Selective Serotonin Reuptake Inhibitors and Adjuvant Tamoxifen Therapy: Risk of Breast Cancer Recurrence and Mortality
2010; Future Medicine; Volume: 6; Issue: 6 Linguagem: Inglês
10.2217/fon.10.65
ISSN1744-8301
AutoresDeirdre Cronin‐Fenton, Timothy L. Lash, Henrik Toft Sørensen,
Tópico(s)Cancer-related cognitive impairment studies
ResumoFuture OncologyVol. 6, No. 6 EditorialFree AccessSelective serotonin reuptake inhibitors and adjuvant tamoxifen therapy: risk of breast cancer recurrence and mortalityDeirdre Cronin-Fenton, Timothy L Lash & Henrik T SørensenDeirdre Cronin-Fenton† Author for correspondence, Timothy L LashDepartment of Clinical Epidemiology, Aarhus University, Olof Palmes Alle 43–46, 8200 Aarhus N, Denmark & Henrik T SørensenDepartment of Clinical Epidemiology, Aarhus University, Olof Palmes Alle 43–46, 8200 Aarhus N, DenmarkPublished Online:8 Jun 2010https://doi.org/10.2217/fon.10.65AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Up to a quarter of women with breast cancer suffer clinical depression during the course of their treatment and recovery [1]. Regardless of whether a depression is premorbid, arises from the distress of the cancer diagnosis itself or occurs as a side effect of breast cancer treatment, managing symptoms of depression may improve compliance with treatment and thereby affect cancer outcome. The majority of breast cancer patients with depression or vasomotor symptoms are prescribed selective serotonin reuptake inhibitors (SSRIs).In cancer treatment, tamoxifen has been used in routine clinical practice as the 'gold standard' for estrogen receptor-positive breast tumors for over 25 years [2,3]. It halves the risk of breast cancer recurrence and reduces the risk of death by 25%. Tamoxifen is also effective as a preventive agent in women at high risk of breast cancer [4]. Both SSRIs and tamoxifen are metabolized primarily by the same enzyme, cytochrome P450 variant 2D6 (CYP2D6) [5,6]. The net result can be competitive inhibition or direct inhibition, resulting in a reduced plasma concentration of one of the active metabolites of tamoxifen, 4-hydroxy-N-desmethyltamoxifen (sometimes known as endoxifen) [7,8]. Given the relatively frequent use of SSRIs by patients receiving tamoxifen treatment, the safety of concurrent use of the two medications is under scrutiny. The key question is whether SSRI-mediated CYP2D6 inhibition reduces or eliminates the survival advantage conferred by tamoxifen in breast cancer patients.Selective serotonin reuptake inhibitors inhibit CYP2D6 to varying degrees. Paroxetine and fluoxetine are the strongest inhibitors, with paroxetine irreversibly inhibiting CYP2D6 activity. Compounds such as fluvoxamine and citalopram are weaker inhibitors [9]. Reduced plasma concentrations of 4-hydroxy-N-desmethyltamoxifen have been reported for women who used paroxetine concomitantly with tamoxifen, but not for those who used tamoxifen together with the selective serotonin norepinephrine reuptake inhibitor venlafaxine – a weak CYP2D6 inhibitor [7,8].Changes in plasma concentrations of 4-hydroxy-N-desmethyltamoxifen suggest that women taking a potent CYP2D6 inhibitor might benefit less, or not at all, from tamoxifen adjuvant therapy. However, findings from clinical epidemiology studies addressing this question have been inconsistent. Our population-based case–control study in Denmark documented that citalopram and its stereoisomer, escitalopram, were the most frequently used SSRIs among Danish breast cancer patients [10–12]. We saw no evidence of an association between concurrent use of citalopram/escitalopram and tamoxifen and risk of breast cancer recurrence, regardless of the duration of overlapping use of the two compounds. In the small subset of women taking more potent CYP2D6 inhibitors (fluoxetine, paroxetine and sertraline), there was also no association with breast cancer recurrence. By contrast, a Canadian study reported higher breast cancer mortality among women who used paroxetine concurrently with tamoxifen. The highest mortality occurred in women with the longest concurrent use of these two medications [13]. A US population-based study presented by Aubert and colleagues at the American Society of Clinical Oncology Annual Meeting in 2009 also found an increased risk of breast cancer recurrence among women concurrently using tamoxifen and the more potent CYP2D6 inhibitors (paroxetine, fluoxetine and sertraline), but not among women using the weaker inhibitors (citalopram, escitalopram and fluvoxamine) [14,15]. Only an abstract of this study is available at the time of writing. More detailed examination of their findings awaits publication of the full report. A recently published Dutch study, also presented at the 2009 American Society of Clinical Oncology meeting, found no association between CYP2D6 inhibitor use (most frequently paroxetine and fluoxetine) in patients treated with tamoxifen and breast cancer recurrence [16]. However, this finding was based on only 18 breast cancer events among SSRI users.Two additional studies, both US-based, reported no association between antidepressants and rates of breast cancer recurrence or mortality, even among users of the most potent CYP2D6 inhibitors [17,18]. However, these studies had low power. No studies have examined the impact of concurrent use of the weaker CYP2D6 inhibitor, fluvoxamine on breast cancer outcome. In a letter to the editor of the British Medical Journal, Jenkinson [19] emphasized that two of the published studies [11,13] reported lowest mortality among users of fluoxetine, despite it being a relatively potent CYP2D6 inhibitor. Thus, findings