CYP2D6 and Tamoxifen: SSRIs Lessen Benefit

Jacob Schor, ND

Current evidence suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen citrate in preventing breast cancer recurrence. This has special relevance because SSRIs are now widely prescribed to treat hot flashes in women with a history of estrogen receptor–positive breast cancers. The risks already inherent in using tamoxifen become more significant if tamoxifen does not provide its promised benefit in reducing breast cancer recurrence.

Medscape Medical News published the following recommendation in June 2009: “Until there are more data, patients who are taking tamoxifen to reduce their risk for breast cancer recurrence should avoid concomitant use of selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft).”¹ There is a significant percentage of women for whom tamoxifen will not work even if they are not taking SSRIs. To understand this, we must detour for a moment and review the pharmacogenomics of tamoxifen.

Tamoxifen is metabolized in the liver into N-desmethyltamoxifen and 4-hydroxytamoxifen (4HT). Tamoxifen and the N-desmethyl metabolite have approximately equal antiestrogenic effects. However, the 4HT metabolite is 100 times more active.² Another more recently elucidated metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen), is equal in activity to 4HT but is produced in larger quantities.³ Thus, these 2 metabolites (4HT and endoxifen, but especially the latter) are the actual source of tamoxifen’s effect on breast cancer.

We should think of tamoxifen as a prodrug that requires conversion or activation by the liver into these active forms. Activation is through the liver cytochrome P450 2D6 pathway.

Recall that P450 enzymes (CYPs) are present in the endoplasmic reticulum of liver cells and in the brush borders of the intestines and are responsible for the breakdown of steroids, lipids, vitamins, and many exogenous chemicals. CYP2D6 has about 78 variants, and most of those forms are inactive. These variants represent the following 4 distinct groups of patients based on how they metabolize various chemicals: a normal group, a poor metabolizing group, an intermediate group, and an ultrarapid metabolizing group.

About 5% to 10% of persons of white race/ethnicity and 1% to 2% of Southeast Asians are poor metabolizers. Almost 30% of Ethiopians are ultrarapid metabolizers.

Poor metabolizers are slow to activate tamoxifen to its active working forms. Thus, the concentration of endoxifen produced will vary by CYP2D6 genotype. In 2007, Schroth and colleagues⁴ published data confirming that the effectiveness of tamoxifen varied based on patient CYP2D6 genotype. They examined DNA from 206 patients receiving tamoxifen and from 280 patients not receiving tamoxifen, testing for CYP2D6 gene variants along with other CYP genetic polymorphisms. Tamoxifen-treated patients carrying CYP2D6 variants that impaired formation of 4HT and endoxifen had more than double the risk of recurrence of breast cancer, shorter relapse-free periods (hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.16-4.33; P = .02), and worse event-free survival rates (HR, 1.89; 95% CI, 1.10-3.25; P = .02) compared with patients with functional CYP2D6. Patients who had enzyme variants that made them fast metabolizers (able to produce endoxifen faster) had far better clinical outcomes, with less than half the risk of recurrence (HR, 0.45; 95% CI, 0.21-0.92; P = .03).

These data suggest that with appropriate screening patients can be identified who will gain little benefit from tamoxifen therapy (CYP2D6 alleles *4, *5, *10, and *41).5 On the other hand, testing (eg, for the CYP2C19 *17 variant) can also identify patients who are more likely to benefit from tamoxifen therapy.⁵

In December 2008, the Mayo Clinic issued a press release reporting the following finding: “Mayo Clinic researchers recommend CYP2D6 gene testing for postmenopausal women about to begin tamoxifen therapy…[because] women with an inherited deficiency in the CYP2D6 gene…have a nearly fourfold higher risk of early breast cancer recurrence compared to women who have not inherited the deficiency.”⁶

CYP2D6 activity is affected by exposure to certain drugs. In 2005, Jin et al³ were the first to investigate what seemed like an obvious question: do the SSRI drugs, which are known to decrease CYP2D6 affect tamoxifen therapy? They followed up 80 women with breast cancer who were beginning treatment with tamoxifen. At the start of treatment, only 17% were taking SSRIs. By 4 months later, 29% were taking SSRIs.

