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Pharmacogenomics

Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps. First draft submitted: 15 October 2015; Accepted for publication: 4 December 2015; Published online: 19 February 2016

Jared M Campbell*,1, Emma Bateman2, Micah DJ Peters1, Joanne M Bowen2, Dorothy M Keefe2 & Matthew D Stephenson1 1 The Joanna Briggs Institute, Faculty of Health Science, University of Adelaide, Level 1, 115 Grenfell Street SA 5005, Australia 2 School of Medicine, Faculty of Health Science, University of Adelaide, Frome Road, Adelaide SA 5000, Australia *Author for correspondence: Tel.: +61 8 8313 8231 [email protected]

Keywords:  adverse events • cancer • chemotherapy • fluoropyrimidine • FU • personalized medicine • pharmacogenetics • pharmacogenomics • platinum • toxicity

Fluoropyrimidine (FU)-based chemotherapies (specifically 5-fluorouracil [5-FU] and prodrugs thereof; i.e., capecitabine, UFT, S-1) are among the most commonly used chemotherapeutic drugs given for the treatment of cancer [1] . They belong to the antimetabolite family of chemotherapeutics, and are believed to function primarily via blocking thymidylate synthase (TYMS) by the binding of the metabolite 5-fluorodeoxyuridine monophosphate to TYMS, resulting in the cessation of conversion of its endogenous substrates [2] . Other metabolites are also formed and contribute to the disruption of RNA synthesis via the incorporation of fluoronucleotides [2] . Other proteins involved in the metabolism and action of FU-based chemotherapies include methylenetetrahydrofolate reductase (MTHFR), dihydropyrimidine dehydrogenase (DPD; coded for by DPYD) and thymidine phosphorylase (TP or PD-ECGF) [1] . FU-based chemotherapies are

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a common treatment, and are used for several cancers including colorectal, gastric, pancreatic, breast and head and neck cancers [3] . As with all chemotherapies, adverse events are a common occurrence in FU treatments, with 10–40% of patients treated with FU chemotherapy developing severe toxicities, including myelosuppression, cardiotoxicity, mucositis, hand–foot syndrome (HFS), nausea and diarrhea [4–7] . Increasing age and gender (female) have been found to be associated with greater risk of FU-induced toxicity  [8–11] . Importantly, FU has been shown to have a treatment-related mortality rate of 0.5–1.0% [6,7] . Platinum-based chemotherapies (i.e., cisplatin, carboplatin, oxaliplatin) are the most common drug treatment for gastric cancer, alongside FU-based chemotherapies [12] , they are also used in the treatment of many other metastatic cancers including breast cancer, small-cell and non-small-cell lung

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ISSN 1462-2416

Review  Campbell, Bateman, Peters, Bowen, Keefe & Stephenson cancer (NSCLC), endometrial cancer, non-Hodgkin lymphoma and head and neck cancers. Platinum agents bind to DNA and form adducts that interfere with transcription and DNA replication, resulting in apoptosis and growth inhibition [13,14] . Other mechanisms of inducing cell death, such as the immunogenic effects of modulation of STAT signaling and the enhancement of the effector immune response, have been proposed to also contribute to the platinum family’s chemotherapeutic effect [14] . Platinum-based agents are their own family of chemotherapeutics, but are sometimes grouped with alkylating agents due to similarities in their mechanism of effect. Toxicities associated with platinum-based chemotherapy include peripheral neurotoxicity, ototoxicity, cardiotoxicity, nephrotoxicity, nausea, constipation and diarrhea [15] . Neurotoxicity is the main dose-limiting toxicity of platinum-based chemotherapies, occurring in 15–60% of patients treated with cisplatin or oxaliplatin. However, it is less common in carboplatin-based chemo­ therapies (4–6%), where the main dose-limiting toxicity is thrombocytopenia [16] . Platinum-induced peripheral neuropathies are typically cumulative and often not fully ­reversible [16] . The adverse events associated with the use of FUand platinum-based chemotherapies greatly complicate their use and necessitate weighing potential benefits against potential harms. Prognostic markers for likelihood of chemotherapy-induced toxicity would allow clinicians to apply personalized medicine and select the safest chemotherapeutic drug to apply and initiate risk management strategies such as increased surveillance, dose reduction or prophylactic interventions. Many studies have investigated patient germline genotypes as potential biomarkers for risk of toxicity from FU- and platinum-based chemotherapy regimens, and promising results from primary studies have been obtained  [17–20] . However, in order for biomarkers to be clinically applied, extensive validation and replication are necessary [21] . Investigations of the pharmaco­ genetics of chemotherapy-induced toxicity generally have relatively small populations, use retrospective data and have a high rate of false discovery [21] . This makes replication and the systematic review of studies especially important for the translation of pharmacogenetic research to clinical practices, as the creation of overall effect estimates and mitigates the risks created by relying on individual studies. Systematic reviews involve a structured search of the literature to identify all available studies that meet prespecified inclusion criteria, critical appraisal for potential sources of bias and, where appropriate, statistical combination through meta-analysis. Although they provide the most rigorous evidence for informing

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Pharmacogenomics (Epub ahead of print)

clinical practice, a single systematic review is seldom inclusive enough to fully cover an area of healthcare. Their strength lies in the use of strict, predefined inclusion criteria, which prevent biased selection of studies; however they consequently tend to answer relatively narrow clinical questions. The association between germline variations and chemotherapy-induced toxicities is a complex, multifaceted question with multiple possible variations in genes investigated, genetic models applied, chemotherapy regimens and types of cancer treated. As such, in this report an ‘umbrella systematic review’; a systematic review of systematic reviews has been undertaken in order to identify and synthesize the findings of all systematic reviews that investigate the pharmaco­ genetics of FU or platinum-induced toxicity. The aim was to identify all genes, polymorphisms, populations and contexts where biomarkers for FU- or platinuminduced toxicity have been validated, and are potentially ready for clinical application as risk factors to add information to personalized medicine knowledge base. Methods The current umbrella systematic review on the pharmacogenetics of FU and platinum chemotherapy-induced toxicities followed an a priori published protocol [22] . Inclusion criteria Types of participants