from the limited observational studies available do not appear to support the biological rationale for a negative impact of CYP2D6 inhibitor use on breast cancer recurrence and mortality in women using tamoxifen. Perhaps the reduction in plasma concentrations of tamoxifen's active metabolites from concurrent SSRI treatment is insufficient to actually eliminate tamoxifen's anti-tumor effects [20,21].Over 90 polymorphic variants of CYP2D6 have been identified, some of which reduce or eliminate CYP2D6 activity [101]. Depending on their CYP2D6 genotype, patients can be classified as poor (two nonfunctional alleles), intermediate (one nonfunctional and one reduced-activity allele), extensive (at least one normal allele) or ultra-rapid metabolizers (two functional alleles) [22–24]. Research has demonstrated reduced plasma concentrations of 4-hydroxy-N-desmethyltamoxifen among patients heterozygous or homozygous for the CYP2D6 variant allele [7,8]. Thus, in theory, a patient's CYP2D6 genotype profile can determine the effectiveness of drugs such as tamoxifen. Nonetheless, the published research, extensively reviewed elsewhere [21], has demonstrated little overall variation in tamoxifen effectiveness, in terms of breast cancer recurrence and mortality, among individuals with functionally variant CYP2D6 alleles, compared with those without variant alleles.To date, two published studies have examined the combined effect of genetic variants and pharmacologic CYP2D6 inhibitors (including antidepressants) on the effectiveness of tamoxifen in reducing breast cancer recurrence and mortality. Using data from a registry of BRCA1/2 carriers, Newman et al. found higher recurrence and mortality among postmenopausal women who were CYP2D6 poor metabolizers (those with CYP2D6 variant alleles or those who took CYP2D6-inhibiting medications), especially among women with the BRCA2 mutation, based on the low numbers of patients with this mutation [25]. A larger study of postmenopausal women by Goetz et al. found that patients with decreased CYP2D6 activity (defined as the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor) had higher breast cancer recurrence rates and poorer survival [26]. In both studies, however, information on CYP2D6-inhibitor drugs was collected from medical records after breast cancer recurrence, and abstractors may not have been blinded to the study outcomes.Several factors may explain the conflicting findings of the few published studies. First, national differences in physicians' preferences for prescribing specific antidepressants (e.g., citalopram is a frequent choice in Denmark), together with variation in the population distribution of CYP2D6 genetic variants, are likely to introduce variation in study results. Second, sources of medication data differ across studies, ranging from medical record review [18,25,27], to prescription claims databases [10–13,15,16,28]. Third, much previous research has had low statistical power owing to limited sample size regarding various drug exposures, making it difficult to draw definitive conclusions [11,18,25,28]. Fourth, published studies provide limited detail on tamoxifen compliance, although prescription claims data are likely to be a good proxy for actual use, especially when multiple prescriptions are filled and patients are reimbursed for a portion of the cost. Finally, very limited data is available on the combined effect of CYP2D6 genetic variants and CYP2D6-inhibiting medications with regard to breast cancer recurrence and mortality. Well-designed studies with prospectively collected data are warranted to investigate these intricate and clinically important gene–drug interactions.Despite its merits in terms of breast cancer prevention and reductions in recurrence and mortality, the antiestrogenic and estrogenic effects of tamoxifen produce mild-to-severe side effects, including hot flashes and vasomotor symptoms, induction or exacerbation of depression, venous thromboembolism and endometrial cancer [3]. Women who experience tamoxifen-induced side effects are more likely to discontinue treatment [29]. Thus, the importance of effective clinical control of such side effects cannot be overstated, both in terms of health-related quality of life and breast cancer outcomes. While the findings of observational studies on the impact of concurrent use of antidepressants and tamoxifen remain inconclusive, mounting evidence suggests that, unless otherwise contraindicated, women on tamoxifen who experience depression and/or vasomotor symptoms can be prescribed weaker CYP2D6 inhibitors (citalopram, escitalopram, venlafaxine) without a negative impact on breast cancer prognosis [102].Financial & competing interests disclosureThis research was supported by grants from the US National Cancer Institute (R01CA118708), the Danish Cancer Society (DP06117) and the Karen Elise Jensen Foundation. 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Tyrosine Kinase Inhibitors and Selective Estrogen Receptor Modulators: A Clinical Pharmacology Laboratory Perspective7 June 2012Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes10 January 2014 | Expert Review of Clinical Pharmacology, Vol. 4, No. 3 Vol. 6, No. 6 STAY CONNECTED Metrics History Published online 8 June 2010 Published in print June 2010 Information© Future Medicine LtdFinancial & competing interests disclosureThis research was supported by grants from the US National Cancer Institute (R01CA118708), the Danish Cancer Society (DP06117) and the Karen Elise Jensen Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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