UGT1A polymorphisms associated with worse outcome in colorectal cancer patients treated with irinotecan-based chemotherapy.

Abstract

PURPOSE:

To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC).

METHODS:

The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at http://www.clinicaltrials.gov ). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients. Kaplan-Meier and Cox regression analyses were used to assess the association between potential signatures and survival outcome.

RESULTS:

We found that UGT1A1*28 variant genotype was significantly associated with decreased progression-free survival (PFS) [adjusted hazard ratio (HR), 1.803; 95% confidence interval (CI), 1.217-2.671] and overall survival (OS) (adjusted HR 1.979; 95% CI 1.267-3.091) compared with wild-type genotype. Patients carrying (TA)7 allele showed a median PFS of 7.5 (95% CI 5.5-9.6) months compared with 9.8 (95% CI 8.6-10.9) months for patients with wild-type genotype. Median OSs were 13.3 (95% CI 10.3-16.2), and 20.8 (95% CI 18.7-23.0) months for (TA)6/7 or (TA)7/7, and (TA)6/6 patients, respectively. Similarly but more significantly, the copy number of haplotype III (composed by rs3755321-T, rs3821242-C, rs4124874-G and rs3755319-C) constructed among the selected SNPs also correlated with survival outcome.

CONCLUSIONS:

UGT1A polymorphisms are predictive of survival outcome of irinotecan-treated Chinese mCRC patients. After validation, UGT1A polymorphisms might be helpful in facilitating stratification of mCRC patients for individualized treatment options.

• Authors: Qianqian Yu, Tao Zhang, Conghua Xie, Hong Qiu, Bo Liu, Liu Huang, Ping Peng, Jueping Feng, Jigui Chen, Aihua Zang, Xianglin Yuan
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 82 Issue 1 Pg. 87-98 (07 2018) ISSN: 1432-0843 [Electronic] Germany
• PMID: 29728798 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives)
• Colorectal Neoplasms (drug therapy, enzymology, genetics)
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Gene Frequency
• Glucuronosyltransferase (genetics)
• Haplotypes
• Humans
• Irinotecan (administration & dosage, adverse effects)
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Prospective Studies
• Survival Rate
• Young Adult