Systematic reviews that included patients with cancer of any type, stage of progression or severity, who received FU or platinum of any schedule or ­formulation were considered were included. Types of exposure

Systematic reviews that evaluated any form of germline polymorphism (e.g., SNPs, short tandem repeats and deletions), whether detected by candidate gene analysis or genome-wide association study, were included. If race, ethnicity or sex were used in place of defined polymorphisms, the review was excluded. Types of outcomes

Systematic reviews that included any FU- or platinuminduced toxicities, adverse events or side effects as outcome measures, as defined by any edition or volume of the common terminology criteria for adverse events, National Cancer Institute Common Toxicity Criteria (NCI–CTC) or any other organizational-, national- or laboratory-specific system, were included. Although measures of treatment-related mortality, treatment termination or treatment reduction were eligible for inclusion, no systematic reviews were found that reported on those outcomes.

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Fluoropyrimidine & platinum toxicity pharmacogenetics 

Types of studies

Data collection

All systematic reviews, including those that synthesized data through narrative synthesis and those that utilized meta-analysis, were included. Where metaanalyses were not presented as part of a systematic review they were excluded, as without a systematic search and defined inclusion criteria they would be open to bias.

Data extraction from the included systematic reviews was carried out using the standardized data extraction tool from JBI-Umbrella Review Assessment and Review of Information (Supplementary Material 3 [23]). The extracted data included specific details about the models, populations, study methods and outcomes of significance to the review question.

Search strategy

Data synthesis

A three-step search strategy was utilized in this review which aimed to find all published and unpublished systematic reviews. An initial limited search of PubMed and EMBASE was undertaken to identify potentially relevant articles, followed by an analysis of titles, abstracts and article index terms. A second search using these keywords and index terms was then undertaken across all included databases. Thirdly, the reference lists of all included systematic reviews were searched for additional reviews. Systematic reviews published in English were considered for inclusion in this review. Only reviews published within the last 5 years, from 2009 to the date of the search (July 2014), were included, as systematic reviews conducted more than 5 years previously would not be ­sufficiently up to date. The included databases were PubMed, EMBASE, Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Database of Abstracts of Reviews of Effects and ProQuest Dissertations and Theses Database. The Cochrane database is indexed in PubMed so was not individually searched. Preliminary key words used were neoplasm, cancer; genotype, genetic variation, polymorphism, pharmacogenetics; drug therapy, chemotherapy, adverse, toxic, toxicities, toxicity, systematic, meta-analysis, HuGE review. The full details of the searches carried out in each database are reported in Supplementary Material 1.

Where overall effect estimates or other similar numerical data were presented in included systematic reviews, findings have been presented through the use of tables. Included reviews presented effect estimates as odds ratios (ORs) or risk ratios (RRs) with 95% CI. The number of studies that have contributed to the outcomes, the number of participants (from included studies) and the heterogeneity of the data are reported. Where there was any overlap of primary research studies between the included systematic reviews (i.e., one study is included across more than one reviews), it has been noted.

Assessment of methodological quality

Systematic reviews that met the inclusion criteria were assessed by two independent reviewers for methodological validity prior to their inclusion in the umbrella review using a standardized critical appraisal instruments from the JBI-Umbrella Review Assessment and Review of Information (Supplementary Material 2 [23]). All disagreements that arose between the reviewers were resolved through discussion; however a third reviewer was available to settle disputes. If a systematic review had fewer than five ‘Yes’ responses (out of a maximum of 11) it would not be included. Systematic reviews with a ‘No’ for question 8 (inappropriate method of study combination; Table 1) were to be ­automatically excluded.

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Results The initial search obtained 290 hits, which was reduced to 250 following the removal of duplicates (Figure 1) . Following the review of titles and abstracts 32 full texts were retrieved for further review, of which six systematic reviews met all of the inclusion criteria. For FU, four systematic reviews were found that investigated the relationship between polymorphisms and toxicity in cancer patients [24–27] . Three of these reviews utilized meta-analysis for toxicity outcomes [24–26] , while the fourth did not [27] . For platinum, three systematic reviews were found that investigated the relationship between polymorphisms and toxicity in cancer patients  [27–29] , one of which utilized meta-analysis for toxicity outcomes [28] , while the other two did not [27,29] . One systematic review investigated both FU and platinum-induced toxicity [27] . Studies that were excluded from the umbrella systematic review at the full-text stage and the reasons for their exclusion are reported in Supplementary Material 4. No systematic reviews were excluded on the basis of critical appraisal for FU or platinum (Table 1 & Figure 1) . One review (Wang et al.  [27]) is included in Table 1 twice as it investigated both FU and platinumbased chemotherapies. For FU, critical appraisal (Q5) was only performed in one review [26] , and never by two reviewers working independently (Q5; Table 1). A similar pattern was seen for platinum where one systematic review did perform critical appraisal, but not by appropriate criteria [28] . Two of the three systematic reviews found for platinum (including Wang et al. [27]) did not

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10.2217/pgs.15.180 Y Y Y 4

Terrazzino et al. (2013)

Wang et al. (2012)

Total/4

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Y 3

Wang et al. (2012)

Yang et al. (2014)

Total/3

3

Y

Y

Y

4

Y

Y

Y

Y

Q2

3

Y

Y

Y

4

Y

Y

Y

Y

Q3

Q1: Is the review question clearly stated? Q2: Were the inclusion criteria appropriate for the review question? Q3: Was the search strategy appropriate? Q4: Were the sources and resources used to search for studies adequate? Q5: Were the criteria for appraising studies appropriate? Q6: Was critical appraisal conducted by two or more reviewers independently? Q7: Were there methods to minimize errors in data extraction? Q8: Were the methods used to combine studies appropriate? Q9: Was the likelihood of publication bias assessed? Q10: Were recommendations for policy and/or practice supported by the reported data? Q11: Were the specific directives for new research appropriate? N: No; NA: Not applicable, U: Unclear; Y: Yes.

