CYP2D6 and Tamoxifen:

SSRIs Lessen Benefit

Jacob Schor ND, FABNO

Writing for OncANP

January 3, 2009

 

CYP2D6 and Tamoxifen:

Current evidence suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen at 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’s June 2009  recommendation is that, “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).”   Even without these drugs, there is still a significant percentage of women even if they are not taking SSRIs for whom tamoxifen will not work. 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 this N-desmthyl metabolite have about equal antiestrogenic effect.  The 4HT metabolite though is 100 times more active. Another more recently elucidated metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen), is equal in activity to 4HT but is produced in larger quantities. Thus these two metabolites 4HT and endoxifen, but especially the later, are really what produce tamoxifen’s effect on breast cancer.  

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

Recall that the 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 create four distinct groups of patients based on how they metabolize various chemicals:

  • Normal group
  • Poor metabolizing group
  • Intermediate group
  • Ultra-rapid metabolizing group

About 5-10% of whites and 1-2% of Southeast Asians are poor metabolizers. Nearly 30% of Ethiopians are ultra-rapid metabolizers. 

Poor metabolizers are slow to activate tamoxifen into its active working forms.  Thus the concentration of endoxifen produced will vary by CYP2D6 genotype.  In 2007, Werner Schroth and colleagues published data confirming that tamoxifen’s effectiveness varied with CYP2D6 genotypes.  They examined DNA from 206 patients receiving tamoxifen and from 280 patients not receiving tamoxifen, testing for variants of the CYP2D6 genes, along with other CYP genetic polymorphisms.

The tamoxifen-treated patients carrying CYP2D6 variants that impaired formation of the 4HT and endoxifen, had more than double the risk of recurrence of breast cancer, shorter relapse-free periods (hazard ratio [HR], 2.24; 95% CI, 1.16 to 4.33; P = .02), and worse event-free survival rates (HR, 1.89; 95% CI, 1.10 to 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 luck as seen in favorable clinical outcome, less than half the risk of recurrence (HR, 0.45; 95% CI, 0.21 to 0.92; P = .03).

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

In December 2008, the Mayo Clinic, in reporting results from a new study, prompted their, “… researchers to 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.”

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

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

Back to Jin’s study: of those 80 patients reported on taking both SSRIs and tamoxifen, 90% were white and 60% had two normal alleles making them normal metabolizers.  About 35% had one normal and one variant allele, making them intermediate metabolizers.  About 4% had no normal alleles, making them slow 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 in the heterozygous slower metabolizers only 43.1 nM and in the non-metabolizers, those with both alleles variant type, only 20nM.  But in women with homozygous normal alleles, normal metabolizers, taking SSRIs, the endoxifen level was only 38.6 nM compared to 91.4 nM in women not taking SSRIs.

Two somewhat conflicting studies were presented in June 2009 at the annual meeting of the American Society of Clinical Oncology (ASCO).  An American study found that women taking tamoxifen and one of three SSRIs, Paxil, Prozac, or Zoloft, were about twice as likely to experience a breast cancer recurrence, compared with women on tamoxifen alone. On the other hand, a Dutch study was unable to find this relationship.

The American study (Aubert et al) was conducted using data from MEDCO a large health provider. Analyzing data collected on MEDCO’s 10.7 million members, researchers from Indiana University followed women who took tamoxifen for a minimum of 2 years.  These 1,298 women were divided into two groups, one group comprised of 353 women (27%) who also took drugs known to be CYP2D6 inhibitors along with tamoxifen.  The other group of 945 women did not use medications that inhibit CYP2D6.

Moderate to Potent CYP2D6 inhibiting SSRIs:

Prozac® (fluoxetine)

Paxil® (paroxetine)

Zoloft® (sertraline)

Weak CYP2D6 inhibiting SSRIs:

Celexa®(citalopram)

Lexapro® (escitalopram)

Luvox® (fluvoxamine)

The inhibitor group was further split into two cohorts based on the strength of the CYP2D6 inhibition caused by the drugs; a group of 213 women taking a potent/moderate inhibitors and another group of 137 women taking weaker inhibitors.  The patients who took any SSRIs while using tamoxifen had a 2-year breast cancer recurrence rate of 13.9%. Those using 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 patients on the weaker SSRI had a cancer recurrence rate of 8.8%, not statistically different from the patients taking only tamoxifen. 

