CYP2D6 Phenotype and Breast Cancer Outcomes: A Bias Analysis and Meta-Analysis

Background: We evaluated the impact of systematic bias due to loss of heterozygosity (LOH) and incomplete phenotyping in studies examining the relationship between CYP2D6 variants and breast cancer recurrence among women treated with tamoxifen. Methods: We performed a systematic review of the literature on tamoxifen, CYP2D6 variants, and breast cancer recurrence. A quantitative bias analysis was performed to adjust for LOH and incomplete phenotyping. Bias-adjusted results were then combined in a meta-analysis. Results: Thirty-three studies informed the bias analysis and meta-analysis on CYP2D6 variants and breast cancer recurrence and/or mortality. An unadjusted meta-analysis suggested increased risk of recurrence and/or mortality for poor relative to normal metabolizers [RR ¼ 1.28; 95% simulation interval (SI), 1.04–1.58] with substantial heterogeneity (I² ¼ 27%; P for heterogeneity ¼ 0.07). Adjusting for LOH and incomplete genotyping resulted in a slight change in the effect estimate and a decrease in heterogeneity (RR ¼ 1.34; 95% SI, 1.10–1.63; I² ¼ 0%; P for heterogeneity ¼ 0.17). Intermediate metabolizers had a slightly increased risk of recurrence and/or mortality relative to normal metabolizers (RR ¼ 1.15; 95% SI, 1.00–1.34; I² ¼ 0%; P for heterogeneity ¼ 0.89). Conclusions: Adjusting for biases such as LOH and incomplete genotyping reduced observed heterogeneity between studies. Individuals with poor CYP2D6 phenotypes were at increased risk for breast cancer outcomes compared with those with normal phenotypes. Impact: Reduction in CYP2D6 activity was associated with an increased risk of breast cancer recurrence and/or mortality, and results underscore the importance of quantitatively adjusting for biases when aggregating study results. See related In the Spotlight, p.