Y Y

Peng et al. (2013)

Platinum

Y

Rosmarin et al. (2014)

Q1

Jennings et al. (2012)

Fluoropyrimidine

Study (year)

3

Y

Y

Y

4

Y

Y

Y

Y

Q4

0

N

N

N

1

N

Y

U

N

Q5

0

NA

NA

N

0

NA

N

U

NA

Q6

3

Y

Y

Y

4

Y

Y

Y

Y

Q7

3

Y

Y

Y

4

Y

Y

Y

Y

Q8

Table 1. Critical appraisal of systematic reviews including fluoropyrimidine or platinum-based chemotherapies.

2

Y

N

Y

3

N

Y

Y

Y

Q9

1

Y

NA

NA

3

NA

Y

Y

Y

Q10

3

Y

Y

Y

4

Y

Y

Y

Y

Q11

[29]

[27]

[28]

[27]

[26]

[25]

[24]

Ref.

Review  Campbell, Bateman, Peters, Bowen, Keefe & Stephenson

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Fluoropyrimidine & platinum toxicity pharmacogenetics 

Review

Papers found by search strategy n = 290

Removal of duplicates n = 250 Papers excluded by title/abstract n = 218 Full texts retrieved n = 32 Papers excluded by full text n = 14

Reviews on chemotherapies n = 18 Reviews not on FU or platinum n = 12 Reviews on platinum or FU critically appraised n=6

Reviews excluded by critical appraisal n=0

FU reviews included n=4

Platinum reviews included n=3

Figure 1. Search flowchart. Flowchart shows inclusions and exclusions as the search strategy progressed through the identified stages. FU: Fluoropyrimidine.

make recommendations for policy or practice relating to the pharmacogenetics of c­hemotherapy-induced ­toxicity and were therefore scored ‘NA’ (Q10). Characteristics of included systematic reviews Fluoropyrimidine

Jennings  et al.  [24] investigated genes with polymorphisms that have a functional impact on folate metabolism and adverse events from chemotherapy for colorectal cancer. Included polymorphisms were TYMS 5’ UTR and methylenetetrahydrofolate reductase (MTHFR) 677C>T. Dihydrofolate reductase (DHFR) was also investigated, however no studies were

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identified that included the analysis of DHFR genotypes. Meta-analyses were conducted using data for the recessive model (homozygous polymorphism compared with hetero or homozygous wild-type). Where data were available for multiple toxicities, the outcome with the most events associated and the highest grades reported (usually grade 3 or 4) was used to obtain an estimate of serious toxicity. Heterogeneity was assessed using the I2 test. Databases searched were MEDLINE and EMBASE, Biobase and Genetic Disease Association databases. Overall, ten studies published between 2001 and 2009 in Denmark, UK, France, Korea, ­Australia, Canada, China, Sweden, Spain, The

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Review  Campbell, Bateman, Peters, Bowen, Keefe & Stephenson Netherlands, Italy, Hungary, Taiwan, Japan, USA and ­Germany were included. Rosmarin et al. [25] investigated associations between 36 candidate polymorphisms, identified by a systematic review of FU-pathway polymorphisms and toxicity (grade ≥3) in patients treated with capecitabine and other FU schedules (infusional FU monotherapy, bolus FU monotherapy, FU combination therapy). Meta-analyses were performed using the allelic test of association model where each allele is considered independently (resulting in each patient being included in the analysis twice). This publication reported directly on primary data from a study conducted by the authors, as well as a systematic review and metaanalysis which incorporated the primary results. Heterogeneity was assessed by the Chi square test and the I2 test. Databases searched were PubMed and Google Scholar. Overall, 17 studies published between 2004 and 2014 in Denmark, France, UK, Spain, Australia, Sweden, Norway, Italy, North America and Germany were included. Terrazzino et al.  [26] investigated the impact of the dihydropyrimidine dehydrogenase (DPYD) variants IVS14+1G>A and 2846A>T on the risk of FU-related toxicities in cancer patients treated with FU, including 5-FU, capecitabine and tegafur-uracil. The primary outcome was overall grade ≥3 toxicity, the secondary outcomes were grade ≥3 hematologic, diarrhea or mucositis toxicity. Meta-analyses were conducted using data for the dominant model (heterozygous polymorphism compared with homozygous wild-type). Heterogeneity was assessed by the Chi square test and the I2 test. Databases searched were PubMed and Web of Knowledge. Overall, 15 studies published between 2004 and 2011 in Portugal, France, Germany, Poland, UK, Czech Republic, Switzerland, Denmark, Bosnia Herzegovina and The Netherlands were included. Wang et al. [27] investigated the association between polymorphisms of excision repair cross-complementation group 1 (ERCC1), glutathione S-transferases (GSTs), TYMS and MTHFR and toxicity outcomes from 5-FU-based chemotherapy for gastric cancer. Databases searched were PubMed and EMBASE. Only studies for TYMS (three studies) and MTHFR (three studies) were found, which, due to differences in evaluation criteria, were not combined by metaanalysis. Overall, four studies published between 2004 and 2010 in Korea, China, Japan and Germany were included. There was extensive overlap between ­Jennings et al. [24] and Rosmarin et al.  [25] with six studies being shared, limited overlap between Rosmarin et al.  [25] and Terrazzino et al.  [26] with four studies being shared, and little overlap between ­Jennings et al.  [24]

