Association Between ABCG2, ABCB1, ABCC2 Efflux Transporter Single‐Nucleotide Variants and Irinotecan Adverse Effects in Patients With Colorectal Cancer: A Real‐Life Study

Among patients treated with irinotecan, homozygous carriers of the UGT1A1*28 allele are at increased risk for neutropenia, but UGT1A1 genotype alone does not account for irinotecan‐induced toxicity. Our aim was to study the association between single‐nucleotide variants in genes encoding for efflux...

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Published in:Clinical pharmacology and therapeutics 2023-03, Vol.113 (3), p.704-711
Main Authors: Barnett‐Griness, Ofra, Rennert, Gad, Lejbkowicz, Flavio, Pinchev, Mila, Saliba, Walid, Gronich, Naomi
Format: Article
Language:English
Subjects:
ATP Binding Cassette Transporter, Subfamily B - genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Genome-Wide Association Study
Genotype
Glucuronosyltransferase - genetics
Humans
Irinotecan - adverse effects
Membrane Transport Proteins - genetics
Multidrug Resistance-Associated Protein 2 - genetics
Multidrug Resistance-Associated Proteins - genetics
Neoplasm Proteins - genetics
Nucleotides - therapeutic use
Polymorphism, Single Nucleotide
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Summary:Among patients treated with irinotecan, homozygous carriers of the UGT1A1*28 allele are at increased risk for neutropenia, but UGT1A1 genotype alone does not account for irinotecan‐induced toxicity. Our aim was to study the association between single‐nucleotide variants in genes encoding for efflux transporters of irinotecan (ABCG2, ABCB1, and ABCC2) and toxicity in real life. The source population was a cohort of patients with colorectal cancer (CRC) in Northern Israel, who had undergone genome‐wide association study. From the source population we chose the patients with CRC prescribed irinotecan, and a comparative cohort of patients with CRC treated with other anticancer systemic therapies. Using Clalit Health Services electronic medical records (including laboratory results) we ascertained hematological and gastrointestinal adverse effects and mortality, within 90 days of the first dose, as a composite outcome. There were 601 patients with CRC who received irinotecan, and 756 patients with CRC treated with other anticancer regimens. The minor allele in rs2231142 (ABCG2) was associated with lower incidence of the composite outcome (odds ratio (OR) = 0.54 (0.33, 0.91); P = 0.02) in irinotecan‐treated patients with CRC, but not in patients with CRC treated with other regimens. ABCB1 rs1045642 and ABCC2 rs3740066 were not associated with the composite outcome. In a sensitivity analysis, adjusted for UGT1A1 status and for possible demographic and clinical confounders, adjusted OR was 0.56 (0.33, 0.94) for the association between rs2231142 (ABCG2) and the composite outcome. In conclusion, we describe a novel association between the minor allele of rs2231142 in the efflux transporter gene ABCG2 and protection against severe side effects in CRC patients treating with irinotecan.
ISSN:0009-9236
1532-6535
DOI:10.1002/cpt.2833