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Individualization of Endocrine Therapy in Breast Cancer
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Amelia B. Zelnak, Ruth M. O’Regan, Clodia Osipo
Tamoxifen undergoes extensive primary and secondary metabolism. The secondary metabolite 4-hydroxy-N-desmethyl tamoxifen (endoxifen) is formed by the CYP2D6-mediated oxidation of N-desmethyl tamoxifen and has been shown to play an important role in the anticancer effect of tamoxifen. CYP2D6 genotyping has revealed that women can be classified as either poor, intermediate, or extensive metabolizers of tamoxifen. Women who are poor metabolizers of tamoxifen, and, therefore, have lower levels of endoxifen, have been shown to have worse disease-free survival. No difference in overall survival has been shown (17). Women who are extensive metabolizers of tamoxifen have also been shown to experience more hot flashes. A recent study showed that women who experience hot flashes while on tamoxifen had a hazard ratio of recurrence of 0.51 compared with women without hot flashes (18). This study suggests that vasomotor symptoms and efficacy of tamoxifen may be related to a women’s pharmacogenetics.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
N-Desmethyltamoxifen is p-hydroxylated mainly by CYP2D6 to its most abundant and therapeutically active metabolite endoxifen (4-hydroxy-N-desmethyltamoxifen, metabolite BX) (Figure 3.96) (Beverage et al. 2007; Crewe et al. 2002; Dehal and Kupfer 1997; Jacolot et al. 1991; Stearns et al. 2003). Endoxifen can also be generated from 4-hydroxytamoxifen via N-demethylation (Desta et al. 2004), but the 4-hydroxylation of N-desmethyltamoxifen by CYP2D6 appears to be the major source of endoxifen production in vivo. Plasma levels of endoxifen are 5- to 10-fold higher than those of 4-hydroxytamoxifen in most women taking tamoxifen (Johnson et al. 2004). Endoxifen exhibits potency similar to 4-hydroxytamoxifen with respect to estrogen receptor binding affinity, suppression of estrogen-dependent cell growth, and gene expression (Johnson et al. 2004). Although both 4-OH-tamoxifen and endoxifen are considered the major active metabolites of tamoxifen that have potent antiestrogenic activity, endoxifen is considered to play a more significant role in tamoxifen pharmacological activity in vivo. CYP2D6 plays a critical role in the activation of tamoxifen to endoxifen by sequential N-demethylation and 4-hydroxylation (Beverage et al. 2007; Crewe et al. 2002; Dehal and Kupfer 1997; Desta et al. 2004; Stearns et al. 2003).
Pharmacogenomics of Tamoxifen
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen or endoxifen. Tamoxifen, which has been clinically used for more than 50 years, is proven to be effective in the adjuvant treatment and metastatic tumor of breast cancer. Tamoxifen is suggested to be used in the treatment of patients with pre- and postmenopausal estrogen receptor (ER)–positive breast cancer. Adjuvant tamoxifen therapy is one of the major endocrine treatment options, especially for women who have ovarian estrogenic activity that cannot be regulated by aromatase inhibitors. Five-year or 10-year adjuvant tamoxifen treatment effectively reduces recurrence of ER-positive tumors [1, 2]. Moreover, tamoxifen is approved for the chemoprevention of breast cancer for women at high risk of developing the disease. Tamoxifen may cause relatively mild adverse effects compared to chemotherapy, but is occasionally (or often) severe requiring to discontinue the treatment. “Hot flash” is the most common adverse event observed in patients treated with tamoxifen.
Benefit–risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John’s wort in breast cancer patients
Published in Climacteric, 2019
X. Ruan, A. O. Mueck, A.-M. Beer, B. Naser, S. Pickartz
Concomitant medication with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) should be avoided in patients using tamoxifen since it leads to reductions of endoxifen levels88. Tamoxifen is metabolized into its active metabolite endoxifen mainly via CYP2D6 and CYP3A4 (Figure 1)89,90. Therefore, inhibition of CYP2D6 (and, as the case may be, inhibition of CYP3A4) reduces the generation of endoxifen and possibly the efficacy of tamoxifen. The pharmacokinetics of tamoxifen is complex, involving additional CYP isoenzymes and the inactivation of tamoxifen and its active metabolites via phase II reactions91. Tamoxifen’s metabolism and the impact of endoxifen levels on tamoxifen’s efficacy are controversially discussed92,93. A recently published prospective multicenter study showed that the objective response rate (using RECIST criteria 1.0), clinical benefit, progression-free survival, and tolerability were not associated with endoxifen levels93.
Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen
Published in Expert Review of Clinical Pharmacology, 2019
A.B. Sanchez-Spitman, J.J. Swen, V.O. Dezentje, D.J.A.R. Moes, H. Gelderblom, H.J. Guchelaar
Another relevant point is the complexity of tamoxifen metabolism and the high number of described active metabolites, which also might be important for predicting tamoxifen efficacy. Endoxifen is considered the most crucial active metabolite of tamoxifen metabolite, but it has a comparable anti-estrogenic activity to 4-hydroxy-tamoxifen. At the same time, other active metabolites, e.g. norendoxifen could also potentially affect tamoxifen efficacy, since it has dual activity. As a consequence, the current approaches in which only a few elements of tamoxifen metabolism, such as CYP2D6 phenotypes, are used, might not be the best manner to predict tamoxifen efficacy. Since many other enzymes and tamoxifen active metabolites are involved, together with non-genetic determinants of response, a more complex analysis including all these key elements could be required in order to improve the prediction of tamoxifen efficacy and safety.
Personalizing tamoxifen therapy in adjuvant therapy: a brief summary of the ongoing discussion
Published in Expert Review of Clinical Pharmacology, 2023
Anabel Sanchez-Spitman, Henk-Jan Guchelaar
As a consequence, there is currently a tendency to take the focus off CYP2D6 and alternatives such as metabolite concentrations are proposed to predict tamoxifen efficacy, e.g. endoxifen or 4-hydroxy-tamoxifen concentrations. In theory, these active metabolites are supposed to be ‘closer to the pharmacological effect’ of tamoxifen than CYP2D6 genotypes or phenotypes only. Among the three principal tamoxifen active metabolites, endoxifen and 4-hydroxy-tamoxifen concentrations have been proposed as feasible alternatives to guide tamoxifen efficacy. In the case of 4-hydroxy-tamoxifen only a few studies have showed a positive association clinical outcome [1], but many others failed to find such a relationship. On the contrary, endoxifen concentrations have been suggested as a better predictor to guide tamoxifen efficacy. Three retrospective studies have obtained a positive association between improved clinical outcomes with higher endoxifen concentrations. Madlensky and colleagues investigated 1370 breast cancer patients and described a ‘threshold’ for endoxifen of 5.97 ng/ml above which individuals had a 26% lower chance of breast cancer relapse [22]. In the same line, Saladores et al. [23] and Helland and colleagues [24] also described even lower ‘cut-off’ values of 5.2 ng/ml and 3.3 ng/ml, respectively. While the aforementioned studies were based on retrospective data, only a few recent studies based on prospective datasets based on the metastatic [25,26], neoadjuvant [25], and adjuvant [27,28]settings have been analyzed, and authors have failed to validate a strong and clinically relevant relationship.