CYP2D6 Genotyping and the Use of Tamoxifen in Breast Cancer

Extract

Cytochrome P450 2D6 ( CYP2D6 ) is involved in the metabolism of many drugs, including tamoxifen ( 1 ), but the potential role of CYP2D6 genotype assessment in determining whether breast cancer patients with estrogen receptor (ER)–positive tumors should receive tamoxifen is controversial. This controversy has been played out in the Journal ( 2–10 ).

The focus of empirical studies regarding this issue has been postmenopausal disease in the adjuvant setting. In these studies, researchers have assumed that CYP2D6 genotype is unrelated to breast cancer outcome, and hence they focus on patients who have received tamoxifen, whether in a clinical trial or in clinical practice. Because tamoxifen is highly effective in delaying recurrence of ER-positive disease ( 11 ), if its effect is substantially reduced in poor metabolizers, then this would be detectable in a study with sufficiently large sample size.

In summarizing the available literature, a June 2010 Technology Assessment Report to the Agency for Healthcare Research and Quality of the US Department of Health and Human Services concluded that “[t]here were no consistent associations between CYP2D6 polymorphisms and outcomes in tamoxifen treated breast cancer across 16 studies included in [this] systematic review” ( 12 ). This conclusion continues to be appropriate; there still does not exist credible empirical evidence showing a benefit for CYP2D6 genotyping. Indeed, two large trials published in the Journal in 2012 showed no association ( 2 , 3 ). The editorialists concluded, “[T]he fact that these two studies confirm each other suggests that this matter has likely been laid to rest” ( 4 ).