Information for this Personal View was obtained by a search of PubMed using the search terms: “tamoxifen” and “CYP2D6.” No language restrictions were imposed. All papers published up to March 1, 2009, regarding the association between CYP2D6 gene variants and the risk of recurrence in women treated with tamoxifen for adjuvant breast cancer therapy were included. Citations within the selected publications and within other publications on this topic were also assessed.
Personal ViewGenotype-guided tamoxifen therapy: time to pause for reflection?
Introduction
Patients with early stage breast cancer and oestrogen-receptor-positive tumours are candidates for adjuvant hormonal therapy, which nearly halves their recurrence risk.1 Current guidelines recommend the following adjuvant hormonal therapies to reduce recurrence risk in patients with breast cancer with oestrogen-receptor-positive disease.2, 3, 4 Premenopausal patients should receive tamoxifen, a selective oestrogen-receptor modulator, for 5 years. Postmenopausal patients should receive aromatase inhibitors either as initial therapy or after treatment with tamoxifen. Postmenopausal women with contraindications to aromatase inhibitors or who decline aromatase inhibitors should receive 5 years of tamoxifen therapy. Thus, tamoxifen remains a cornerstone of adjuvant breast cancer therapy.
Tamoxifen and aromatase inhibitors prevent the oestrogen receptor from promoting tumour-cell growth by different mechanisms.5 Aromatase inhibitors block the conversion of circulating adrenal androgens to oestrogen by the enzyme aromatase in peripheral tissues,6 thus almost entirely removing the main source of oestrogen production in postmenopausal women, and leaving little or no hormone to stimulate the oestrogen receptor. Tamoxifen's metabolites antagonise the effects of oestrogen in breast tumours by competing with the hormone at receptor-binding sites.7
Mechanisms of resistance to tamoxifen therapy, and predictive markers of susceptibility to resistance, have been widely researched.8, 9, 10 Accurate markers would allow prediction of tamoxifen response and personalisation of combined therapies (figure 1).11, 12 The suggestion has been made that patients with oestrogen-receptor-positive breast cancer with inherited non-functional alleles of the cytochrome P450 CYP2D6 gene might be poor candidates for adjuvant tamoxifen therapy.13, 14, 15 The postulation that CYP2D6 inhibition might reduce the protection conferred by tamoxifen therapy is based on two lines of evidence.16 First, women with CYP2D6 variant alleles that reduce the enzyme function, or who take CYP2D6-inhibiting drugs, such as some selective serotonin-reuptake inhibitors (SSRIs), have reduced concentrations of the tamoxifen metabolites that most strongly bind the oestrogen receptor.17 Second, in some studies, women with CYP2D6 variant alleles have a higher risk of recurrence than women with two functional alleles.13
Our objective is to critically consider both the pharmacological and epidemiological evidence regarding the association between CYP2D6 inhibition and risk of breast cancer recurrence.
Section snippets
Pharmacological evidence
Tamoxifen requires activation to its metabolites to function fully.18 Tamoxifen and its primary metabolite (N-desmethyltamoxifen) are metabolised to 4-hydroxytamoxifen7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 4-hydroxy-N-desmethyltamoxifen20 (sometimes called endoxifen21, 22). These 4-hydroxylated metabolites bind the receptor more than 100-times more readily than tamoxifen, so are the most important modulators of the oestrogen receptor in the tamoxifen pathway.23 Genetic polymorphisms
Epidemiological evidence
Ten epidemiological studies of the association between inheriting a variant CYP2D6 allele and the risk of breast cancer recurrence have been published.42, 43, 44, 45, 46, 47, 48, 49, 50, 51 An additional abstract has appeared, reporting a cross-sectional design to study the association in a survivor population.52 An association in the prevention setting has been presented only as an abstract and a letter.53, 54 We do not discuss this association further because we do not have the complete
Conclusion
The postulation that inhibition of CYP2D6 activity reduces the protection against breast cancer recurrence conferred by tamoxifen therapy rests on the finding that women carrying the variant allele or taking CYP2D6-inhibiting drugs have lower serum concentrations of active metabolites.17, 24, 34 Dose-setting studies with clinical and biomarker outcomes, studies associating clinical outcomes with serum concentrations of tamoxifen and its metabolites, and a simple model of receptor binding, all
Search strategy and selection criteria
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Cited by (98)
Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics
2018, Advances in PharmacologyCitation Excerpt :EMs have slightly higher Z-endoxifen concentrations than IMs (Madlensky et al., 2011). Some research suggests that the total concentration of tamoxifen and its metabolites is sufficiently high so as to overwhelm and inhibit estrogen binding to the estrogen receptor, irrespective of an individual's CYP2D6 genotype and phenotype (Lash, Lien, Sorensen, & Hamilton-Dutoit, 2009). This may be especially relevant in premenopausal women as they have higher estrogen concentrations compared with their postmenopausal counterparts (Burger, Hale, Dennerstein, & Robertson, 2008; Fan et al., 2009; Freour, Barriere, & Masson, 2017).
From tamoxifen to dendrogenin A: The discovery of a mammalian tumor suppressor and cholesterol metabolite
2016, BiochimieCitation Excerpt :Despite the established efficacy of Tam, a complete cure for ER + BC can be hindered by acquired resistance and tumor recurrence after 5 years of treatment [3]. These treatment failures can only be partially explained by ERα status, ERα polymorphisms, or patient susceptibility to Tam metabolism [3,4]. However, Tam is known to display a complex pharmacology and can modulate several other targets [5].
Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-desmethyltamoxifen 4-hydroxylation activity
2014, Drug Metabolism and PharmacokineticsValue of therapeutic drug monitoring of endoxifen in Egyptian premenopausal patients with breast cancer given tamoxifen adjuvant therapy: A pilot study
2023, Journal of Oncology Pharmacy PracticeCross-Ancestry Genome-Wide Association Study Defines the Extended CYP2D6 Locus as the Principal Genetic Determinant of Endoxifen Plasma Concentrations
2023, Clinical Pharmacology and TherapeuticsImproving the transparency of meta-analyses with interactive web applications
2021, BMJ Evidence-Based Medicine