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and Terrazzino et al.  [26] with one study being shared. Overall, only one study was included in all three of these systematic reviews [30] . Wang et al.  [27] did not have any studies in common with the other systematic reviews. The characteristics of the included systematic reviews are summarized in Supplementary Material 5. Notably, only one of the included reviews searched for gray literature [25] . Platinum

Peng  et al.  [28] investigated the relationship between the glutathione-S-transferase pi 1 (GSTP1) gene Ile105Val polymorphism and oxaliplatin-induced neuropathy in adult (≥18 years) cancer patients. Where the oxaliplatin-specific scale was used to grade neuropathy in primary studies, data were extracted for grade ≥2 neurotoxicity, while when the National Cancer Institute common toxicity criteria were used, data were extracted for grade ≥3 neurotoxicity (the authors noted that this distinction was made on the basis of clinical relevance). Heterogeneity was assessed by Dersimonian and Laird’s Q test and the I2 test. Databases searched were PubMed, EMBASE and the Cochrane library. Overall, 14 studies published between 2006 and 2013 in China, Taiwan, Spain, Korea, Canada, Japan, France, Netherlands, Germany and Italy were included. Yang et al. [29] investigated the relationship between polymorphisms of ERCC1 (C118T and C8092A) and ERCC2 (Asp312Asn and Lys751Gln) and toxicity in NSCLC patients treated with platinum-based chemotherapy. Databases searched were PubMed, EMBASE and the China National Knowledge Infrastructure database. Due to differences in evaluation criteria, results were not combined in meta-analysis despite numerous studies being found for ERCC1 polymorphisms (12 studies) and ERCC2 polymorphisms (14 studies). Overall, 16 studies published between 2004 and 2013 in Spain, Italy, Greece, Netherlands, Japan, USA and China were included. Wang et al. [27] investigated the relationship between the same genes for platinum-induced toxicity in gastric cancer patients as they did for FU-induced toxicity (ERCC1, GSTs, TYMS and MTHFR). Databases (PubMed and EMBASE) were also the same. Only studies for ERCC1 (two studies) and GSTs (two studies) were found. Due to differences in evaluation criteria results were not combined in meta-analysis. Overall three studies published between 2009 and 2010 in Korea, China and Germany were included. As stated above, Wang et al.  [27] included few studies. Of these, two out of three were also included in Peng et al. [28] . However, there was no overlap between Yang et al. [29] and Peng et al. [28] . The ­methodological

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Treatment (population)

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Capecitabine (Caucasian)

Capecitabine (Caucasian)

Infusional FU (Caucasian)

Infusional FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

 

 

DPYD*2A IVS14+1G>A

 

DPYD 496A>G

 

 

 

DPYD*5 1627A>G

 

 

 

FU

FU

FU

FU

FU

 

 

 

DPYD 2846A>T

 

Diarrhea

Global

Mucositis

Diarrhea

Hematological

Global

Neutropenia

Mucositis/ stomatitis

Diarrhea

Global

Neutropenia

Mucositis/ stomatitis

Diarrhea

Global

Diarrhea

Global

HFS

Diarrhea

Global

Toxicity

FU: Fluoropyrimidine; HFS: Hand–foot syndrome; NR: Not reported; OR: Odds ratio.

FU

DPYD IVS14+1G>A

Terrazzino (dominant model)

Capecitabine (Caucasian)

DPYD*2A IVS14+1G>A

Rosmarin (allelic association)

Polymorphism

Table 2. DPYD meta-analyses findings.

3

6

5

6

7

13

2

2

2

2

2

2

2

2

2

2

2

2

2

Studies (n)

721

2308

1015

1526

1554

3499

452

452

452

452

379

379

379

379

720

732

1033

1035

1035

Population (n)

6.04

8.18

7.48

5.54

15.77

5.42

0.73

0.49

0.79

0.71

1.17

0.92

1.40

1.25

7.71

6.71

1.98

3.14

3.02

OR

1.77–20.66

2.65–25.25

3.03–18.47

2.31–13.29

6.36–39.06

2.79–10.52

0.35–1.51

0.27–0.88

0.49–1.28

0.49–1.02

0.52–2.60

0.47–1.79

0.81–2.42

0.78–2.03

1.61–36.9

1.66–27.71

0.52–7.54

0.71–13.9

0.78–11.7

95% CI

0.004

A variant allele and global toxicity following FU treatment (OR: 5.42; 95% CI: 2.79–10.52). No significant publication bias was found, and exclusion of individual studies did not substantially alter the result. Furthermore, patients carrying the DPYD IVS14+1G>A polymorphism had an increased risk of hemato­logical toxicity (OR: 15.77; 95% CI: 6.36–39.06), diarrhea (OR: 5.54; 95% CI: 2.31–13.29) and mucositis (OR: 7.48; 95% CI: 3.03–18.47). For DPYD 2846A>T meta-analysis using the random-effects model showed a clinically significant association between carrying the DPYD 2846T allele and global toxicity (OR: 8.18; 95% CI: 2.65–25.25) from FU-based chemotherapy [26] . Moderate hetero­ geneity was present and was statistically significant by the p T and global toxicity was found only among studies with a lower incidence of global toxicity (OR: 16.59; 95% CI: 5.06–54.43; p T variant allele and global toxicity when analysis was restricted to prospective studies (OR: 18.14; 95% CI: 6.26–52.58; p T polymorphism and toxicity in colorectal cancer patients treated with 5-FU-based chemotherapy. Substantial heterogeneity was found between studies and the random-effects model was used. Sensitivity analysis did not show any substantial changes to the overall results. However, Rosmarin et al. [25] found that for bolus FU monotherapy MTHFR 677C>T had a significant protective effect for neutropenia (OR: 0.60; 95% CI: 0.37–0.97) and a borderline protective effect for global toxicity (OR: 0.79; 95% CI: 0.62–1.00), but no significant effects for diarrhea or mucositis. Wang et al. [27] included two studies that found no significant associations between MTHFR polymorphisms and toxicity in patients with gastric cancer treated with 5-FU-based chemotherapy, however one study reported that MTHFR TT (homozygous variant) was associated with a higher frequency of nonhematologic toxicity (nausea/vomiting) (p = 0.002). Additional genes

