Association of UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic polymorphisms with irinotecan‐induced toxicity in Asian cancer patients: Meta‐analysis

Abstract

Effects of UGT1A1*6 and UGT1A1*28 genetic polymorphisms on irinotecaninduced severe toxicities in Asian cancer patients are inconclusive. Also, ABCC2 c.3972C>T may affect toxicity of irinotecan. The aim was to assess the aggregated risk of neutropenia or diarrhea in Asian cancer patients taking irinotecan and inherited UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic variants. A PubMed literature search for eligible studies was conducted. Odds ratios (ORs) were measured using RevMan software where p values <0.05 were statistically significant.Patients that inherited both UGT1A1*6 and UGT1A1*28 genetic variants (heterozygous: UGT1A1*1/*6 + *1/*28 and homozygous: UGT1A1*6/*6 + *28/*28) were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1 (neutropenia: OR 2.89; 95% CI 1.97-4.23; p < 0.00001; diarrhea: OR 2.26; 95% CI 1.71-2.99; p < 0.00001). Patients carrying homozygous variants had much stronger effects in developing toxicities (neutropenia: OR 6.23; Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Cancer patients taking irinotecan and inheriting either UGT1A1*6 or UGT1A1*28 genetic polymorphisms or a combination of these variants (UGT1A1*6 + UGT1A1*28) are associated with severe toxicities such as neutropenia or diarrhea, but the aggregated risk is highly inconsistent, especially in Asian cancer patients. Also, the ABCC2 c.3972C>T genetic polymorphism is associated with irinotecan-induced toxicities. WHAT QUESTION DID THIS STUDY ADDRESS?Is the combination of UGT1A1*6 and UGT1A1*28 genetic polymorphisms or ABCC2 c.3972C>T genetic variant associated with severe neutropenia or diarrhea in Asian cancer patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Asian cancer patients, irrespective of the type of cancer, who carried both the UGT1A1*6 and UGT1A1*28 genetic variants were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1, and the effects were even more striking in cancer patients with homozygous variants than those with heterozygous variants. In addition, dose-dependent analysis indicated that a high dose of irinotecan (>150 mg/m 2 ) was significantly associated with diarrhea in cancer patients that carried both the UGT1A1*6 and UGT1A1*28 genetic variants compared to patients on medium and low doses of irinotecan. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with irinotecan-induced toxicities. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?The results presented in this meta-analysis will greatly enhance the clinical practice of irinotecan therapy considering UGT1A1*6 and UGT1A1*28 pharmacogenetics. The findings of this study will also assist clinicians in suggesting genotyping for UGT1A1*6 and UGT1A1*28 polymorphisms prior to administering irinotecan therapy as part of standard care and may advance the translation of irinotecan pharmacogenetics to the bedside. | 1615 UGT1A1 AND ABCC2 IRINOTECAN-INDUCED TOXICI...

UGT1A1 genotype‐guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN‐38 concentration

“…17 However, the impact of the UGT1A1*6 polymorphism on the adverse effects of irinotecan remains controversial. 18 Furthermore, adjusting the dose of irinotecan-based on the UGT1A1*6 polymorphism has yet to be investigated.…”

“…The UGT1A1*6 allele is thought to compensate for the lower prevalence of the UGT1A1*28 allele among Asians 17 . However, the impact of the UGT1A1*6 polymorphism on the adverse effects of irinotecan remains controversial 18 . Furthermore, adjusting the dose of irinotecan‐based on the UGT1A1*6 polymorphism has yet to be investigated.…”

Genotyping of UGT1A1*80 as an Alternative to UGT1A1*28 Genotyping in Spain

“…Severe diarrhea and neutropenia are common adverse events of irinotecan [ 1 ]. Several genetic variants in UGT1A1 have been associated with toxicity induced by irinotecan [ 2 ] and by other cancer drugs [ 3 ].…”