Article

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

Liverpool Reviews and Implementation Group (LRiG), University of Liverpool, Liverpool, UK.
Health technology assessment (Winchester, England) 09/2011; 15(33):1-102. DOI: 10.3310/hta15330
Source: PubMed

ABSTRACT

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.
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.
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.
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.
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.
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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    • "The wide variety of responses and side effects of tamoxifen in different patients, questioned whether these differences result from an inter-individual genetic variability [11] [12]. Since 2003, more than 20 studies tried to define the role of CYP2D6 polymorphisms in the efficacy of tamoxifen in females with breast cancer [13] [14]. "
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    ABSTRACT: Tamoxifen remains the standard hormonotherapy for Male breast cancer patients (MBC). Previous studies, in women, tried to evaluate the impact of CYP2D6 polymorphisms in tamoxifen efficacy with conflicting results. Herein we analyze the relation between CYP2D6*4 polymorphism and survival in MBC patients. Fifty-three patients, proposed to tamoxifen in adjuvant setting, were enrolled. Clinical information was collected from records and histological revision with additional immunochemistry analysis was done to better characterize the tumors. Comprehensive CYP2D6*4 genotyping from blood or tumor tissue was performed and translated into two predicted metabolic activity groups. Patients included in the two CYP2D6*4 groups did not differ concerning to age, histological characteristics, and primary treatments performed. Median age at diagnosis was 63 years-old and patients were submitted at least to mastectomy and adjuvant hormonotherapy. Recurrence was observed in 7 patients (13.2%) and 13 patients (25.5%) died with a 5-year disease-free survival of 86.2%. The poorer metabolizer group had a high risk for recurrence (p = 0.034) and this outcome effect remains in different subgroups: in tumors larger than 2 cm (p < 0.001), nodal status, N0 vs N+ (p = 0.04) and in advanced stage, stage III (p < 0.001). Poorer metabolizer patients had also a worse overall survival when tumors were larger than 2 cm (p = 0.03). In our series, there was an association between CYP2D6*4 polymorphism and a probability of recurrence, with a consistent effect in risk groups defined by classic prognostic factors. Multicentric studies with larger samples are needed to validate these results. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · May 2015 · Breast (Edinburgh, Scotland)
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    • "Determination of the CYP2D6 genotype was undertaken in the molecular biology laboratories of both institutions using the FDAcleared , CE-IVDeapproved AmpliChip CYP450 test (Roche Diagnostics , Indianapolis, IN, USA), according to the manufacturer's instructions. This is a highly reliable method for CYP2D6 genotyping which identifies 33 CYP2D6 alleles (including variants associated to impaired enzyme activity and seven gene duplications ) using the Affymetrix microarray platform [20]. Once the genotype was known, according to the conventional classification system, the AmpliChip CYP450 test predicted the metabolizer phenotype as PM if they carry two non-functional alleles; IM if they carry one non-functional allele and one associated with reduced activity or two reduced activity alleles; EM if they carry at least one functional allele and UM if they carry at least three copies of a functional allele [21] [22]. "
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    ABSTRACT: Background CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM). Patients and methods Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg). Results Eleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively). Conclusion In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype.
    Full-text · Article · Aug 2014 · Breast (Edinburgh, Scotland)
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    • "Determination of the CYP2D6 genotype was undertaken in the molecular biology laboratories of both institutions using the FDAcleared , CE-IVDeapproved AmpliChip CYP450 test (Roche Diagnostics , Indianapolis, IN, USA), according to the manufacturer's instructions. This is a highly reliable method for CYP2D6 genotyping which identifies 33 CYP2D6 alleles (including variants associated to impaired enzyme activity and seven gene duplications ) using the Affymetrix microarray platform [20]. Once the genotype was known, according to the conventional classification system, the AmpliChip CYP450 test predicted the metabolizer phenotype as PM if they carry two non-functional alleles; IM if they carry one non-functional allele and one associated with reduced activity or two reduced activity alleles; EM if they carry at least one functional allele and UM if they carry at least three copies of a functional allele [21] [22]. "

    Full-text · Article · Mar 2014 · The Breast
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