Rosmarin et al. [25] investigated a number of genes that were not included in any of the other systematic reviews (CDA, CES2, TYMP; Supplementary Material 7). The only significant findings were made for TYMP where TYMP intronic rs470119 was found to have a trend for a small protective effect at the global level (OR: 0.85; 95% CI: 0.70–1.02) in Caucasian patients who received capecitabine monotherapy, and a significant effect for HFS (OR: 0.80; 95% CI: 0.65–0.99). Conclusions from included FU reviews

Terrazino  et al.  [26] concluded that their results confirmed the clinical validity of DPYD polymorphisms for the prediction of the development of severe toxicities following fluoropyrimidine treatment, as did Rosmarin  et al.  [25] , specifically for capecitabine toxicity (while also noting a possible association with toxicity in other FU monotherapy regimens). Rosmarin et al. also noted that TYMS 5´UTR 2R/3R and TYMS 3´UTR 6 bp ins/del were significant predictors of toxicity, however, Jennings et al. – who found similar relationships for TYMS polymorphisms with toxicity from 5-FU chemotherapy for colorectal cancer – noted that

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Treatment (population)

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5-FU (colorectal)

Capecitabine (Caucasian)

Capecitabine (Caucasian)

Capecitabine (Caucasian)

Capecitabine (Caucasian)

Capecitabine (Caucasian)

Infusional FU (Caucasian)

Infusional FU (Caucasian)

Infusional FU (Caucasian)

Infusional FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

Bolus FU(Caucasian)

Bolus FU (Caucasian)

Bolus FU (Caucasian)

 

 

MTHFR 1298A>C

 

 

MTHFR 677C>T

 

MTHFR 1298A>C

 

MTHFR 677C>T

 

 

 

MTHFR 1298A>C

 

 

 

Neutropenia

Mucositis/ stomatitis

Diarrhea

Global

Neutropenia

Mucositis/ stomatitis

Diarrhea

Global

Diarrhea

Global

Diarrhea

Global

HFS

Diarrhea

Global

HFS

Diarrhea

Global

Any

Toxicity

FU: Fluoropyrimidine; HFS: Hand–foot syndrome; NR: Not reported; OR: Odds ratio; RR: Risk ratio.

Capecitabine (Caucasian)

MTHFR 677C>T

Rosmarin (allelic association)

MTHFR 677C>T

Jennings (recessive model)

Polymorphism

Table 4. MTHFR meta-analysis findings.

3

3

3

3

3

3

3

3

2

2

3

3

3

3

3

3

3

3

6

Studies (n) 

786

786

786

786

788

788

788

788

474

474

1112

1129

1058

1059

1051

1066

1068

1061

2524

Population (n)

OR: 1.36

OR: 0.98

OR: 1.01

OR: 1.03

OR: 0.60

OR: 0.99

OR: 0.75

OR: 0.79

OR: 0.88

OR: 1.01

OR: 0.88

OR: 0.92

OR: 1.04

OR: 0.99

OR: 0.97

OR: 1.05

OR: 1.03

OR: 1.09

RR: 1.24

OR/RR

0.90–2.06

0.73–1.32

0.74–1.39

0.81–1.29

0.37–0.97

0.73–1.33

0.54–1.06

0.62–1.00

0.52–1.49

0.67–1.53

0.58–1.33

0.70–1.22

0.84–1.30

0.73–1.34

0.79–1.18

0.85–1.32

0.76–1.39

0.89–1.32

0.87–1.78

95% CI:

0.14

0.88

0.94

0.83

0.039

0.93

0.10

0.05

0.64

0.94

0.54

0.57

0.71

0.97

0.74

0.64

0.85

0.40

0.24

p-value

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

p = 0.35

p = 0.27

p = 0.20

p = 0.95

p = 0.45

p = 0.74

p = 0.008; I2 = 68%

Heterogeneity

Fluoropyrimidine & platinum toxicity pharmacogenetics 

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Review  Campbell, Bateman, Peters, Bowen, Keefe & Stephenson the effect size was small and indicated ­limited clinical utility [24] . Jennings et al., also concluded that their findings did not support the use of MTHFR genotyping for the prediction of 5-FU-based chemotherapy toxicity in colorectal cancer [24] . Based on their findings Rosmarin et al.  [25] , recommended that there are unwarranted polymorphisms included in currently available FU toxicity tests which could be excluded to improve performance and lower costs, although they noted that a genetic test comprised of the polymorphisms they have ‘validated’ would only provide modest predictive power (estimated 26% sensitivity, 86% specificity and 49% positive predictive power). Finally, Wang et al. did not make any conclusions with regards to their findings for the association of polymorphisms of the TYMS and MTHFR genes and toxicity from 5-FU-based chemotherapy for gastric cancer [27] . Platinum-induced toxicity

in patients with gastric cancer, and two studies that found an association between GSTP1 poly­morphisms and toxicity. Both found that patients with the GSTP1–105 A/A genotype were at significantly higher risk of experiencing hematological and neurological toxicity compared with patients with the A/G or G/G genotypes. Both of the two studies that reported significant differences in Wang et al. were included in the meta-analysis conducted by Peng et al.,  [28] who ultimately found no statistically significant difference. Yang et al.  [29] also did not undertake meta-analysis. From the 16 included studies, one study found that ERCC2 Asp/Asp was associated with grade 2–4 neutropenia, and one study found that ERCC2 Lys/Gln was associated with grade ≥3 vomiting/nausea as well as alopecia. None of the other 14 studies reported any significant associations between the ERCC1/2 SNPs of interest and ­platinum-induced toxicity in patients with NSCLC.

