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Abstract
ObjectiveTo evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through.DesignSystematic 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 SourcesPubMed (inception-2012) and EMBASE (inception-2012).Eligibility Criteria for Selecting StudiesCriteria for inclusion were studies reporting breast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene.ResultsTwenty-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).ConclusionsBased on these findings, there is insufficient evidence to recommend CYP2D6 genotyping to guide tamoxifen treatment.
Highlights
Breast cancer is one of the leading causes of cancer-related mortality in women [1,2]
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 cytochrome P450 2D6 (CYP2D6) reduced function allele had a relative risk (RR) of 1.27
Six of 25 (24%) studies reported that genotype ascertainment was conducted with blinding to clinical outcomes, and only three studies (12%) reported that clinical outcomes were ascertained with blinding to CYP2D6 genotype (Table S3)
Summary
Breast cancer is one of the leading causes of cancer-related mortality in women [1,2]. A selective estrogen receptor modulator, was first approved by the U.S Food and Drug Administration (FDA) in 1977 for the treatment of metastatic breast cancer [3], and has been approved for primary prevention in women at high risk of breast cancer, for adjuvant treatment (given after primary treatment), and for ductal carcinoma in situ [4]. A meta-analysis of 20 randomized clinical trials (RCTs) including 10,645 women with estrogen receptor positive breast cancer demonstrated that, compared to no tamoxifen, adjuvant tamoxifen reduced breast cancer recurrence (relative risk (RR) 0.53, 95% CI: 0.47 to 0.59) and breast cancer mortality (RR 0.71, 95% CI: 0.61 to 0.81) at 5 years [5]. A U.S Food and Drug Administration (FDA) Clinical Pharmacology Subcommittee convened in 2006 and agreed that “the scientific evidence on the metabolism of tamoxifen demonstrates CYP2D6 is an important pathway in the formation of endoxifen” and recommended the drug label be updated to reflect this [10]
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