Current evidence suggests that selective serotonin reuptake inhibitors SSRIs may reduce the effectiveness of tamoxifen citrate in preventing breast cancer recurrence. Tamoxifen and poor metabolizers 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 To understand this, we must detour for a moment and review the pharmacogenomics of tamoxifen, tamoxifen and poor metabolizers.
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 times more active, tamoxifen and poor metabolizers. 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 P 2D6 pathway. Recall that P 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, tamoxifen and poor metabolizers, vitamins, and many exogenous chemicals.
CYP2D6 has about 78 variants, tamoxifen and poor metabolizers, and most of those forms are inactive. These variants represent the following 4 distinct groups of patients based on how they metabolize various chemicals: Poor metabolizers are slow to activate tamoxifen to its active working forms.
Thus, the concentration of endoxifen produced will vary by CYP2D6 genotype. InSchroth and colleagues 4 published data confirming that the effectiveness of tamoxifen varied based on patient CYP2D6 genotype.
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. Patients who had enzyme variants that made them fast metabolizers able to produce endoxifen faster had far better clinical outcomes, tamoxifen and poor metabolizers, with less than half the risk of recurrence HR, 0.
In Decemberthe Mayo Clinic issued a press release reporting the following finding: CYP2D6 activity is affected by exposure to certain drugs. InJin et al 3 were the first to investigate what seemed like an obvious question: They followed up 80 women with breast cancer who were beginning treatment with tamoxifen.
It should be noted that SSRIs in recent years have become a mainstay for the treatment of hot flashes in women with breast cancer. When after 4 months tamoxifen and poor metabolizers and other tamoxifen metabolites had reached a steady state, as expected, endoxifen levels differed by patient genotype.
Endoxifen levels in the normal metabolizers were In women with homozygous normal alleles normal metabolizers taking SSRIs, endoxifen levels were only Two somewhat conflicting studies were presented in June at the annual meeting of the American Society of Clinical Oncology. An American study 8 found that women taking tamoxifen and 1 of tamoxifen and poor metabolizers 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 study 9 was unable to find this relationship, tamoxifen and poor metabolizers. The American study Aubert et al 8 was conducted tamoxifen and poor metabolizers data from Medco, a large health provider. These women were divided into 2 groups. One group comprised women who also took drugs known to be CYP2D6 inhibitors along with tamoxifen, tamoxifen and poor metabolizers.
The other group comprised women did not use medications that inhibit CYP2D6. The group was further split into the following 2 cohorts based on the strength of CYP2D6 inhibition caused by the drugs: Patients who took only tamoxifen had a recurrence rate of 7. The subgroup of patients taking the weaker SSRIs had an 8. In the second American Society of Clinical Oncology study cited, Dutch researchers Dezentje et al 9 used medical databases to identify women with breast cancer who were treated with tamoxifen between and Among these women, also used an SSRI during tamoxifen treatment, of them for 2 months or longer.
While Aubert et al 8 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 The recurrence rate for women who took tamoxifen alone or with an SSRI for less than 1 month was 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 study 10 published in 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 The Mayo Clinic announced in December that it was performing CYP2D6 gene testing in patients with breast cancer before instituting tamoxifen therapy. However, tamoxifen and poor metabolizers, until this announcement, testing for the gene had not been performed routinely at most medical centers.
According to the press release, the study determined that CYP2D6 gene variations identified a subgroup of patients at higher risk of recurrence within the ABCSG-8 trial. 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. 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 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 tamoxifen and poor metabolizers 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 tamoxifen and poor metabolizers 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 sinus allergy and vertigo 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. Lack topamax side effects and info 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.
Finally, an excellent patient handout summarizing tamoxifen and other drug interactions is available for download at www. He served as president tamoxifen and poor metabolizers the CANP from to He has served on the board of directors of the OncANP since and currently acts as secretary to the board.
He was utterly shocked and humbled at the 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 tamoxifen and poor metabolizers with his wife, Rena Bloom, ND.
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