Meta-analyses

Only one of the systematic reviews, Peng et al.  [28] undertook meta-analysis. They found no significant association between the GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy under the dominant model (AA or AG vs GG; OR: 1.08; 95% CI: 0.67–1.74, 14 studies, 2191 patients, p = 0.754; I2 = 67.9%; p T was also shown to greatly increase the likelihood of toxicity in patients who undertook FU-based chemotherapy. Polymorphisms of TYMS were also consistently found to have a statistically significant relationship with FU-induced toxicity; however, this relationship was comparatively weak and lacked clinical significance. In one systematic review, a risk score was used to investigate the utility of simultaneous consideration of at-risk polymorphisms (TYMS 5´UTR 2R/3R and 3´UTR 6 bp ins/del), and although significant associations with global toxicity were found for Caucasian patients treated with capecitabine or infusional FU, in

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Fluoropyrimidine & platinum toxicity pharmacogenetics 

both cases the OR was ≤1.3  [25] . MTHFR was largely not found to have any association with FU-induced toxicity, with the exception of a small protective effect for bolus FU in Caucasian cancer patients [25] , and it was recommended that MTHFR should not be used for the prediction of FU-induced toxicity [24] . No significant associations were found for platinum-induced toxicity, with the sole meta-analysis performed resulting only in the conclusion that there was no evidence to support GSTP1 Ile105Val being associated with ­oxaliplatin-induced neuropathy. The DPYD alleles IVS14+1G>A and 2846A>T are both loss-of-function mutations, IVS14+1G>A being the most commonly found example thereof. They result in the product of the DPYD gene, the enzyme DPD, being unable to perform its normal function, which is the rate-limiting step in pyrimidine catabolism. This prevents FU clearance, resulting in drug build-up, which is believed to be the cause of the associated toxicity [31,32] . The presence of these polymorphisms has been found to not affect overall survival or progression free survival (in patients with advanced colorectal cancer treated with capecitabine), although they are associated with mean dose reductions of 50 and 25%, respectively, due to severe toxicity [33] . Consequently, it has been recommended that carriers of these polymorphisms should receive initial dose reductions followed by further dose titrations on clinical tolerability in order to reduce the risk of severe toxicity while maintaining their likelihood of response to treatment [33,34] . The findings of the included systematic reviews supported this recommendation [25,26] although clinical trials to establish the actual effectiveness (and c­ost­– ­effectiveness) of this proposed strategy are still needed. One prospective study has been conducted which concluded that screening for DPYD IVS14+1G>A, with dose reduction in heterozygous patients, was effective at reducing the incidence of severe toxicity compared with a historic control group of unscreened patients [35] . However, this finding has not been replicated and further research is needed. Interestingly, one included review found that DPYD IVS14+1G>A had an increased impact in studies with an overall lower rate of severe FU-induced toxicity  [26] . They hypothesized that it was due to DPYD IVS14+1G>A being present in only 1.5% of the population, and therefore only exerting a notable influence when other causes of toxicity had been ameliorated. The nature of TYMS’ involvement in FU-induced toxicity differs greatly from that of DPYD. FU is an inhibitor of the TYMS enzyme, which is one of its primary means of therapeutic effect, and sufficiently low TYMS activity results in adverse outcomes. [24,36,37] As such, the decreased TYMS expression that is associated

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with the TYMS polymorphisms 5´UTR 2R and 3´UTR 6 bp ins/del [38–40] , is reasoned to be why patients who are carriers are more susceptible to ­FU-induced toxicity. Interestingly, TYMS polymorphisms have been extensively investigated for their association with clinical outcome. It was shown by meta-analysis that TYMS 5´UTR 2R/2R was significantly associated with increased likelihood of a colorectal cancer patient having a clinical benefit from the FU treatment [24] . However, as with the effect of TYMS polymorphisms on toxicity, this effect was not clinically significant. TYMS genotype could possibly be incorporated into a panel of other prognostic markers, however its effect on clinical outcome means that, unlike DPYD, adjusting FU dose to decrease the likelihood of toxicity could result in some patients having their likelihood of a beneficial outcome from FU chemotherapy reduced. As such, personalized FU dosing informed by TYMS genotype could only be applied after exhaustive investigation of the effect of pre-emptive dose reduction on patient survival. Based on the clinically nonsignificant effect that TYMS polymorphisms have on FU-induced toxicity, research efforts and resources would be better directed elsewhere. However, TYMS genotyping could be used to inform the institution of prophylactic ­measures or increased surveillance. One research gap identified by this umbrella review was that meta-analyses have not been carried out on the association between several less common polymorphisms of DPYD that have been found to be associated with FU-induced toxicity (such as DPYD*3, DPYD*13 and DPYD rs67376798T>A [33,34,41,42]) or the DPYD haplotype B3, which has been identified as being predictive of FU-induced toxicities [43] . Additionally, no subgroup analyses by ethnicity (which influenced allelic frequency for both DPYD and TYMS  [44]), dosage or cancer types were carried out. These are important considerations for providing clinicians with greater certainty that results and recommendations have applicability to their clinical context. Schedule of administration, however, was very thoroughly investigated by Rosmarin et al.  [25] . With regards to platinum, the identified systematic reviews were mostly unable to carry out meta-analyses and were generally very specific with regard to type of cancer, toxicity or gene investigated. Looser inclusion criteria in the conduct of systematic reviews in this field could be warranted, however it should be noted that in the case of Yang  et al.  [29] the lack of meta-analyses was due to heterogeneity of toxicity evaluation criteria. For FU, the critical appraisal of included systematic reviews indicated that, overall, the methodologies of systematic reviews in this area were thorough. One exception to this was conduct of critical appraisal in

