Pharmacogenomics

The clinical effectiveness and costeffectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: A systematic review

by Nigel Fleeman

Co-authored with Saborido, C. M. Payne, K. Boland, A. Dickson, R. Dundar, Y. Santander, A. F. Howell, S. Newman, W. Oyee, J. Walley, T.

Background: Breast cancer is the most common cancer affecting women in the UK. Tamoxifen (TAM) is considered as the... more Background: Breast cancer is the most common cancer affecting women in the UK. Tamoxifen (TAM) is considered as the standard of care for many women with oestrogen receptor positive breast cancer. However, wide variability in the response of individuals to drugs at the same doses may occur, which may be a result of interindividual genetic differences (pharmacogenetics). TAM is known to be metabolised to its active metabolites N-desmethyl TAM and 4-hydroxytamoxifen by a number of CYP450 enzymes, including CYP2D6, CYP3A4, CYP2C9, CYP2C19 and CYP2B6. N-desmethyl TAM is further metabolised to endoxifen by CYP2D6. Endoxifen, which is also formed via the action of CYP2D6, is 30- to 100-fold more potent than TAM in suppressing oestrogen-dependent cell proliferation, and is considered an entity responsible for significant pharmacological effects of TAM. Thus, an association between the cytochrome P450 2D6 (CYP2D6) genotype and phenotype (expected drug effects) is believed to exist and it has been postulated that CYP2D6 testing may play a role in optimising an individual's adjuvant hormonal treatment. Objectives: To determine whether or not testing for cytochrome P450 2D6 (CYP2D6) polymorphisms in women with early hormone receptor positive breast cancer leads to improvement in outcomes, is useful for health decision-making and is a cost-effective use of health-care resources. Data sources: Relevant electronic databases and websites including MEDLINE, EMBASE and HuGENet™ [Centers for Disease Control and Prevention (Office of Public Health Genomics), Human Genome Epidemiology Network] were searched until July 2009. Further studies that became known to the authors via relevant conferences or e-mail alerts from an automatically updated search of the Scopus database were also included as the review progressed, up to March 2010. Review methods: A systematic review of the clinical effectiveness and cost-effectiveness of CYP2D6 testing was undertaken. As it was not possible to conduct meta-analyses, data were extracted into structured tables and narratively discussed. An exploratory analysis of sensitivity and specificity was undertaken. A review of economic evaluations and models of CYP2D6 testing for patients treated with TAM was also carried out. Results: A total of 25 cohorts were identified which examined clinical efficacy (overall survival and relapse/recurrence), adverse events and endoxifen plasma concentrations by genotype/phenotype. Significantly, six cohorts suggest extensive metabolisers (Ems) appear to have better outcomes than either poor metabolisers (PMs) or PMs + intermediate metabolisers in terms of relapse/recurrence; however, three cohorts report apparently poorer outcomes for EMs (albeit not statistically significant). There was heterogeneity across the studies in terms of the patient population, alleles tested and outcomes used and defined. One decision model proposing a strategy for CYP2D6 testing for TAM was identified, but this was not suitable for developing a model to examine the costeffectiveness of CYP2D6 testing. It was not possible to produce a de novo model because of a lack of data to populate it. Conclusion: This is a relatively new area of research that is evolving rapidly and, although international consortia are collaborating, the data are limited and conflicting. Therefore, it is not possible to recommend pharmacogenetic testing in this patient population. Future research needs to focus on which alleles (including, or in addition to, those related to CYP2D6) reflect patient response, the link between endoxifen levels and clinical outcomes, and the appropriate pathways for implementation of such pharmacogenetic testing in patient care pathways. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic …

by Nigel Fleeman

Co-authored with Dundar, Y. Dickson, R. Jorgensen, A. Pushpakom, S. McLeod, C. Pirmohamed, M. Walley, T.

The attached PDF is an earlier draft of this paper - a copy of published paper may be available via PubMed

The full version of this report is available from
http://www.hta.ac.uk/fullmono/mon1403.pdf

There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been... more There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and meta-analyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.The Pharmacogenomics Journal advance online publication, 28 September 2010; doi:10.1038/tpj.2010.73.

Providing patients with information on pharmacogenetic testing

by Nigel Fleeman

Co-authored with Dickson, R

The attached paper is an earlier draft version - the published paper is available from the URL

This article outlines the key issues to be considered before recommending the use of pharmacogentic tests that may... more This article outlines the key issues to be considered before recommending the use of pharmacogentic tests that may predict a patient’s response to a particular drug

mRNA Transcript Diversity Creates New Opportunities for Pharmacological Intervention

by Ryan Smith

Published in Molecular Pharmacology 02/07/2012

Most protein coding genes generate multiple RNA transcripts through alternative splicing, variable 3' and 5'UTRs, and... more Most protein coding genes generate multiple RNA transcripts through alternative splicing, variable 3' and 5'UTRs, and RNA editing. While drug design typically targets the main transcript, alternative transcripts can have profound physiological effects, encoding proteins with distinct functions or regulatory properties. Formation of these alternative transcripts is tissue-selective and context-dependent, creating opportunities for more effective and targeted therapies with reduced adverse effects. Moreover, genetic variation can tilt the balance of alternative versus constitutive transcripts or generate aberrant transcripts that contribute to disease risk. Additionally, environmental factors and drugs modulate RNA splicing, affording new opportunities for the treatment of splicing disorders. For example, therapies targeting specific mRNA transcripts with splice-site directed oligonucleotides that correct aberrant splicing are already in clinical trials for genetic disorders such as Duchenne muscular dystrophy. High-throughput sequencing technologies facilitate discovery of novel RNA transcripts and protein isoforms, with applications ranging from neuromuscular disorders to cancer. Consideration of a gene’s transcript diversity should become an integral part of drug design, development, and therapy.

