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Tamoxifen, a cornerstone in the adjuvant treatment of estrogen receptor-positive breast cancer, significantly reduces breast cancer recurrence and breast cancer mortality; however, its standard adjuvant dose of 20 mg daily presents challenges due to a broad spectrum of adverse effects, contributing to high discontinuation rates. Dose reductions of tamoxifen might be an option to reduce treatment-related toxicity, but large randomized controlled trials investigating the tolerability and, more importantly, efficacy of low-dose tamoxifen in the adjuvant setting are lacking. We conducted an extensive literature search to explore evidence on the tolerability and clinical efficacy of reduced doses of tamoxifen. In this review, we discuss two important topics regarding low-dose tamoxifen: (1) the incidence of adverse effects and quality of life among women using low-dose tamoxifen; and (2) the clinical efficacy of low-dose tamoxifen examined in the preventive setting and evaluated through the measurement of several efficacy derivatives. Moreover, practical tools for tamoxifen dose reductions in the adjuvant setting are provided and further research to establish optimal dosing strategies for individual patients are discussed., (© 2024. The Author(s).)

Background: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14-16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM)., Methods: This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration < 16 nM. The primary endpoint of the study was the percentage of patients with an endoxifen level ≥ 16 nM at 6 months after the start of therapy compared with historical data, in other words, 80% of patients with endoxifen levels ≥ 16 nM with standard therapy., Results: In total, 145 patients were included. After 6 months, 89% of the patients had endoxifen levels ≥ 16 nM, compared with a literature-based 80% of patients with endoxifen levels ≥ 16 nM at baseline (95% confidence interval 82-94; P = 0.007). In patients with an affected CYP2D6 allele, it was not always feasible to reach the predefined endoxifen level of ≥ 16 nM. No increase in tamoxifen-related adverse events was reported after dose escalation., Conclusion: This study demonstrated that it is feasible to increase the percentage of patients with endoxifen levels ≥ 16 nM using TDM. TDM is a safe strategy that offers the possibility of nearly halving the number of patients with endoxifen levels < 16 nM., (© 2021. The Author(s).)

Background and Objective: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen., Methods: Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study., Results: Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159-637 nM·h] versus 99.2 nM·h [range 70.0-210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects., Conclusion: In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients.

The aim of this study was to validate an earlier developed high-performance highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for quantification of tamoxifen and its three main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen) in scalp hair. This non-invasive method might, by segmental analysis of hair, be useful in the determination of the concentration of drugs and its metabolites over time, which can be used to study a wide variety of clinical relevant questions. Hair samples (150-300 hair strands, cut as close to the scalp as possible from the posterior vertex region of the head) were collected from female patients taking tamoxifen 20mg daily (n=19). The analytes were extracted using a liquid-liquid extraction procedure with carbonate buffer at pH 8.8 and a mixture of n-hexane/isopropranol method, followed by UPLC-MS/MS chromatography, based on an earlier validated method. The calibration curves were linear in the range of 1.00-200 pmol for tamoxifen and N-desmethyl-tamoxifen, with lower limit of quantitation of 1.00 pmol and 0.100-20.0 pmol with lower limit of quantitation of 0.100 pmol for endoxifen and 4-hydroxy-tamoxifen. Assay performance was fair with a within-run and between-run variability less than 9.24 at the three quality control samples and less than 15.7 for the lower limit of quantitation. Importantly, a steep linear decline was observed from distal to proximal hair segments. Probably, this is due to UV exposure as we showed degradation of tamoxifen and its metabolites after exposure to UV-light. Furthermore, higher concentrations of tamoxifen were found in black hair samples compared to blond and brown hair samples. We conclude that measurement of the concentration of tamoxifen and its main metabolites in hair is possible, with the selective, sensitive, accurate and precise UPLC-MS/MS method. However, for tamoxifen, it seems not possible to determine exposure over time with segmental analysis of hair, probably largely due to the effect of UV irradiation. Further research should therefore focus on quantification of other anticancer drugs, in segmented scalp hair, that are less sensitive to UV irradiation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen.

