UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan

Area of Science:

• Pharmacogenomics
• Oncology
• Clinical Trial Research

Background:

• Irinotecan (CPT-11) is a key drug in metastatic colorectal cancer treatment but is associated with severe toxicities.
• Adjuvant chemotherapy regimens, including 5-fluorouracil (5FU) and CPT-11, are used for high-risk stage III colon cancer.
• Understanding genetic factors influencing toxicity is crucial for personalized treatment strategies.

Purpose of the Study:

• To evaluate the impact of specific genetic polymorphisms on hematologic toxicities and disease-free survival in stage III colon cancer patients undergoing adjuvant chemotherapy with 5FU and CPT-11.
• To assess the predictive value of UGT1A1 and other gene polymorphisms in relation to treatment outcomes and toxicity.

Main Methods:

• A prospective randomized phase III trial involving 400 patients comparing LV5FU2 with LV5FU2 + CPT-11.
• DNA analysis of 184 patients to genotype polymorphisms in ABCB1 (3435C>T), CYP3A5 (6986A>G), and UGT1A1 (*28 and -3156G>A).

Main Results:

• No significant association was found between ABCB1 or CYP3A5 polymorphisms and toxicity or disease-free survival.
• UGT1A1*28 homozygous patients exhibited higher rates of severe hematologic toxicity (50%) compared to UGT1A1*1 homozygous patients (16.2%).
• Patients homozygous for the UGT1A1 -3156G>A mutant allele showed significantly increased severe hematologic toxicity (50%) and earlier onset compared to wild-type homozygotes. The hazard ratio for severe toxicity was 8.4 for A/A vs. G/G genotypes (P=0.005).

Conclusions:

• Identification of UGT1A1 promoter polymorphisms, particularly -3156G>A, is clinically valuable for predicting early hematologic toxicity in patients treated with LV5FU2 + CPT-11.
• The UGT1A1 -3156G>A polymorphism appears to be a more effective predictor of toxicity than the UGT1A1 (TA) repeat polymorphism.