Tamoxifen: New Developments

The debate about the extent to which CYP2D6 activity affects tamoxifen efficacy in patients with breast cancer continues, but the plot has thickened considerably since we last discussed this issue on these pages in March 2009. Since then, research papers have continued to appear on both sides of the issue, some suggesting that reduced CYP2D6 activity due to genetics or CYP2D6-inhibiting drugs reduces tamoxifen efficacy, leading to earlier breast cancer relapse and reduced survival, and others failing to find any effect. We also have more evidence that drug interactions involving other tamoxifen metabolic pathways and adenosine triphosphate—binding cassette transporters may also affect tamoxifen efficacy.

CYP2D6 Inhibitors

CYP2D6 is the most important enzyme in the metabolism of tamoxifen to its primary active metabolite (endoxifen), so it is biologically plausible that the concurrent use of moderate to strong CYP2D6 inhibitors with tamoxifen would inhibit its anticancer effects. Two epidemiological studies published in the past year failed to find any effect of CYP2D6 inhibitors on tamoxifen efficacy,^1,2 but it seems unwise to use these results to conclude that we can ignore CYP2D6 inhibitors in patients receiving tamoxifen for the following reasons:

• Other epidemiological studies did in fact find reduced tamoxifen efficacy with CYP2D6 inhibitors,^3-5 so we have evidence on both sides.
• The negative studies had 1 or more significant limitations including a short follow-up, using total mortality instead of cancer mortality, inadequate adjustment for other CYP2D6 inhibitors, and other limitations.
• Epidemiological studies of tamoxifen efficacy are particularly difficult to conduct because of the long period of follow-up required, the many other causes of the outcome (treatment failure), complex CYP2D6 polymorphisms, multiple metabolic pathways for tamoxifen, inability to assess nonadherence, pre- versus postmenopausal patients, lack of tamoxifen dose information, and lack of information on concurrent OTC or herbal medications.⁶

Other Enzymes and Transporters

There is growing evidence that tamoxifen and endoxifen are substrates for P-glycoprotein,⁷ which might reduce tamoxifen bioavailability and increase endoxifen efflux from cancer cells. Theoretically, then, patients with higher P-glycoprotein activity due to genetics or drug therapy would have impaired tamoxifen efficacy. Preliminary evidence supports this hypothesis. In 1 study, the median time to develop recurrence and metastasis was just 12 months in breast cancer patients with decreased CYP2D6 activity and high P-glycoprotein activity, compared with 48 months in patients with either decreased CYP2D6 or high P-glycoprotein activity alone.⁸ So it may be that decreased CYP2D6 activity and increased P-glycoprotein activity can work in concert to impair tamoxifen efficacy.

Enzyme inducers may also be a problem in patients on tamoxifen. In a prospective study, breast cancer patients on tamoxifen were given rifampin 600 mg/day for 15 days.⁹ Endoxifen area under the concentration time curve decreased by about 70% after rifampin, leading the researchers to stop the study prematurely to avoid patient harm. The mechanisms for the large reductions in endoxifen concentrations following rifampin are not known and may involve more than one pathway. Rifampin is known to induce CYP3A4, CYP2C9, CYP2C19, glucuronidation, and P-glycoprotein, all of which are known to be involved in the disposition of tamoxifen or its metabolites.¹⁰ Until data are available, one should assume that other enzyme inducers can also reduce endoxifen concentrations.

Table 1: CYP2D6 Inhibitors

Abiraterone

Amiodarone

Bupropion

Celecoxib

Chloroquine

Chlorpheniramine

Chlorpromazine

Cinacalcet

Clobazam

Cobicistat

Darifenacin

Diphenhydramine

Dronedarone

Eliglustat

Fluoxetine

Goldenseal

Halofantrine

Haloperidol Hydroxychloroquine

Lorcaserin

Lumefantrine

Mirabegron

Moclobemide

Panobinostat

Paroxetine

Perphenazine

Promethazine

Propafenone

Quinacrine

Quinidine

Quinine

Ritonavir

Rolapitant

Terbinafine

Thioridazine

End Note

We can’t ignore that there is simply too much information suggesting that drug interactions can reduce tamoxifen efficacy. If we commit a type I error and assume that the interactions are important when they are not, we have taken only a little extra time to avoid certain concurrent medications. If we commit a type II error and assume that there is no interaction when there is, women with breast cancer will have an increased risk of cancer recurrence and death. The choice seems clear and leads to the following recommendations for patients on tamoxifen:

• Avoid concurrent use of moderate to strong CYP2D6 inhibitors (Table 1).
• Avoid enzyme inducers (Table 2).
• Counsel patients on tamoxifen to avoid OTC or herbal drugs that may inhibit CYP2D6 (goldenseal) or induce enzymes (St John’s wort).

Table 2: Enzyme Inducers

Armodafinil

Barbiturates

Bexarotene

Bosentan

Carbamazepine

Dabrafenib

Dexamethasone

Efavirenz

Enzalutamide

Eslicarbazepine

Etravirine

Fosphenytoin

Griseofulvin

Lumacaftor

Mitotane

Modafinil

Nevirapine

Oxcarbazepine

Phenytoin

Primidone

Rifabutin

Rifampin

Rifapentine

St John’s wort

Troglitazone

Vemurafenib

Vinblastine

Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy. For an electronic version of this article, including references, visit hanstenandhorn.com.

References

• Haque R, Shi J, Schottinger JE, et al. Tamoxifen and antidepressant drug interaction in a cohort of 16,887 breast cancer survivors. J Natl Cancer Inst. 2015;108(3). doi: 10.1093/jnci/djv337.
• Donneyong MM, Bykov, K, Bosco-Levy P, et al. Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study. BMJ. 2016;354:i5014. doi.org/10.1136/bmj.i5014.
• Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010:340:c693. doi:10.1136/bmj.c693.
• Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007;101(1):113-121.
• Chubak J, Boles EJ, Yu O, et al. Breast cancer recurrence in relation to antidepressant use. Cancer Causes Control. 2016;27(1):125-136. doi: 10.1007/s10552-015-0689-y.
• Juurlink D. Revisiting the drug interaction between tamoxifen and SSRI antidepressants. BMJ. 2016;354:i5309. doi: 10.1136/bmj.i5309.
• Teft WA, Mansell SE, Kim RB. Endoxifen, the active metabolite of tamoxifen, is a substrate of the efflux transporter P-glycoprotein (multidrug resistance 1). Drug Metab Dispos. 2011;39(3):558-562. doi: 10.1124/dmd.110.036160.
• Teh LK, Mohamed NI, Salleh MZ, et al. The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1. AAPS J. 2012;14(1):52-59. doi: 10.1208/s12248-011-9313-6.
• Binkhorst L, van Gelder T, Loos WJ, et al. Effects of CYP induction by rifampicin on tamoxifen exposure. Clin Pharmacol Ther. 2012;92(1):62-67. doi: 10.1038/clpt.2011.372.
• Powers JL, Buys SS, Fletcher D, et al. Multigene and drug interaction approach for tamoxifen metabolite patterns reveals possible involvement of CYP2C9, CYP2C19, and ABCB1. J Clin Pharmacol. 2016;56(12):1570-1581. doi: 10.1002/jcph.771.