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

Effects of UGT1A1*6 and UGT1A1*28 genetic polymorphisms on irinotecan‐induced 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; 95% CI 3.11–12.47; p < 0.00001; diarrhea: OR 3.21; 95% CI 2.13–4.85; p < 0.00001) than those with heterozygous variants. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with neutropenia (OR 1.67; 95% CI 0.98–2.84; p = 0.06) and were significantly associated with a reduction in irinotecan‐induced diarrhea (OR 0.31; 95% CI 0.11–0.81; p = 0.02). Asian cancer patients should undergo screening for both UGT1A1*6 and UGT1A1*28 genetic variants to reduce substantially irinotecan‐induced severe toxicities.

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/m²) 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.