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

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