It should be noted that SSRIs in recent years have become a mainstay for the treatment of hot flashes in women with breast cancer. Although they have no estrogenic effect, these drugs decrease hot flashes by 50% to 60%.^4,7 Thus, they were considered viable alternatives to using supplemental estrogen.

In the study by Jin and colleagues,³ of 80 patients taking both SSRIs and tamoxifen, 90% were of white race/ethnicity, and 60% had 2 normal alleles, making them normal metabolizers. About 35% had 1 normal allele and 1 variant allele, making them intermediate metabolizers. About 4% had no normal alleles, making them poor metabolizers. When after 4 months endoxifen and other tamoxifen metabolites had reached a steady state, as expected, endoxifen levels differed by patient genotype. Endoxifen levels in the normal metabolizers were 78.0 nM, while levels in the heterozygous slower metabolizers were only 43.1 nM and in the nonmetabolizers (those with both alleles of variant type) only 20 nM. In women with homozygous normal alleles (normal metabolizers) taking SSRIs, endoxifen levels were only 38.6 nM compared with 91.4 nM in women not taking SSRIs.³

Two somewhat conflicting studies were presented in June 2009 at the annual meeting of the American Society of Clinical Oncology. An American study⁸ found that women taking tamoxifen and 1 of 3 SSRIs (paroxetine, fluoxetine hydrochloride, or sertraline hydrochloride) were about twice as likely to experience a breast cancer recurrence compared with women taking tamoxifen alone. On the other hand, a Dutch study⁹ was unable to find this relationship.

The American study (Aubert et al⁸) was conducted using data from Medco, a large health provider. Analyzing data collected among Medco’s 10.7 million members, the Indiana University, Bloomington, researchers followed up women who took tamoxifen for a minimum of 2 years. These 1298 women were divided into 2 groups. One group comprised 353 women who also took drugs known to be CYP2D6 inhibitors along with tamoxifen. The other group comprised 945 women did not use medications that inhibit CYP2D6. Moderate to potent CYP2D6-inhibiting SSRIs include fluoxetine, paroxetine, and sertraline. Weak CYP2D6-inhibiting SSRIs include citalopram hydrobromide, escitalopram, and fluvoxamine maleate.

The group was further split into the following 2 cohorts based on the strength of CYP2D6 inhibition caused by the drugs: one group of 213 women taking moderate to potent inhibitors and another group of 137 women taking weaker inhibitors.8 Patients who took any SSRIs while using tamoxifen had a 2-year breast cancer recurrence rate of 13.9%. Patients who took only tamoxifen had a recurrence rate of 7.5%. The subgroup of women taking the stronger CYP2D6-inhibiting SSRIs had a 16% recurrence rate. The subgroup of patients taking the weaker SSRIs had an 8.8% recurrence rate, which was not statistically different from that of patients taking only tamoxifen.⁸

In the second 2009 American Society of Clinical Oncology study cited, Dutch researchers (Dezentje et al⁹) used medical databases to identify 1990 women with breast cancer who were treated with tamoxifen between 1994 and 2006. Among these women, 215 also used an SSRI during tamoxifen treatment, 150 of them for 2 months or longer. While Aubert et al⁸ found that taking an SSRI almost doubled the 2-year recurrence risk, Dezentje et al did not find a significant association. Their group reported that women taking an SSRI and tamoxifen had a 13.3% recurrence rate over 4 years. The recurrence rate for women who took tamoxifen alone or with an SSRI for less than 1 month was 14.6%. The contradictory nature of the Dutch results has been discounted because of the small percentage of women taking both drugs concurrently for significant periods.

