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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00973

DOI=10.3389/fphar.2020.00973

ISSN=1663-9812

ABSTRACT=<p>Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the <italic>UGT1A1*28/*28</italic> genotype. An explanation for idiopathic toxicity beyond the <italic>UGT1A1</italic> 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 <italic>ABCB1</italic>. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in <italic>ABCB1</italic> 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 <italic>ABCB1</italic> (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 (<italic>P</italic>=0.014 and <italic>P</italic>=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (<italic>P</italic>&lt;0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.</p>