Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy

Abstract

The UGT1A1*28 polymorphism was suggested to be significantly connected with irinotecan-induced toxicity and response to chemotherapy. However, the results of previous studies are controversial. Hence we carried out a meta-analysis to investigate the effect of UGT1A1*28 polymorphism on severe diarrhea, neutropenia, and response of patients who had undergone irinotecan-based chemotherapy. The PubMed, Web of Science, Wanfang, and CNKI databases were searched for clinical trials assessing the association of UGT1A1*28 polymorphism with severe diarrhea, neutropenia, and response to irinotecan-based chemotherapy. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship under a fixed- or random-effects model. Fifty-eight studies including 6087 patients with cancer were included. Our results showed that patients carrying the TA6/7 and TA7/7 genotypes had a greater prevalence of diarrhea and neutropenia than those with the TA6/6 genotype (TA6/7+TA7/7 vs. TA6/6: diarrhea, OR = 2.18, 95%CI = 1.68-2.83; neutropenia, OR = 2.15, 95%CI = 1.71-2.70), particularly patients with metastatic colorectal cancer. Stratified analysis showed that Asians with the TA6/7 and TA7/7 genotypes were more likely to have diarrhea and neutropenia, and Caucasians with the TA6/7 and TA7/7 genotypes were more likely to have neutropenia than other groups. However, patients with the TA6/7+TA7/7 genotypes showed a higher response than patients with TA6/6 genotype (OR = 1.20, 95%CI = 1.07-1.34), particularly Caucasians (OR = 1.23, 95%CI = 1.06-1.42) and patients with metastatic colorectal cancer (OR = 1.24, 95%CI = 1.05-1.48). Our data showed that the UGT1A1*28 polymorphism had a significant relationship with toxicity and response to irinotecan-based chemotherapy. This polymorphism may be useful as a monitoring index for cancer patients receiving irinotecan-based chemotherapy.

Relationship between <em>UGT1A1*6/*28</em> gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

“…Many studies have shown that UGT1A1*28 is significantly associated with CPT-11-induced toxicity, especially neutropenia 20–24. Caucasians with mutant genotypes are more likely to have neutropenia 12. However, UGT1A1*6 is more prevalent in Asian countries than in Caucasian populations, suggesting that UGT1A1*6 polymorphisms should be considered in addition to UGT1A1*28 polymorphisms for more individualized CPT-11-based chemotherapy.…”

“…However, most studies have found no correlation between different UGT1A1 genotypes and clinical efficacy 30,31. Further, a meta-analysis of 6,087 patients found that both homozygous and heterozygous UGT1A1*28 mutant types had a higher response than wild-type patients, particularly Caucasians 12. In our study, we observed that the tumor response in patients with UGT1A1*28 mutant genotypes with colorectal cancer was better than in those with the wild-type genotype; however, the difference was not statistically significant ( P =0.178).…”

“…UGT1A1*6 and UGT1A1*28 are considered to be the most important alleles for preventing severe SN-38-induced adverse reactions such as neutropenia and delayed diarrhea. Asians with mutant genotypes are more likely to develop neutropenia and delayed diarrhea; however, Caucasians with mutant genotypes are more likely to develop neutropenia 12. Further, the prevalence of the UGT1A1*6 polymorphism is higher in Asian populations than that in Caucasian populations.…”

“…Therefore, we considered the UGT1A1*6 polymorphism in Asian populations. Previously, studies have shown that UGT1A1*6/*28 gene polymorphisms can be used to assess the risk of neutropenia; Chinese people are more likely to suffer delayed diarrhea than Japanese and Thai people 12–16…”

Genetic polymorphisms analysis of pharmacogenomic VIP variants in Bai ethnic group from China

“…Rs4148323 is an intron variant of the UGT1A1 gene on human chromosome 2q37, which encodes a UDP‐glucuronosyltransferase, an enzyme of the glucuronidation pathway (Sugatani et al, ). It plays an important role in catalyzing the formation of bound bilirubin by unbound bilirubin (Liu, Lu, et al, ). Clinical studies have found that cancer patients carrying the GG genotype may reduce the risk of thrombocytopenia (Han, Lim, Park, Lee, & Lee, ) or diarrhea (Takekuma et al, ) when treated with irinotecan‐based regimens and may also increase tumor response, progression‐free survival Period or overall survival compared with patients with AA or AG genotype.…”