Practice Essentials
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. Irinotecan combined with 5-fluorouracil (5FU) is widely used in the treatment of colorectal cancer. [1] 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. [2, 3, 4, 5, 6, 7]
Adverse effects of irinotecan treatment include severe diarrhea, myelosuppression, and neutropenia. [8] 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. [9, 10]
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. [11] 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. [1] This variant causes reduced levels of UGT1A1 gene expression. UGT1A1*28 occurs at high frequency in white and African populations (26-31% and 42-56%, respectively) and at lower but appreciable frequency in Asian populations (9-16%). [12, 13] Two other promoter variants, UGT1A1*36 and UGT1A1*37, increase and decrease expression levels of UGT1A1, respectively, and occur at appreciable frequencies in African populations (3-10% and 2-7%, respectively). [12, 13]
UGT1A1*6 G71R, a nonsynonymous variant also known to reduce UGT1A1 activity, occurs at a frequency of 13-32% in Asian populations, but at very low frequency in other populations. [14] Another nonsynonymous variant observed in Asian populations, UGT1A1*27 P229Q, occurs at even lower frequency (< 3%), but almost completely abolishes UGT1A1 activity. [15, 16]
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. [3] However, 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] Similar findings were reported in a study with patients screened for both UGT1A1*28 and UGT1A1*6. [17]
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. [4] In addition, other variants may potentially impact outcome in patients receiving irinotecan-based chemotherapy for colorectal cancer. [18]
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. [19] Studies of pretherapeutic UGT1A1 genotyping have found a high level of evidence for a higher incidence of irinotecan-induced severe toxicity in homozygous carriers of UGT1A1*28 or UGT1A1*6. [19]
The intestinal bacterial β-glucuronidase (BGUS) has been implicated in the onset of irinotecan-induced diarrhea, and BGUS selective inhibitors may limit the intestinal toxicity of irinotecan. [20, 21]
Using data from the PETACC3 trial, which randomized patients in the adjuvant setting to 6 months of leucovorin (LV) and 5FU (LV5/FU2) or LV5/FU2 + irinotecan, Tejpar et al found that a number of risk factors are involved in the development of toxicity, including UGT1A1. Parameters such as sex, age, and performance status were stronger predictors than the UGT1A1*28 genotype. UGT1A*28 genotype was associated with an increased incidence of grade III-IV neutropenia. The main predictors for grade IV neutropenia were sex, age, performance score and UGT1A1. The main predictors for diarrhea were female sex and age. [1]
In a study by Garcia et al that evaluated the relationship between polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer, the polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Also, those patients with wild type in UGT family genes had lower rates of toxicity associated with irinotecan treatment. [22]
Riera et al studied 308 patients with metastatic colorectal cancer treated with irinotecan-based regimens who were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). They found that rs1128503 was significantly associated with severe diarrhea and mucositis, and rs2032582 was also associated with severe mucositis. [23]
Salvador-Martin et al analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan for toxicity reactions. The SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematologic and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. [24]
