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Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.

ABSTRACT: Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.

SUBMITTER: Hegyi M

PROVIDER: S-EPMC5354739 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.

Hegyi Marta M Arany Adam A Semsei Agnes F AF Csordas Katalin K Eipel Oliver O Gezsi Andras A Kutszegi Nora N Csoka Monika M Muller Judit J Erdelyi Daniel J DJ Antal Peter P Szalai Csaba C Kovacs Gabor T GT

Oncotarget 20170201 6

Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesi ...[more]

PMID: 27566582

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Project description:Background:The role of Methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in the efficacy and toxicity of MTX-based therapy remains uncertain. Our purpose was to clarify whether these two polymorphisms are associated with the outcome of chemotherapy in a cohort of Chinese osteosarcoma (OS) patients treated by high-dose MTX. Methods:109 OS patients who had sequentially received high-dose MTX therapy were included in this study. Plasma MTX level was measured routinely at 0, 24, 48 and 72?h after the administration of MTX. Two variants of MTHFR were genotyped using TaqMan SNP Genotyping Assay, including rs1801133 (C667T) and rs1801131 (A1298C). The extent of toxicity induced by MTX, including hematological toxicity, hepatic toxicity, renal toxicity and mucositis, was scored from grade 1 to 4. Severe toxicity was defined as a grade score of ?3. Patients were dichotomized as follows: grade <3 or ?3 for toxicity, and ?0.2 µmol/L or >0.2 µmol/L for plasma MTX level at 72?h. The frequencies of genotypes and allele were compared between the dichotomized groups with the Chi-square test. Results:24.8% (27/109) of the patients were found to have significantly high plasma MTX level at the 72?h. Patients with high MTX level at 72?h were found to have significantly higher frequency of genotype TT of rs1801133 (p?=?0.002). As for rs1801131, no significant association was found with plasma MTX level. Patients with severe hepatic toxicity or mucositis were found to have remarkably higher incidence of genotype TT of rs1801133 than those with mild toxicity (33.3% vs. 14.8%, p?=?0.04 for hepatic toxicity; 34.8% vs. 19.8%, p?=?0.05 for mucositis). Conclusions:Variant rs1801133 was confirmed to have remarkable influence on the MTX-induced toxicity. We recommend identification of the genotype of MTHFR variant prior to the application of high-dose MTX to OS patients, which could be an important predictor to screen severe toxicities and thus improve treatment outcomes.

Project description:ObjectiveTo compare the treatment success and failure rates, as well as side effects and surgery rates, between methotrexate protocols.Data sourcesPubMed, Embase, and the Cochrane library searched up to July 2018.Study eligibility criteriaRandomized controlled trials that compared women with ectopic pregnancies receiving the single-dose, two-dose, or multi-dose methotrexate protocols.Study appraisal and synthesis methodsOdds of treatment success, treatment failure, side effects, and surgery for tubal rupture, as well as length of follow-up until treatment success, were compared using random and fixed effects meta-analysis. Sensitivity analyses compared treatment success in the groups with high human chorionic gonadatropin (hCG) values and a large adnexal mass, as defined by individual studies. The Cochrane Collaboration tool was used to assess risk of bias.ResultsThe 2-dose protocol was associated with higher treatment success compared to the single-dose protocol (odds ratio [OR], 1.84; 95% CI, 1.13, 3.00). The 2-dose protocol was more successful in women with high hCG (OR, 3.23; 95% CI, 1.53, 6.84) and in women with a large adnexal mass (OR, 2.93; 95% CI, 1.23, 6.9). The odds of surgery for tubal rupture were lower in the 2-dose protocol (OR, 0.65; 95% CI, 0.26, 1.63), but this was not statistically significant. The length of follow-up was 7.9 days shorter for the 2-dose protocol (95% CI, -12.2, -3.5). The odds of side effects were higher in the 2-dose protocol (OR, 1.53; 95% CI, 1.01, 2.30). Compared to the single-dose protocol, the multi-dose protocol was associated with a nonsignificant reduction in treatment failure (OR, 0.56; 95% CI, 0.28, 1.13) and a higher chance of side effects (OR, 2.10; 95% CI, 1.24, 3.54). The odds of surgery for tubal rupture (OR, 1.62; 95% CI, 0.41, 6.49) and time to follow-up (OR, -1.3; 95% CI, -5.4, 2.7) were similar.ConclusionThe 2-dose methotrexate protocol is superior to the single-dose protocol for the treatment of ectopic pregnancy in terms of treatment success and time to success. Importantly, these findings hold true in patients thought to be at a lower likelihood of responding to medical management, such as those with higher hCGs and a large adnexal mass.

Dataset Information

Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.

Publications

Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.

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