A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes

Abstract

To predict precisely severe toxicity of irinotecan, we evaluated the association of UGT1A variants, haplotypes and the combination of UGT1A genotypes to severe toxicity of irinotecan. UGT1A1*6 (211G>A), UGT1A1*28 (TA6>TA7), UGT1A1*60 (−3279T>G), UGT1A7 (387T>G), UGT1A7 (622T>C), and UGT1A9*1b (−118T9>T10, also named *22) were genotyped in 123 patients with metastatic colorectal cancer who had received irinotecan-based chemotherapy. Among the 123 patients, 73 were enrolled in either of two phase II studies of the FOLFIRI (leucovorin, 5-fluorouracil and irinotecan) regimen; these patients constituted the training population, which was used to construct the predicting system. The other 50 patients constituted the validation population; these 50 patients either had participated in a phase II study of irinotecan/5′-deoxy-5-fluorouridine or were among consecutive patients who received FOLFIRI therapy. This prediction system used sequential forward floating selection based on statistical pattern recognition using UGT1A genotypes, gender and age. Several UGT1A genotypes [UGT1A1*6, UGT1A7 (387T>G), UGT1A7 (622T>C) and UGT1A9*1b] were associated with the irinotecan toxicity. Among the haplotypes, haplotype-I (UGT1A1: −3279T, TA6, 211G; UGT1A7: 387T, 622T; UGT1A9: T10) and haplotype-II (UGT1A1: −3279T, TA6, 211A; UGT1A7: 387G, 622C; UGT1A9: T9) were also associated with irinotecan toxicity. Furthermore, our new system for predicting the risk of irinotecan toxicity was 83.9% accurate with the training population and 72.1% accurate with the validation population. Our novel prediction system using statistical pattern recognition depend on genotypes in UGT1A, age and gender; moreover, it showed high predictive performance even though the treatment regimens differed among the training and validation patients.

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

“…In this study, the genotype frequency of UGT1A1*6 and UGT1A1*28 were similar to previous reports in Asia [5, 20]. Both UGT1A1*6 and UGT1A1*28 related to G3–4 neutropenia, rather than delayed diarrhea, which was consistent with several large-sample analysis in Asia [4–7]. Several small-sample analyses also noted that UGT1A1*28 and UGT1A1*6 could predict severe irinotecan-induced severe diarrhea [21, 22], which did not appear in the current study.…”

Toward Optimum Benefit‐Risk and Reduced Access Lag For Cancer Drugs in Asia: A Global Development Framework Guided by Clinical Pharmacology Principles

“…For example, UGT1A1*6 is an important Asian‐selective allelic variant that contributes to decreased clearance of UGT1A1 substrates in addition to other established allelic variants of global cross‐population significance, such as UGT1A1*28 . Studies with irinotecan (whose active metabolite SN‐38 is primarily cleared via UGT1A1‐mediated glucuronidation) in Asian patients with cancer have consistently demonstrated an association between UGT1A1*6 ‐containing genotypes and severe neutropenic toxicity . In a phase I, dose‐escalation study of nanoliposomal irinotecan (PEP02) in Taiwanese patients with advanced solid tumors, treatment‐related severe toxicities (grade 4 febrile neutropenia, grade 4 thrombocytopenia with bleeding, and grade 4 diarrhea) led to death in a patient with combined heterozygosity of UGT1A1*6/*28 and increased SN‐38 exposure .…”

Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver

“…At relatively high irinotecan dose levels (>250 mg/m 2 ), patients homozygous for the UGT1A1*28 may experience a greater risk of clinically important neutropenia, but at lower doses (100–125 mg/m 2 ), the negative impact of UGT1A1*28 has less clinical relevance [44]. Recently, a novel prediction system using a statistical pattern based on UGT1A genotypes, age, and sex was developed; despite the difference in treatment regimens between the training and validation patients, its predictive performance was high [45]. Others investigators explored the correlation between biliary index (irinotecan total x SN-38 total/SN-38G) and toxicity in patients treated with HAI irinotecan, and unfortunately, no correlation was seen [24].…”