Avoidance of CYP2D6 Inhibitors in Patients Receiving Tamoxifen

Abstract

Tamoxifen remains an important drug in the adjuvant treatment of patients with estrogen receptor?positive breast cancer.1 Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 isoenzyme 2D6 (CYP2D6) isoform, to the active metabolite endoxifen.2 CYP2D6 activity can be reduced both by genetic variation or concurrent use of drug inhibitors, which, in turn, can significantly reduce endoxifen plasma concentrations.3?5Drug interactions are particularly relevant in the context of tamoxifen therapy, given that selective serotonin reuptake inhibitor antidepressants, commonly used to treat depression and hot flashes in patients with breast cancer, inhibit CYP2D6 to varying degrees. Various pharmaco-epidemiologic studies have attempted to correlate concomitant CYP2D6 inhibitor use to tamoxifen outcome and have reported mixed conclusions.6?10 In this context, Dezentj� et al8 did not confirm an association between CYP2D6 inhibitor use and breast cancer recurrence, in contrast with two recent studies supporting a clinically significant drug interaction between tamoxifen and CYP2D6 inhibitors.9,10 Small sample size, incomplete follow-up and recurrence data, potentially confounding variables, such as other adjuvant therapies, differences in eligibility criteria, and the consideration of weak inhibitors, may account for the discordant analyses. Moreover, both differences in CYP2D6 genotype frequencies and lack of data regarding the indication for antidepressant treatment could lead to confounding bias.Interestingly, Dezentj� et al8 also reported that compliance with instructions for prescribed medication and adherence to the regimen are critical in achieving maximum benefits with tamoxifen. In a pharmacogenetic study of more than 600 patients with breast cancer treated with adjuvant tamoxifen, examining the comprehensive effect of CYP2D6 genotype, adherence, and coadministration of CYP2D6 inhibitors on disease recurrence, we identified that genotype and adherence, but not potent CYP2D6 inhibitors, were associated with disease relapse.11Despite the lack of agreement on the relative importance of adherence and co-medication, there is increasing consensus that an association exists between the CYP2D6 genotype and clinical outcomes.11,12 Although commercial tests for CYP2D6 genotyping are available, the position of such tests in clinical practice remains uncertain.13Consequently, we conducted a survey to assess the current practice of breast oncologists in the United Kingdom with respect to CYP2D6 testing and selective serotonin reuptake inhibitor cotreatment. An e-survey questionnaire was sent in March 2010 to oncologists and surgeons in the United Kingdom Breast Intergroup (the advisory group for adjuvant breast cancer trials in the United Kingdom). Among the 69 respondents, most working in high volume or academic centers, 41% believe that determination of CYP2D6 is important for the choice of endocrine treatment, and 40% discuss with their patients that genetic factors may affect the efficacy of tamoxifen. However, at present, 97% do not offer CYP2D6 genetic testing before commencing tamoxifen treatment. Reasons given for not offering the test included: test availability (52%), insufficient evidence to recommend use (29%), cost (8%), or a combination of these reasons. Twenty-two percent of respondents stated that there was enough evidence to routinely use CYP2D6 testing, 37% required more evidence, and 41% were unsure. There was general agreement (80%) that concomitant medications might affect the clinical efficacy of tamoxifen, and 86% indicated that they discuss drug interactions with their patients. Importantly, 93% would not prescribe a potent CYP2D6 inhibitor concomitant with tamoxifen and prescribe alternative treatments, where available.The jury may still be out as to whether CYP2D6 genotyping is ready for standard practice,13 and the decision must await the results of major randomized trials of tamoxifen versus aromatase inhibitors. In the interim, however, avoidance of moderate or potent CYP2D6 inhibitors is a pragmatic approach.