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The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review.

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 cost-effectiveness 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.

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