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Review  Campbell, Bateman, Peters, Bowen, Keefe & Stephenson the systematic reviews themselves. Two did not carry out critical appraisal at all, one did but it was by a single reviewer working alone contrary to accepted standards [45] , and a fourth did not report sufficient details on the process to make decisions on the appropriateness of its conduct. Critical appraisal is an important step of the systematic review process, and is doubly important for systematic reviews conducted in the field of pharmacogenetics where an increased risk of bias [46,47] , and false positives [21] are generally acknowledged. Similarly, none of the systematic reviews on platinum-induced toxicity carried out appropriate critical appraisal. Recommendations for policy or practice (question 10) were also rarely made; however, this was generally due to none being warranted based on the reviews’ findings. Although there were numerous instances of primary studies being included in more than one systematic review (and one instance of a primary study being included in three systematic reviews), all reviews were conducted with large differences in their focus. In particular, Rosmarin et al. [25] , which included numerous studies that were also in Terrazzino et al.  [26] and ­Jennings  et al. [24] , was extremely granular and specific in the conduct of its meta-analysis and produced a number of overall effect estimates based on few primary studies. This has been compensated for by the other two reviews which investigated the same genes, and many of the same polymorphisms, but in a more general way. These reviews, therefore, were able to make less detailed but statistically more powerful findings. Unlike primary research, little is gained by the replication of up to date systematic reviews. As such, if an umbrella review only finds systematic reviews conducted in the same way, on the same topic, containing the same papers, it does not add significantly to the field of knowledge. The synthesis of findings that is presented in this umbrella systematic review, however, provides a comprehensive overview of what pharmacogenetic makers have been validated by replication and meta-analysis as being associated with FU-induced toxicity, and should serve as a useful resource for researchers and clinicians alike. For platinum-based chemotherapy, Wang et al. [27] included very few studies and only one was not included in Peng et al.  [28] . However, Yang et al.  [29] and Peng et al.  [28] did not have any overlap. A limitation of this umbrella systematic review is that it did not find any systematic reviews that investigated dose reduction or delays (although a survey of the primary literature suggests that reporting on these outcomes for the pharmacogenetics of FU-induced toxicity may be limited). Additionally, it was specified in the a priori protocol that only toxicity outcomes, and not those relating to patient survival or

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Pharmacogenomics (Epub ahead of print)

disease progression, would be included in the review. This information provides important context for toxicity data and would have strengthened this umbrella review. Finally, only reviews published in English were included. Conclusion This umbrella systematic review has identified all relevant systematic reviews and meta-analyses that bring together and validate the findings of primary studies on the pharmacogenetics of FU or platinum-induced toxicity. The loss of function DPYD polymorphisms IVS14+1G>A and 2846A>T were the only pharmacogenetic markers that were found to have clinical and statistical significance for the predication of FU-induced toxicity. Important research gaps for future systematic reviews have been identified and discussed. However, the most pressing need for research is primary studies that investigate the clinical and ­cost­– ­effectiveness of genotyping patients undergoing FU-based chemotherapy for these DPYD polymorphisms, so that clinicians finally have evidence as to whether they can be applied in personalized medicine to reduce morbidity and mortality resulting from chemotherapy toxicity. Future perspective The competing demand for safety and efficacy in chemotherapy is not a problem which will be resolved soon. However, research on the pharmacogenetics of toxicity is nearing the point where it will be able to make a meaningful contribution to the issue. Technological advances are steadily improving the cost–effectiveness of genetic testing, which will bring personalized medicine, informed by patients’ individual genetic information, into the reach of most if not all patients, depending on the setting. Better informed decisions regarding choice of drug and dosage for chemotherapy will lead to improvements in patients’ quality and length of life, mitigating the societal impact of cancer. Supplementary data To view the supplementary data that accompany this paper, please visit the journal website at: www.futuremedicine.com/ doi/full/10.2217/pgs.15.180

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert ­testimony, grants or patents received or pending, or ­royalties. No writing assistance was utilized in the production of this manuscript.

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Review

Executive summary The pharmacogenetics of fluoropyrimidine toxicity • DPYD genotyping, specifically for the IVS14+1G>A and 2846A>T polymorphisms, statistically and clinically predicts fluoropyrimidine (FU)-induced toxicity. • Primary studies that investigate the clinical and cost–effectiveness of DPYD genotyping to inform FU-based chemotherapy are needed. • TYMS genotyping, specifically for the 5´UTR 2R and 3´UTR 6 bp ins/del polymorphisms, predicts FU-induced toxicity with statistical, but not clinical, significance. • Coupled with the fact that TYMS loss-of-function polymorphisms are associated with improved mortality, this makes it a poor candidate biomarker for informing FU dosage. • MTHFR polymorphisms do not predict FU-induced toxicity.

The pharmacogenetics of platinum toxicity • GSTP1 genotyping, specifically for the Ile105Val polymorphism, does not predict platinum-induced toxicity. • There is no strong evidence for pharmacogenetic biomarkers for platinum-induced toxicity. significantly associated with gender, increasing age and cycle number. Tomudex International Study Group. Eur. J. Cancer 34(12), 1871–1875 (1998).

References Papers of special note have been highlighted as: • of interest Scartozzi M, Maccaroni E, Giampieri R et al. 5-fluorouracil pharmacogenomics: still rocking after all these years? Pharmacogenomics 12(2), 251–265 (2011).