If this discussion seems vaguely familiar, it should be. The idea that antidepressant use was associated with an increased risk of breast cancer has been floating around for years, even independent of drug interactions with tamoxifen. A Canadian study¹⁰ published in 2000 reported that using antidepressants for more than 2 years nonsignificantly doubled the risk of breast cancer and that using paroxetine for 2 years significantly increased the risk by a factor of 7. Note that the HR reached statistical significance only for the latter paroxetine finding.

The Journal of the National Cancer Institute had issued a press release on this subject in 2003. It was entitled “Hot Flash Drug May Hinder Effectiveness of Tamoxifen.”1¹

The Mayo Clinic announced in December 2008 that it was performing CYP2D6 gene testing in patients with breast cancer before instituting tamoxifen therapy.¹² Mayo Clinic researchers had already reported that tamoxifen was less effective in postmenopausal patients with breast cancer who had the wrong CYP2D6 variant. However, until this announcement, testing for the gene had not been performed routinely at most medical centers. In announcing the results of a new more definitive study, lead investigator Matthew Goetz suggested that “…going forward, postmenopausal patients being considered for tamoxifen therapy should be tested for CYP2D6 before beginning therapy.”¹²

Goetz and colleagues had examined DNA from women treated in the ABCSG-8 study.¹² This study had randomized and followed up almost 3900 postmenopausal women who had a history of estrogen receptor–positive breast cancer that had been surgically treated and who then had taken either tamoxifen for 5 years or tamoxifen for 2 years, followed by anastrozole for 3 years. The initial results, reported in 2005, demonstrated that women who switched to anastrozole had a 40% reduced risk of breast cancer recurrence compared with women who stayed on tamoxifen.

According to the press release, the 2008 study determined that CYP2D6 gene variations identified a subgroup of patients at higher risk of recurrence within the ABCSG-8 trial. “Among the patients randomized to tamoxifen, poor metabolizers had a 3.8-fold increase in risk of developing breast cancer recurrence than extensive metabolizers across the five-year span,” said Michael Gnant, a contributor to the study.1²

It may be that we will not have the option of ordering genomic tests in some patients. However, we may be able to make a guess at the effectiveness of tamoxifen simply by how it affects hot flashes.

Mortimer and colleagues¹³ in the Women’s Healthy Eating and Living (WHEL) Study Group reported in April 2008 that they had analyzed data from the WHEL trial to see whether the occurrence of hot flashes was an independent predictor of tamoxifen efficacy. Of 1551 women enrolled in the study, 864 (56%) were taking tamoxifen. Of these women, 674 (78%) reported hot flashes. After 7.3 years’ follow-up, 127 of those taking tamoxifen at the start of the study had a breast cancer recurrence. The researchers reported: “Women who reported hot flashes at baseline were less likely to develop recurrent breast cancer than those who did not report hot flashes (12.9% vs 21%, P = 0.01). Hot flashes were a stronger predictor of breast cancer specific outcome than age, hormone receptor status, or even the difference in the stage of the cancer at diagnosis….”1³

This information leads me to the following 3 conclusions. First, physicians prescribing tamoxifen should be testing for CYP2D6 status. If they are not, we should strongly encourage them to do so. Even if we do not badger them directly, we can do so indirectly by educating their patients to ask for the test. This is of particular importance in those patients who for various reasons are indecisive about taking tamoxifen. Finding out whether or not tamoxifen will be effective for them may help them reach a decision. Clearly, it would be less beneficial for a poor metabolizer to use tamoxifen.

Second, women should not use SSRIs while undergoing tamoxifen therapy. If they insist on doing so, they should avoid the stronger ones. Physicians prescribing these drugs should be educated about the risk they are putting their patients in.

