ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients.

Pau Riera,Ana Sebio,David Páez,Anna C Virgili,María Jesús Arranz,Alícia Artigas-Baleri,Juliana Salazar

doi:10.3389/fphar.2020.00973

Abstract

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.

Highlights

Irinotecan (CPT-11) is an antitumor agent that is broadly used in metastatic colorectal cancer patients and normally coadministered with infusional 5-fluorouracil/leucovorin (FOLFIRI regimen)
This study shows the ABCB1 rs1128503 variant is a promising predictor of irinotecan-induced severe gastrointestinal toxicity, in particular diarrhea and mucositis
The Food and Drug Administration (FDA) drug label for irinotecan includes therapeutic recommendations for UGT1A1*28 homozygous patients to reduce the risk of developing neutropenia [Irinotecan (CAMPTOSAR) drug label

Summary

Introduction

Irinotecan (CPT-11) is an antitumor agent that is broadly used in metastatic colorectal cancer (mCRC) patients and normally coadministered with infusional 5-fluorouracil/leucovorin (FOLFIRI regimen). Its use is hampered by toxicities such as severe diarrhea and neutropenia in more than one-third of the patients (Fuchs et al, 2003). CPT-11 is converted to 7-ethyl-10-hydroxycamptothecin (SN-38), which is responsible for both the efficacy and the toxicity of the drug. The presence of seven TA repeats (UGT1A1*28 allele) in the promoter region of this gene reduces enzymatic activity (Bosma et al, 1995) and patients homozygous for this variant have a higher risk of irinotecan-induced toxicity (Innocenti et al, 2004; Marcuello et al, 2004; Rouits et al, 2004; Riera et al, 2018). UGT1A1 genetic status does not always explain severe toxicity, suggesting that other mechanisms contribute to the appearance of side effects

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