Role of Pharmacogenetics as Predictive Biomarkers of Response and/or Toxicity in the Treatment of Colorectal Cancer

Shriya Bhushan; Howard McLeod; Christine M. Walko


Clin Colorectal Cancer. 2009;8(1):15-21. 

In This Article


Irinotecan exerts its chemotherapeutic effect by interaction with the enzyme topoisomerase I (topo I). Topoisomerase I plays a critical role in uncoiling DNA for replication and transcription by causing transient single-strand DNA breaks that are eventually repaired. Irinotecan stabilizes these breaks made by topo I, ultimately leading to DNA fragmentation and cell death.

Irinotecan is converted to the active metabolite, SN-38, which is then conjugated by UDP-glucuronosyl-transferase 1A1 (UGT1A1) to SN-38G and prepared for elimination.[9,10] The UGT1A1*28 polymorphism is associated with reduced UGT1A1 expression and decreased glucuronidation of SN38. This results in increased toxicity because of increased blood levels of the active metabolite. The UGT1A1*28 polymorphism is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ([TA]7 TAA, instead of [TA]6 TAA).[11] Patients with the 7/7 genotype are at higher risk of developing irinotecan-associated neutropenia and diarrhea.

In July 2005, the Federal Drug Administration recommended an addition to the irinotecan package insert to include the UGT1A1*28 genotype as a risk factor for severe neutropenia. This decision was based upon the findings of 4 pharmacogenetic trials assessing the relationship between irinotecan toxicity and UGT1A1*28 genotype. A recent meta-analysis of 10 irinotecan pharmacogenetic studies enrolling a total of 825 patients assessed the correlation between irinotecan-induced hematologic toxicities in UGT1A1*28 patients, irinotecan dose, and overall toxicity.[12] The results suggest the risk of experiencing irinotecan-induced hematologic toxicity for homozygous UGT1A1*28 patients is a function of the dose of irinotecan administered (Figure 3). The study supported the routine use of genotype when dosing irinotecan at high doses (> 200 mg/m2) but suggested that testing was of modest benefit at intermediate doses, such as the commonly used FOLFIRI (5-U/leucovorin [LV]/irinotecan) regimen that uses an irinotecan dose of 180 mg/m2 every 14 days. UGT1A1*28 testing did not appear to have any utility at doses < 150 mg/m2, unless the drug was administered concomitantly with a myelotoxin (eg, oxaliplatin).

Irinotecan Metabolism and Mechanism of Action

Relationships Between Irinotecan Dose and Incidence of Hematologic Toxicity in Patients with a UGT1A1*28/*28 Genotype (A) and in Those with a UGT1A1*1/*1 or UGT1A1*1/*28 Genotype (B)
Results from 10 samples (triangles in panel A and circles in panel B) were included in the analysis. Solid lines = predicted probabilities of experiencing hematologic toxicity under the generalized linear mixed model at any dose level in the original dose range. Dotted lines represent 95% confidence intervals.
Adapted from: Hoskins JM, et al. J Natl Cancer Inst 2007; 99:1290-5.


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