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Review
. 2013 Oct 2;8(10):e76648.
doi: 10.1371/journal.pone.0076648. eCollection 2013.

CYP2D6 genotype and tamoxifen response for breast cancer: a systematic review and meta-analysis

Danny W K Lum  1 , Pablo Perel, Aroon D Hingorani, Michael V Holmes
Affiliations
Review

CYP2D6 genotype and tamoxifen response for breast cancer: a systematic review and meta-analysis

Danny W K Lum et al. PLoS One. .

Abstract

Objective: To evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through.

Design: Systematic review and meta-analysis of prospective, cross-sectional and case-control studies published to 2012. For each study, relative risks and 95% confidence intervals were extracted and pooled with a fixed and random effects model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed.

Data sources: PubMed (inception-2012) and EMBASE (inception-2012).

Eligibility criteria for selecting studies: Criteria for inclusion were studies reporting breast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene.

Results: Twenty-five studies of 13,629 individuals were identified, of which 22 investigated the association of CYP2D6 genotype with outcomes in breast cancer women all receiving tamoxifen treatment ("treatment-only" design). Three randomized trials evaluated the effect of CYP2D6 genotype on tamoxifen response ("effect modification" design). In analysis of treatment-only studies, the relative risk (RR) of all-cause mortality (>307 events in 4,936 patients) for carriers of a CYP2D6 reduced function allele was 1.11 (95% confidence interval (CI): 0.94 to 1.31) compared to individuals with normal/increased function CYP2D6 alleles. When we investigated a composite outcome including all-cause mortality and surrogate endpoints for overall survival (>307 events in 6,721 patients), carriers of a CYP2D6 reduced function allele had a RR of 1.27 (95% CI: 1.11 to 1.45). From two randomized trials that permitted effect-modification analysis, one had only 154 patients and showed evidence of effect modification of tamoxifen by CYP2D6 genotype for distant recurrence but was directionally opposite to that predicted, whereas a larger trial of 2,537 patients failed to show evidence of effect modification for breast cancer-free interval (P values for interaction 0.02 and 0.44, respectively).

Conclusions: Based on these findings, there is insufficient evidence to recommend CYP2D6 genotyping to guide tamoxifen treatment.

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Conflict of interest statement

Competing Interests: Professor Hingorani was previously the principal investigator receipt of a Biomarker Award from the Medical Research Council with Pfizer as an Industrial partner. This award was to investigate complement factor H in the prediction or pathogenesis of age-related macular disease or coronary heart disease. The award is now closed. The DNA extraction for TPT study (for which Professor Hingorani provided free advice to colleagues at University College London (London, UK) on the design and analysis of pharmacogenetic studies including an analysis of Lp(a) genotype as a predictor of aspirin response) was funded by Celera through a contract with University College London and Medical Research Council (who funded the original TPT trial). Professor Hingorani has provided non-remunerated advice to the Roche Actemra Cardiovascular Advisory Board. All other co-authors report no conflicts of interest. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Meta-analysis pooled estimates from treatment-only analysis of the association of any, one or two copies of a reduced function CYP2D6 allele vs. none with composite breast cancer outcomes.
Footnotes: § P-value represents test for trend, conducted using metaregression assuming a linear dose-response relationship between number of CYP2D6 alleles and summary effect estimate.
Figure 2
Figure 2. Meta-analysis pooled estimates from treatment-only analysis of the association of any CYP2D6 reduced function alleles vs. none with individual outcomes.
Footnotes: Non-fatal events included breast cancer outcomes that were not fatal.
Figure 3
Figure 3. Subgroup analyses of the association between any reduced function CYP2D6 allele vs. none for the composite outcome of all-cause mortality and surrogate endpoints for overall survival (including non-fatal events).
See this image and copyright information in PMC

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