Third, we should pay attention to clinical reactions to tamoxifen. Women who tolerate it well and do not complain of hot flashes may be gaining little benefit from taking it. Hot flash intensity may be a cheapskate’s alternative to genomic testing when it comes to CYP2D6 variants. Lack of tamoxifen-triggered hot flashes may tell us which patients are slow detoxifiers and which patients are less likely to benefit from tamoxifen therapy. This may also enable us to gauge the benefit accrued by patients who underwent tamoxifen therapy in years past. In those patients who glided through their 5 years of tamoxifen with little or no complaint, the risk of cancer recurrence is increased along with the need for more proactive treatment for preventing recurrence and the need for more active monitoring to detect recurrence.

As in all things, you get what you pay for; it is far more prudent to run the CYP2D6 test than to try to guess gene variants by a patient’s estimate of hot flash intensity. Finally, an excellent patient handout summarizing tamoxifen and other drug interactions is available for download at www.medicine.iupui.edu/clinpharm/COBRA/TamoxifenGuide.pdf.

Jacob Schor, ND, FABNO is a 1991 graduate of NCNM and has practiced in Denver for the past 17 years. He served as president of the CANP from 1992 to 1999. He has served on the board of directors of the OncANP since 2006 and currently acts as secretary to the board. He is a Fellow of the ABNO. He was utterly shocked and humbled at the 2008 convention of the AANP to be presented with the Vis Award, an honor bestowed in the memory of William Mitchell. He is incredibly lucky to practice with his wife, Rena Bloom, ND. Dr. Schor writes newsletters for his patients that are popular with doctors and students.

1. Chustecka Z. ASCO 2009: avoid SSRIs in breast cancer patients on tamoxifen. Medscape Medical News. June 2, 2009. https://login.medscape.com/login/sso/getlogin?ac=401&urlCache=aHR0cDovL3d3dy5tZWRzY2FwZS5jb20vdmlld2FydGljbGUvNzAzNzQ0P3Nzc2RtaD1kbTEuNDgwMDg4JnNyYz1ubGNvbmZuZXdzJnNwb249Nw%3D%3D. Accessed December 22, 2010.
2. Jordan VC, ed. Long-term Tamoxifen Treatment for Breast Cancer. Madison: University of Wisconsin Press; 1994.
3. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30-39.
4. Stearns V. Serotonergic agents as an alternative to hormonal therapy for the treatment of menopausal vasomotor symptoms. Treat Endocrinol. 2006;5(2):83-87.
5. Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007;25(33):5187-5193.
6. Mayo Clinic. Mayo Clinic research on tamoxifen leads to recommendation for CYP2D6 gene test [press release]. December 13, 2008. http://www.mayoclinic.org/news2008-rst/5125.html. Accessed December 20, 2010.
7. Stearns V, Slack R, Greep N, et al. Paroxetine Is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol. 2005;23(28):6919-6930.
8. Aubert R, Stanek E, Yao J, et al. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors [abstract]. J Clin Oncol. 2009;27(18 suppl):abstr CRA508.
9. Dezentje V, Van Blijderveen N, Gelderblom H, et al. Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: a pharmacoepidemiologic study [abstract]. J Clin Oncol. 2009;27(18 suppl):abstr CRA509.
10. Cotterchio M, Kreiger N, Darlington G, Steingart A. Antidepressant medication use and breast cancer risk. Am J Epidemiol. 2000;151(10):951-957.
11. Wang L, Arnold K. Press release: hot flash drug may hinder effectiveness of tamoxifen. J Natl Cancer Inst. 2003;95(23):1733. http://jnci.oxfordjournals.org/content/95/23/1733.3.full. Accessed December 22, 2010.
12. Mayo Clinic News. Gene testing may be key for treating some women with breast cancer. http://newsblog.mayoclinic.org/2008/12/11/gene-testing-may-be-key-for-treating-some-women-with-breast-cancer/. Accessed December 20, 2010.
13. Mortimer JE, Flatt SW, Parker BA, et al; WHEL Study Group. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat. 2008;108(3):421-426.