Pharmacogenomics of tamoxifen: Ready for prime time?

Tamoxifen is the most common hormonal therapy prescribed to women with hormone receptor-positive breast cancer. Tamoxifen requires metabolic activation by the CYP2D6 enzyme to form its active metabolite endoxifen. However, the activity of CYP2D6 is highly variable. Women who are poor metabolizers due to genetic polymorphisms in the gene encoding for a null or low activity enzyme or due to concomitant use of a potent inhibitor have a significantly lower concentration of endoxifen compared with those with one or two wild-type genes (intermediate or extensive metabolizers, respectively). The past few years have seen a spurt in studies evaluating the role of CYP2D6 genotype as a predictor of tamoxifen-associated outcomes. Although the majority of studies have reported a positive association between poor metabolizers of CYP2D6 and worse breast cancer outcomes among women taking adjuvant tamoxifen, other studies have reported opposite results. Due to the retrospective nature and other limitations associated with the majority of studies published to date, the standard incorporation of CYP2D6 genotype testing of all women who are candidates for tamoxifen cannot be recommended. Nevertheless, there are certain circumstances where CYP2D6 testing might be helpful, and the decision should be individualized. Importantly, tamoxifen users should avoid the concomitant use of potent CYP2D6 inhibitors, such as paroxetine, and consider non-inhibitors, such as venlafaxine, for hot flashes or psychiatric conditions. A deeper understanding of interaction between host polymorphisms, tumor biology, and environmental factors will optimize the therapeutic potential of tamoxifen and successfully transform the promise of personalized medicine into reality.