Association of single nucleotide polymorphisms (SNP) in the ABCB1 gene with neutropenia and diarrhea protection in capecitabine and 5-fluorouracil-treated colorectal cancer patients respectively.

Abstract

Background: ABCB1 polymorphisms have been identified as predictors for response of 5-fluorouracil (5- FU) in colorectal cancer (CRC) although there is limited data regarding toxicity. Our purpose was to assess the association between the ABCB1 C3435C>T, G2677G>T/A, and C1236C>T SNPs with adverse effects in CRC patients treated with 5-FU or capecitabine-based regimens. Methods: The study was carried out at Gregorio Maranon Hospital in 120 CRC patients. 56 patients were receiving 5-FU alone or in combination and 64 capecitabine alone or combined. Patients were genotyped for C1236 (rs1128503), G2677 (rs2032582) and C3435 (rs1045642) SNPs in ABCB1 gene. Toxicity was assessed according to CTCAE. Results: Neutropenia and diarrhea were the most common adverse reactions related to capecitabine and 5-FU. Moderate-severe neutropenia was observed in 42.85% and 12.5% of patients treated with 5-FU or capecitabine-based regimens respectively. Moderate-severe diarrhea was reported in 31.48% and 26.56% of 5-FU or capecitabine-treated patients respectively. A significant association was found between rs1128503 and moderate-severe neutropenia in patients receiving any capecitabine-based regimen (p = 0.026). Mild-severe neutropenia was reported in 31.2% of wild-type homozygous (C/C) and 9.4% of heterozygous (C/T) for rs1128503. Patients with homozygous mutant (T/T) genotype for rs1128503 did not develop moderate-severe neutropenia. Diarrhea was associated with rs1045642 in patients with any 5-FU-based regimen (p = 0.031). Mild-severe diarrhea was more frequent in patients homozygous for the mutant allele of rs1045642 (46.2%) than in heterozygous (37%) or homozygous wild type carriers (6.2%). There were no differences on these frequencies when irinotecan-treated patients were excluded. Conclusions: Homozygous TT genotype for ABCB1 C1236T SNP could be consider a prognostic biomarker of CRC patient's resistance to develop neutropenia associated to capecitabine-based regimen, whereas homozygous CC genotype for ABCB1 C3435T SNP may be a prognostic marker of resistance for diarrhea in 5-FU-treated patients.