency of 13% to 32% in Asian populations, but at very low frequency in other populations. Another nonsynonymous variant observed in Asian populations, UGT1A1*27 P229Q, occurs at even lower frequency (< 3%), but almost completely abolishes UGT1A1 activity. [1213Two other promoter variants, UGT1A1*36 and UGT1A1*37, increase expression levels of UGT1A1 and occur at appreciable frequencies in African populations (3% to 10% and 2% to 7%, respectively). [89]

Clinical Implications

The role of routine testing for the presence of germline isoforms of UGT1A remains unsettled. Evidence indicates that, at relatively high irinotecan dose levels (>250 mg/m2), patients who are homozygous for the UGT1A1*28 variant experience a greater risk of clinically important neutropenia. [3However, at the lower doses of irinotecan (100-125 mg/m2) that are most commonly used in the practice setting, the negative impact of UGT1A1*28 is far more modest and of questionable clinical relevance. [3]

Further complicating this issue are data demonstrating that irinotecan combined with particular chemotherapy agents (eg, oxaliplatin) may cause excessive neutropenia in the presence of this specific genetic variant. However, this complication does not occur when other agents (eg, 5-fluorouracil) are added. [4In addition, other variants may potentially impact outcome in patients receiving irinotecan-based chemotherapy for colorectal cancer. [14]

Given this uncertainty, for patients scheduled to receive a high-dose irinotecan regimen, or one that combines irinotecan with oxaliplatin, it is reasonable (but not absolutely mandatory) to determine the UGT1A genetic background to assist in toxicity management.

Testing for the Genetic Mutation

Commercial testing for the UGT1A1*28 variant, which determines the number of TA repeats in the UGT1A1 promoter, is available. Repeat length is inversely correlated with UGT1A1 expression levels and, thus, correlated with risk of toxicity.

Genotyping tests are available through the following companies: