Irinotecan ADRs predicted by UGT1A1*28 polymorphisms
A recent meta-analysis revealed up to a 4-fold increase in the risk of neutropenia in patients with a polymorphisms in the UGT1A1 enzyme who were treated with irinotecan (Camptosar, Pfizer), as compared with patients with no polymorphisms. Patients with a deficient UGT1A1 genotype had a 2-fold increased risk for diarrhea, with findings limited to studies using a high dose of irinotecan or in combination with 5-fluorouracil.
Although colorectal cancer is frequently treated with irinotecan, this agent is associated with a relatively high incidence of side effects that can lead to significant dose adjustments and poor patient outcomes. The UGT1A1*28 polymorphism has been linked to decreased inactivation of a toxic irinotecan metabolite (SN-38). To date, analyses of this association have been limited by heterogeneity in statistical power, sample size, or malignancies. Additional data are needed to clarify the role of UTG1A1 polymorphisms in irinotecan toxicity in individuals with colorectal cancer.
In the current study, investigators searched PubMed and Embase to identify relevant clinical trials or well-characterized observational studies that explored the link between UGT1A1*28 and irinotecan-induced neutropenia or diarrhea in patients with colorectal cancer published through May 2012. Case reports, reviews, opinions, studies of non-colorectal cancer patients, and those that reported only general toxicities (instead of neutropenia or diarrhea) were excluded.
Researchers performed subgroup meta-analyses based on the irinotecan regimen and/or dose.
Investigators identified a total of 32 studies, with 16 meeting inclusion criteria. Within these studies, the UGT1A1*28/*28 genotype was associated with increased risk of severe irinotecan-associated neutropenia as compared with UGT1A1*1/*1 (OR = 4.79; 95% CI 3.28-7.01) or UGT1A*1/*28 (OR 3.44; 95% CI 2.45-4.82) across all subgroups. As compared with wild-type patients, presence of UGT1A1*1/*28 was also linked with increased risk of neutropenia (OR = 1.90; 95% CI 1.44-2.51).
Regarding diarrhea, the UGT1A1*28/*28 (but not the UGT1A1*1/*28) genotype, was associated with an increased risk for severe diarrhea (OR = 1.84; 95% CI 1.24-2.72) as compared with UGT1A1*1/*1. Subgroup analyses revealed the increased diarrhea risk was limited to studies using higher doses of irinotecan or in combination with 5-fluorouracil.
This meta-analysis is one of the first to review the association between UGT1A1 polymorphisms and irinotecan-induced neutropenia or diarrhea in colorectal cancer. Results are important as the UGT1A1*28/*28 polymorphism is present in approximately 10% of Americans. Investigators commented that the association with significant neutropenia was “consistent and strong,” while the link to irinotecan-induced diarrhea was weaker.
Study findings also support current FDA-labeled recommendations to reduce the irinotecan dose by at least one level in patients homozygous for the UGT1A1*28 allele. Although Dutch Pharmacogenetics Working Group guidelines recommend no dose adjustments in patients with UGT1A1*1/*28 genotype, they advise a 30% dose reduction in homozygous deficient patients receiving irinotecan >250mg/m2 (no adjustment for lower doses). Guidelines for UGT1A1-guided irinotecan therapy are currently in development by the Clinical Pharmacogenetics Implementation Consortium. Although test availability is subject to change, the UGT1A1 genetic test may currently be ordered through major commercial laboratory providers, including Quest Diagnostics and LabCorp.
Analysis limitations included inherent heterogeneity among trials, restriction to English-language studies, inadequate data for subgroup analyses in some trials, and possibility of information and selection bias.
Liu X et al. Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians. Pharmacogenomics J. 2014;14:120-29.