Treatment for tobacco dependence: a potential application for stratified medicine?

by Alistair Brock

Alistair J Brock, Andrea Takeda, Caroline Brennan & Robert T Walton. Personalized Medicine. 2011; 8(5):571–579.

Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on... more Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on society. Therefore, ways of helping people to overcome nicotine dependence are a key element of strategies aimed at improving public health. Current treatments are only partially effective and there is a need to develop more efficient approaches to help smokers to stop. There exists a substantial genetic variability in smoking behavior and the likelihood of cessation – tailoring treatment according to an individual’s genetic profile is now technologically feasible and could lead to more successful cessation attempts. Here we review studies of the genetic effects on smoking cessation in randomized controlled trials of pharmacological therapy and discuss the potential value of a personalized approach to help people stop smoking.

Might Community Pharmacists have a Role in Delivering Personalised Medicine?

by Kimberly Jamie

Published in The Pharmaceutical Journal

This article examines potential ways in which genetic technologies could be integrated into practice and outlines the... more This article examines potential ways in which genetic technologies could be integrated into practice and outlines the challenges for pharmacy that may arise.
Pharmacogenetics, or personalised medicine, is concerned with genetically determined variability in drug response. It is underpinned by the principle of providing the right therapy at the right dose in order to maximise benefits and minimise adverse effects. Adverse drug reactions (ADRs) are estimated to cost the NHS around £1.9bn annually with 6.5 per cent of hospital admissions being caused by ADRs and the equivalent of three 800-bed hospitals being permanently occupied by ADR patients.
Although some of these ADRs are predictable, dosage-related type A reactions, a strong relationship has been shown between genetic polymorphisms and non immune-mediated idiosyncratic type B reactions.
The most widely extolled clinical employment of pharmacogenetics is in pre-prescription testing, whereby patients are tested for genetic variations known to have an effect on drug metabolism in order to provide them with the most effective treatment at the most effective dosage.

Pharmacogenomics in clinical trials

by Jacob Lagercrantz

CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events: A Systematic Review and Meta-analysis

by Michael V Holmes

Co-authored with  Pablo Perel, Tina Shah, Aroon Hingorani and Juan P. Casas

Context The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to... more Context The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have argued evidence is insufficient to support CYP2C19 genotype testing.

Objective To appraise evidence on the association of CYP2C19 genotype and clopidogrel response through systematic review and meta-analysis.

Data Sources PubMed and EMBASE from their inception to October 2011.

Study Selection Studies that reported clopidogrel metabolism, platelet reactivity or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype were included.

Data Extraction We extracted information on study design, genotyping, and disease outcomes and investigated sources of bias.

Results We retrieved 32 studies of 42 016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. Six studies were randomized trials (“effect-modification” design) and the remaining 26 reported individuals exposed to clopidogrel (“treatment-only” design). In treatment-only analysis, individuals with 1 or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (relative risk [RR], 0.84; 95% CI, 0.75-0.94; absolute risk reduction of 5-8 events per 1000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09-1.28; absolute risk increase of 8-12 events per 1000 individuals). However, there was evidence of small-study bias (Harbord test P = .001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86-1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD end points or bleeding (P > .05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes.

Conclusion Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events.

Fulfilling the promise of personalized medicine? Systematic review and field synopsis of pharmacogenetic studies

by Michael V Holmes

Co-authored with Shah T, Vickery C, Smeeth L, Hingorani AD, Casas JP.

BACKGROUND: Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and... more BACKGROUND: Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).
OBJECTIVES:
We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.
DATA SOURCES:
Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans. STUDY APPRAISAL AND SYNTHESIS METHODS: Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.
RESULTS:
From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of >or=4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not Registered.

Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy

by Ryan Smith

The use of pharmacogenomic biomarkers can enhance treatment outcomes. Regulatory polymorphisms are promising... more The use of pharmacogenomic biomarkers can enhance treatment outcomes. Regulatory polymorphisms are promising biomarkers that have proven difficult to uncover. They come in two flavors: those that affect transcription (regulatory single-nucleotide polymorphisms (rSNPs)) and those that affect RNA functions such as splicing, turnover, and translation (termed structural RNA SNPs (srSNPs)). This review focuses on the role of srSNPs in drug metabolism, transport, and response. An understanding of the nature and diversity of srSNPs and rSNPs enables clinical scientists to evaluate genetic biomarkers.

Direct-to-consumer genome testing: opportunities for pharmacogenomics research?

by Barbara Prainsack

With Howard Wolinsky

This commentary examines the role that commercial providers of SNP-based genome-wide personalized risk profiles play... more This commentary examines the role that commercial providers of SNP-based genome-wide personalized risk profiles play in facilitating pharmacogenomics research. We first take a look at how personal genomics services, exemplified by the company 23andMe, communicate information on drug response to customers. We then discuss the most important benefits and issues we see arising with the idea of ‘crowdsourcing’ pharmacogenomics research via commercial genome-scan providers. We conclude with a brief vision for the future.

Pharmacogenetics of drug dependence: role of gene variations in susceptibility and treatment

by Jibran Khokhar