Association between ABCG2, ABCB1, ABCC2 efflux transporters SNP's and irinotecan adverse effects in colorectal cancer patients: 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 SNP's in genes encoding for efflux transporters of irinotecan (ABCG2, ABCB1, and ABCC2) and toxicity in real-life. The source population was a cohort of colorectal (CRC) patients in Northern Israel, who had undergone genome-wide-association-study. From the source population we chose the CRC patients prescribed irinotecan, and a comparative cohort of patients with CRC treated with other anti-cancer 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 first dose, as a composite outcome. There were 601 patients with CRC who received irinotecan, and 756 patients with CRC treated with other anti-cancer regimens. The minor allele in rs2231142 (ABCG2) was associated with lower incidence of the composite outcome (OR=0.54 [0.33, 0.91]; p=0.02) in irinotecan-treated CRC patients, but not in CRC patients 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 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.