Impact of CYP2D6 polymorphism on tamoxifen therapy: where are we?

Abstract

Tamoxifen is a mainstay in the treatment of hormone-receptor sensitive breast cancer. To be effective, it needs conversion into 4-hydroxy-tamoxifen and endoxifen. The key enzyme involved is encoded by the gene CYP2D6 of which several, sometimes population-specific alleles are known. Corresponding enzyme variants may result in poor, intermediate, and extensive metabolization and therefore different steady-state plasma levels of active metabolites. Those are hypothesized to be linked to clinical outcomes of tamoxifen therapy. However, a wealth of mostly retrospective cohort studies came up with conflicting results. Appraisal of these studies is difficult and a metaanalysis impossible due to heterogeneity of patient populations, disease factors, treatment modalities, and measured outcomes. As standardization would not overcome intrinsic limitations of retrospective analyses, prospective trials comparing genotype-guided versus unsighted tamoxifen treatment are required to prove whether routine CYP2D6 genotyping is clinically effective and cost-effective.

Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors

“…This element should be further exploited and analyzed in larger series of tamoxifen resistant patients. However, an element not taken into account in all these studies (including ours) is a possible specific effect of tamoxifen metabolites in mediating some of the resistance‐related phenomena, including transcription and the induction of stemness (see Barnadas et al., 2011; Brauch and Jordan, 2009; de Souza and Olopade, 2011; Huber‐Wechselberger et al., 2012, for reviews). Analysis of tamoxifen metabolites in patients that developed resistance to tamoxifen and further study of their effect on the patients' transcriptome could provide further insights in endocrine therapy resistance.…”

Consensus statement for non-hormonal-based treatments for menopausal symptoms

“…5 We know too that the impact on cytochrome P450 is dependent on genotype and thus any SSRI may potentially inhibit tamoxifen efficacy for some patients. 40…”

“…5 We know too that the impact on cytochrome P450 is dependent on genotype and thus any SSRI may potentially inhibit tamoxifen efficacy for some patients. 40 Since paroxetine is the SSRI with the best evidence for efficacy 19,23 effective at 10 mg daily, it is the SSRI of choice for patients not taking tamoxifen and the more usual 20 mg dose chosen if an antidepressant effect is also required.…”

Consensus statement for non-hormonal based treatments for menopausal symptoms

“…5 We know too that the impact on cytochrome P450 is dependent on genotype and thus any SSRI may potentially inhibit tamoxifen efficacy in some patients. 40 Since paroxetine is the SSRI with the best evidence for efficacy 19,23 effective at 10 mg daily although the more usual dose of 20 mg may be used if an antidepressant effect is also required, it is the SSRI of choice for patients not taking tamoxifen. Venlafaxine is the preferred treatment for breast cancer survivors taking tamoxifen and at 75 mg there is significant reduction in hot flushes with concomitant improvement in fatigue, mental health and sleep disturbance.…”