Impacts of polymorphisms in drug-metabolizing enzyme and transporter genes on irinotecan toxicity and efficacy in Thai colorectal cancer patients

by Natthakul Akarapredee, Chalirmporn Atasilp, Chonlaphat Sukasem, Pimonpan Jinda, Rattanaporn Sukprasong, Jiraporn Jensuriyarkun, Soravit Wongjitjanyong, Patompong Satapornpong, Natchaya Vanwong

Irinotecan is a chemotherapy agent commonly prescribed for metastatic colorectal cancer but often leads to neutropenia. Variations in genes encoding drug-metabolizing enzymes and transporters may affect the toxicity and effectiveness of irinotecan. This study aimed to examine the impact of these genetic polymorphisms on irinotecan outcomes in Thai colorectal cancer patients.

The study retrospectively analyzed 41 metastatic colorectal cancer patients treated with irinotecan-based chemotherapy. Genotyping was conducted for 23 single nucleotide polymorphisms in genes including UGT1A1, CYP3A4, CYP3A5, CES1, ABCB1, ABCC2, ABCC5, ABCG1, ABCG2, and SLCO1B1.Toxicity and efficacy were assessed, with statistical significance set at a Bonferroni-corrected P value  Results

In terms of toxicity, UGT1A1*6 was significantly associated with both all-grade and severe neutropenia in the first cycle (p p p ABCC2 -24C > T variant was linked to all-grade neutropenia in the second cycle (p = 0.001). For efficacy, patients with the wild-type UGT1A1*6 had longer progression-free survival (PFS) (p SLCO1B1 521T > C variant was associated with improved PFS (p  Conclusion

UGT1A1*6 and ABCC2 -24C > T variants emerge as potential predictors of irinotecan-induced neutropenia, while UGT1A1*6 and SLCO1B1 521T > C may serve as markers of prolonged PFS in Thai patients. Validation through larger prospective studies is essential to confirm and refine these genetic associations.