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Relevance of MTHFR polymorphisms with response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer: a meta-analysis.

ABSTRACT: OBJECTIVE:To evaluate the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer. DESIGN:Meta-analysis. METHODS:We searched PubMed, Embase and Web of Science databases from inception up to October 2017 for relevant studies. The statistical analysis was performed using STATA V.12.0 software. The pooled ORs and 95% CIs were used to assess the strength of the association under the allele, dominant and recessive models. We also conducted subgroup analysis stratified by cancer type, ethnicity and study design. Additionally, the sensitivity analysis was performed by sequential omission of individual studies, and the publication bias was detected using both Begg's test and Egger's test. RESULTS:A total of 2020 patients from 12 studies were included in this meta-analysis. The results showed that there was no significant association between MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (T vs C: OR 0.93, 95%?CI 0.76 to 1.15; C vs A: OR 0.88, 95%?CI 0.56 to 1.40. CT+TT?vs CC: OR 0.94, 95%?CI 0.72 to 1.23; AC+CC?vs AA: OR 0.80, 95%?CI 0.47 to 1.35. TT vs CC+CT: OR 1.02, 95%?CI 0.74 to 1.39; CC vs AA+AC: OR 1.15, 95%?CI 0.50 to 2.67). When stratified by cancer type, ethnicity or study design, the association was still not significant in all subgroups. CONCLUSIONS:This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer.

SUBMITTER: Zhong L

PROVIDER: S-EPMC5988135 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Relevance of <i>MTHFR</i> polymorphisms with response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer: a meta-analysis.

Zhong Lei L Fu Qi Q Zhou Shu S Chen Lu L Peng Qian Q

BMJ open 20180526 5

<h4>Objective</h4>To evaluate the association between methylenetetrahydrofolate reductase (<i>MTHFR</i>) polymorphisms and the response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer.<h4>Design</h4>Meta-analysis.<h4>Methods</h4>We searched PubMed, Embase and Web of Science databases from inception up to October 2017 for relevant studies. The statistical analysis was performed using STATA V.12.0 software. The pooled ORs and 95% CIs were used to assess the strength of the associ ...[more]

PMID: 29804062

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Project description:BackgroundThe fluoropyrimidine drug 5-Fluorouracil (5-FU) and the prodrug capecitabine have been extensively used for treatment of many types of cancer including colorectal, gastric, head and neck. Approximately, 10 to 25% of patients suffer from severe fluoropyrimidine-induced toxicity. This may lead to dose reduction and treatment discontinuation. Pharmacogenetics research could be useful for the identification of predictive markers in chemotherapy treatment. The aim of the study was to investigate the role of five genetic polymorphisms within two genes (DPYD, TYMS) in toxicity and efficacy of fluoropyrimidine-based chemotherapy.MethodsTotal genomic DNA was extracted from 83 cancer patients treated with fluoropyrimidine-based chemotherapy. In this study, three polymorphisms were genotyped in dihydropyrimidine dehydrogenase gene c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798) and two polymorphisms, besides the Variable Number of Tandem Repeat (VNTR) polymorphism and 6-bp insertion/deletion polymorphism in thymidylate synthase gene. The analysis of polymorphisms for rs3918290, rs55886062, rs67376798 and 6-bp insertion/deletion in TYMS was done by Polymerase Chain Reaction-restriction Fragment Length Polymorphism (PCRRFLP) TYMS VNTR analysis. 5-FU-related toxicities such as anemia, febrile neutropenia, neurotoxicity, vomiting, nausea, and mucositis were evaluated according to NCI-CTC criteria version 4.0. T-test and chi-square were used and p-values less than 0.05 were considered statistically significant.ResultsDPYD gene polymorphisms were not observed in this study. The frequency of the TYMS +6 bp allele was 40.35% and the -6 bp allele was 59.65% in this study. The frequency of VNTR 2R allele was 48.75% and 3R allele was 51.15%. Toxicity grade II diarrhea, mucositis, nausea, vomiting, and neurotoxicity was 2.2, 24.1, 15.7, 6, and 51.8%, respectively. Thymidylate synthase ins/del polymorphisms were associated with increased grade III neurotoxicity (p=0.02). Furthermore, anemia grade III was significantly associated with 2R/2R genotype (0.009).ConclusionThymidylate synthase gene polymorphisms may play a key role in fluoropyrimidne -based chemotherapy. Although rare DPYD polymorphisms were not observed in our study, according to large population studies, DPYD gene polymorphisms could be used as a predictive biomarker for patient treatments.

Project description:What is already known about this subject* Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.What this study adds* This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.AimsTo test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.MethodsAdvanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).ResultsNone of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).ConclusionsThese results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.

Project description:BackgroundAlthough treatment of localized anal cancer (AC) is well established, very little evidence is available to inform the management of advanced tumors, and the prognosis of these patients remains poor. We have analyzed treatment pathways and outcomes of a single-institution series of advanced AC patients in order to provide insight into the management of this rare condition.Materials and methodsInclusion criteria included epidermoid histology, inoperable locally recurrent or metastatic disease, and availability of full medical records. The primary objective was overall survival (OS). Prognostic factors were analyzed in univariate models.ResultsSixty-four patients (1997-2014) were included: 16 (25.0%) with inoperable locally advanced and 48 (75.0%) with metastatic tumors. Fifty-one (79.7%) received at least one line of chemotherapy; of these, 37% underwent multimodality treatment. A combination of a platinum agent plus a fluoropyrimidine was the most common first-line regimen (74.5%), with an objective response rate (ORR) of 34.4% (95% confidence interval [CI], 18.6%-53.2%). Paclitaxel-based chemotherapy was used in 15 patients as front-line or salvage treatment, and the overall ORR was 53.3% (95% CI, 26.6%-78.7%). Median progression-free survival (PFS) after first- and second-line chemotherapy was 5.8 (interquartile range [IQR], 2.8-7.6) and 3.2 (IQR, 2.5-7.1) months, respectively. Five-year OS in the overall population was 15% (95% CI, 7.0%-25.0%). Age ≤65 years and liver metastases were predictive of better PFS (hazard ratio [HR], 0.39; 95% CI, 0.16-0.97; p = .04) and worse OS (HR, 2.25; 95% CI, 1.25-4.03; p = .01), respectively.ConclusionA platinum agent plus a fluoropyrimidine and paclitaxel-based chemotherapy are active regimens for advanced AC. Clinical trials are needed to standardize treatment pathways, investigate the potential of novel therapeutics, and improve the poor prognosis of this rare condition. The Oncologist 2017;22:402-408Implications for Practice: Because of the lack of randomized trials, the optimal management of advanced anal cancer is uncertain. Despite its retrospective analysis and relatively small sample size, this is the second largest study ever conducted in this setting, and, as such, it has the potential to serve as a valuable source of information for everyday clinical practice. These findings suggest that chemotherapy with a platinum agent plus a fluoropyrimidine or paclitaxel-containing regimens are reasonable treatment options for patients with inoperable locally recurrent or metastatic anal carcinoma.

Dataset Information

Relevance of MTHFR polymorphisms with response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer: a meta-analysis.

Publications

Relevance of <i>MTHFR</i> polymorphisms with response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer: a meta-analysis.

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