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Li QF, Yao RY, Liu KW, Lv HY, Jiang T, Liang J. Genetic polymorphism of GSTP1: prediction of clinical outcome to oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. J. Korean Med. Sci. 25(6), 846–852 (2010).

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Campbell JM, Peters MDJ. The association of chemotherapyinduced toxicities with germline polymorphisms: an umbrella review of systematic reviews and meta-analyses. JBISRIR 12(10), 40–46 (2014).

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Yang Y, Xian L. The association between the ERCC1/2 polymorphisms and the clinical outcomes of the platinumbased chemotherapy in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis. Tumour Biol. 35(4), 2905–2921 (2014).



A systematic review that met the inclusion criteria of this umbrella review. Investigated the pharmacogenetics of ERCC1/2 SNPs in non-small-cell lung cancer platinuminduced toxicity.

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Braun MS, Richman SD, Thompson L et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J. Clin. Oncol. 27(33), 5519–5528 (2009).

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Lee A, Ezzeldin H, Fourie J, Diasio R. Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy. Clin. Adv. Hematol. Oncol. 2(8), 527–532 (2004).

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Deenen MJ, Tol J, Burylo AM et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin. Cancer Res. 17(10), 3455–3468 (2011).

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Caudle KE, Thorn CF, Klein TE et al. Clinical pharmacogenetics implementation consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin. Pharmacol. Ther. 94(6), 640–645 (2013).

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Deenen MJ, Cats A, Mandigers CM et al. Prevention of severe toxicity from capecitabine, 5-fluorouracil and tegafur by screening for DPD-deficiency. Ned. Tijdschr. Geneeskd. 156(48), A4934 (2012).

A systematic review that met the inclusion criteria of this umbrella review. Investigated the pharmacogenetics of the DPYD variants IVS14+1G>A and 2846A>T and fluoropyrimidine-induced toxicities as well as the sensitivity and specificity of DPYD variants for the prediciton of toxicity.

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Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J. Clin. Oncol. 6(10), 1653–1664 (1988).

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Papamichael D. The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status. Stem Cells 18(3), 166–175 (2000).

Wang Z, Chen JQ, Liu JL, Qin XG, Huang Y. Polymorphisms in ERCC1, GSTs, TS and MTHFR predict clinical outcomes of gastric cancer patients treated with platinum/5-Fu-based chemotherapy: a systematic review. BMC Gastroenterol. 12, 137 (2012).

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Matsusaka S, Lenz HJ. Pharmacogenomics of fluorouracil -based chemotherapy toxicity. Expert Opin. Drug Metabol. Toxicol. 11(5), 811–821 (2015).

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Mandola MV, Stoehlmacher J, Muller-Weeks S et al. A novel single nucleotide polymorphism within the 5´ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF–1 binding and alters transcriptional activity. Cancer Res. 63(11), 2898–2904 (2003).

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Zhang QA, Zhao YP, Liao QA et al. Associations between gene polymorphisms of thymidylate synthase with its protein expression and chemosensitivity to 5-fluorouracil in pancreatic carcinoma cells. Chinese Med. J. 124(2), 262–267 (2011).

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Van Kuilenburg AB, Haasjes J, Richel DJ et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin. Cancer Res. 6(12), 4705–4712 (2000).

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Jennings BA, Kwok CS, Willis G, Matthews V, Wawruch P, Loke YK. Functional polymorphisms of folate metabolism and response to chemotherapy for colorectal cancer, a systematic review and meta-analysis. Pharmacogenet. Genomics 22(4), 290–304 (2012).



A systematic review that met the inclusion criteria of this umbrella review. Investigated the pharmacogenetics of of functional polymorphisms of folate metabolism (TYMS, MTHFR, DHFR) on response to chemotherapy, including toxicity, for colorectal cancer.

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Rosmarin D, Palles C, Church D et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J. Clin. Oncol. 32(10), 1031–1039 (2014). A systematic review that also reported on the findings of a primary study that met the inclusion criteria of this umbrella review. Invesitgated the pharmacogenetics of a wide range of polymorphisms for toxicity induced by capecitabine and other fluoropyrimidine schedules. Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA. DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidinerelated toxicity: a meta-analysis. Pharmacogenomics 14(11), 1255–1272 (2013).

A sytematic review that met the inclusion criteria of this umbrella review. Investigated the pharmacogeneitics of polymorphisms of ERCC1, GSTs, TS and MTHFR in predicting clinical outcomes of gastric cancer patients treated with 5-Fu or platinum-based chemotherapies.

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Peng Z, Wang Q, Gao J et al. Association between GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy: a systematic review and meta-analysis. Cancer Chemother. Pharmacol. 72(2), 305–314 (2013).



A systematic review that met the inclusion criteria of this umbrella review. Investigated the pharmacogenetics of GSTP1 Ile105Val and neurotoxicity induced by oxaliplatin in cancer chemotherapy.

Pharmacogenomics (Epub ahead of print)

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Vreken P, Van Kuilenburg AB, Meinsma R, Van Gennip AH. Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum. Genet. 101(3), 333–338 (1997).

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Shamseer L, Moher D, Clarke M et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 349, g7647 (2015).

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Caudle KE, Thorn CF, Klein TE et al. Clinical pharmacogenetics implementation consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin. Pharmacol. Ther. 94(6), 640–645 (2013).

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Wood L, Egger M, Gluud LL et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 336(7644), 601–605 (2008).

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Suzen HS, Yuce N, Guvenc G, Duydu Y, Erke T. TYMS and DPYD polymorphisms in a Turkish population. Eur. J. Clin. Pharmacol. 61(12), 881–885 (2005).

Balk EM, Bonis PA, Moskowitz H et al. Correlation of quality measures with estimates of treatment effect in metaanalyses of randomized controlled trials. JAMA 287(22), 2973–2982 (2002).

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Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthe...
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