In the second 2009 ASCO  study, Dutch researchers used medical databases to identify 1,990 women with breast cancer who were treated with tamoxifen between 1994 and 2006 (Dezentje et al).  Of these women, 215 also used a SSRI during tamoxifen treatment, 150 of them for 2 months or longer.  While Aubert found that taking a SSRI nearly doubled the two-year recurrence risk, Dezentje did not find a significant association.  His group reported that women taking a SSRIs and tamoxifen had a 13.3% recurrence rate over 4 years.  Recurrence rate for women who either took tamoxifen alone or with an SSRI for less than a month was 14.6%.   The contradictory nature of these Dutch results has been discounted because of the relatively small percentage of women taking both drugs concurrently for significant periods of time.

 

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 study published in 2000 reported that using antidepressants for more than two years insignicantly doubled risk of breast cancer and that Paxil, used for 2 years, significantly increased risk by a factor of 7.  Note that only the later Paxil hazard ratio reached statistical significance.

The Journal of the National Cancer Institute was issuing press releases back in 2003 that: “Hot Flash Drug May Hinder Effectiveness of Tamoxifen.”

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

Goetz and his researchers had examined DNA from women treated in the ABCSG-8 study.  This is the study that had randomized and followed nearly 3,900 postmenopausal women with a history of ER+ breast cancer and who had been surgically treated and then taken either five years of tamoxifen, or tamoxifen for two years followed by three years of anastrozole. The initial results, reported in 2005, concluded that women who switched to anastrozole had a 40 percent reduced risk of breast cancer recurrence compared to staying on tamoxifen.

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, one of the study contributors.

 

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

  Joanne Mortimer and colleagues in the Women's Healthy Eating and Living (WHEL) Study Group reported in April 2008 they had analyzed data from the WHEL trial to see whether hot flashes were an independent predictor of tamoxifen efficacy.  Of the 1,551 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.  “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.”

This information leads me to three conclusions. 

First, doctors prescribing tamoxifen should be testing for CYP2D6 status.  If they aren’t doing so, we should strongly encourage them to do so. Even if we don’t 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 slow 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.  The doctors prescribing these drugs should be educated to the risk they are putting their patients in. 

Three, 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 who are less likely to benefit from tamoxifen therapy.  This may also give us a way to gauge the benefit accrued by patients who underwent tamoxifen therapy in years past.  In those patients who glided through their five years of tamoxifen with little or no complaint, risk of cancer recurrence is increased along with the need for more proactive treatment for preventing recurrence and the need for more active monitoring in order to detect recurrence.  As in all things you do get what you pay for; it is far more prudent to run the test than to try and guess gene variants through the patient’s estimate of hot flash intensity.

 

Note: an excellent patient handout summarizing tamoxifen and drug interactions is available for download at:
www.medicine.iupui.edu/clinpharm/COBRA/TamoxifenGuide.pdf

References:

             

Chustecka Z. Avoid SSRIs in Breast Cancer Patients on Tamoxifen. Medscape Medical News ASCO 2009:

Jordan, CV.  Long-Term Tamoxifen Treatment for Breast Cancer

Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005 Jan 5;97(1):30-9

Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H. Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5187-5193

Mayo Clinic Press Release: Mayo Clinic Research on Tamoxifen Leads to Recommendation for CYP2D6 Gene Test. December 13, 2008. http://www.mayoclinic.org/news2008-rst/5125.html

Stearns V, Slack R, Greep N, et al. Paroxetine Is an Effective Treatment for Hot Flashes: Results From a Prospective Randomized Clinical Trial. Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 6919-6930

Stearns V. Serotonergic agents as an alternative to hormonal therapy for the treatment of menopausal vasomotor symptoms. Treat Endocrinol. 2006;5(2):83-7.

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 Jan 5;97(1):30-9.

Aubert R, Stanek E, Yao J, et al. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. J Clin Oncol 27:18s, 2009 (suppl; abstr CRA508)

Dezentje V, Van Blijderveen N, Gelderblom H, et al. Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: A pharmacoepidemiologic study. J Clin Oncol 27:18s, 2009 (suppl; abstr CRA509)

Cotterchio M, Kreiger N, Darlington G, Steingart A. Antidepressant medication use and breast cancer risk. Am J Epidemiol. 2000 May 15;151(10):951-7.

JNCI Journal of the National Cancer Institute 2003 95(23):1733; doi:10.1093/jnci/95.23.1733-a  2003 Oxford University Press “Press Release: Hot Flash Drug May Hinder Effectiveness of Tamoxifen.”

Mayo Clinic News: http://newsblog.mayoclinic.org/2008/12/11/gene-testing-may-be-key-for-treating-some-women-with-breast-cancer/

Mortimer JE, Flatt SW, Parker BA, Gold EB, Wasserman L, Natarajan L, Pierce JP; WHEL Study Group. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat. 2008 Apr;108(3):421-6.