Clinical response to tamoxifen varies widely among women treated with this drug for hormone receptor-positive breast cancer. The principal active metabolite - endoxifen - is generated through hepatic metabolism of tamoxifen, with key roles for cytochrome P450 (CYP) CYP2D6 and CYP3A. By influencing endoxifen formation, genetic variants of CYP2D6 may affect response to tamoxifen. After a decade of research, examining the effects of CYP2D6 genetic variants on tamoxifen efficacy, there is still no agreement on the clinical utility of CYP2D6 genotype as biomarker for the prediction of breast cancer outcome, because studies revealed conflicting results. However, tamoxifen metabolism is complex and involves several other drug-metabolizing enzymes. Genetic variants of other CYP enzymes, including CYP3A4 and CYP2C9/19, as well as co-medication interfering with the metabolic activity of CYP2D6 and CYP3A4 have been shown to affect endoxifen concentrations and may also contribute to the variability in response to tamoxifen. Phenotyping strategies can predict endoxifen exposure more accurately than CYP2D6 genotype, but do not take into account all factors influencing endoxifen exposure. Therapeutic drug monitoring (TDM) is likely to be the optimal strategy for individualization of tamoxifen treatment. According to a growing amount of literature, endoxifen concentration seems to be a predictor of clinical outcome. The relationship between endoxifen levels and breast cancer outcomes has to be replicated and confirmed and the value of TDM should be evaluated in prospective clinical trials. Caution is advised regarding the concomitant use of medications which could interact with tamoxifen, including inhibitors and inducers of CYP enzymes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Tamoxifen is a largely inactive pro-drug, requiring metabolism into its most important metabolite endoxifen. Since the cytochrome P450 (CYP) 2D6 enzyme is primarily involved in this metabolism, genetic polymorphisms of this enzyme, but also drug-induced CYP2D6 inhibition can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy of tamoxifen treatment. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have been effectively used for the treatment of depression and hot flashes, both of which occur frequently in tamoxifen-treated women. Due to the drug-drug interaction considerably reduced endoxifen concentrations by inhibition of CYP2D6 will be the result. Evidence of a significant influence of strong CYP2D6-inhibiting drugs on the pharmacokinetics of tamoxifen has resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants (e.g., paroxetine, fluoxetine) in patients treated with tamoxifen for breast cancer. Nevertheless, dispensing data for tamoxifen and seven regularly used SSRIs/SNRIs in the period between 2005 and 2010, obtained from a large community pharmacy database in the Netherlands (3,000,000 people), show that the potent CYP2D6-inhibiting drug paroxetine remains one of the most frequently used antidepressants in tamoxifen-treated patients. Moreover, trends in the use of SSRIs/SNRIs in the population of all women were similar with trends in women using tamoxifen. Apparently, the recommendations to avoid paroxetine in tamoxifen-treated women have not been implemented into clinical practice. Several reasons may underlie continued use of this drug-drug combination. Contrary to CYP2D6 polymorphisms, drug-induced CYP2D6 inhibition can easily be avoided, since alternative drugs are available. In clinical practice, one should strive to avoid potent CYP2D6 inhibitors as much as possible in tamoxifen-treated patients to reduce the risk of compromising the efficacy of the hormonal therapy. Co-medication should be reviewed by both physicians and pharmacists and potent CYP2D6 inhibitors ought to be switched to weaker alternatives.

Tamoxifen is a commonly prescribed drug in both early and metastatic breast cancer. Prospective studies in Asian populations demonstrated that tamoxifen‐related liver steatosis occurred in more than 30% of the patients within 2 years after start of treatment. No well‐designed prospective studies on potential tamoxifen‐related liver steatosis have been conducted in Caucasian patients so far. Therefore, our prospective study aimed to assess the incidence of tamoxifen‐related liver steatosis for a period of 2 years in a population of Caucasian breast cancer patients treated with tamoxifen. Patients with an indication for adjuvant treatment with tamoxifen were included in this study. Data were collected at 3 months (T1) and at 2 years (T2) after start of tamoxifen treatment (follow‐up period of 21 months). For the quantification of liver steatosis, patients underwent liver stiffness measurement by transient elastography with simultaneous controlled attenuation parameter (CAP) determination using the FibroScan. A total of 95 Caucasian breast cancer patients were included in this evaluation. Liver steatosis was observed in 46 of 95 (48%) and 48 of 95 (51%) of the patients at T1 and T2, respectively. No clinically relevant increase in liver steatosis was observed during the treatment period of 2 years with tamoxifen (median CAP = 243 ± 49 dB/m (T1) and 253 ± 55 dB/m (T2), respectively; p = 0.038). Conclusion: In this prospective longitudinal study in Caucasian breast cancer patients, no clinically relevant alterations in liver steatosis in terms of CAP values and liver/lipid parameters were observed after 2 years of tamoxifen treatment. This study therefore demonstrates an absence of tamoxifen‐related adverse events such as steatosis and (early) development of fibrosis or cirrhosis during a treatment period of at least 2 years. [ABSTRACT FROM AUTHOR]

Introduction: In breast cancer patients treated with the anti-estrogen tamoxifen, low concentrations of the active metabolite endoxifen are associated with more disease recurrence. We hypothesized that we could increase endoxifen concentrations by induction of its formation and inhibition of its metabolism by co-administration of probenecid. Methods: We conducted a crossover study and measured endoxifen concentrations in patients on steady-state tamoxifen monotherapy and after 14 days of combination treatment with probenecid. Eleven evaluable patients were included. Results: Treatment with tamoxifen and probenecid resulted in a 26% increase of endoxifen area under the plasma concentration–time curve from 0 to 24 h (AUC0–24h) compared to tamoxifen monotherapy (95% confidence interval [CI]: 8–46%; p < 0.01), while the maximum observed endoxifen concentration increased with 24% (95% CI: 7–44%; p < 0.01). The metabolic ratio of endoxifen to tamoxifen increased with 110% (95% CI: 82–143%; p < 0.001) after the addition of probenecid. Conclusion: Probenecid resulted in a clinically relevant increase of endoxifen concentrations in breast cancer patients treated with adjuvant tamoxifen. This combination therapy could provide a solution for patients with a CYP2D6-poor metabolizer phenotype or endoxifen concentrations below the threshold despite earlier tamoxifen dose. [ABSTRACT FROM AUTHOR]

Background and Objectives: Endoxifen is the active metabolite of tamoxifen, and a minimal plasma concentration of 16 nM has been suggested as a threshold above which it is effective in reducing the risk of breast cancer recurrence. The aim of the current analysis was to investigate the cost-effectiveness of therapeutic drug monitoring (TDM)-guided tamoxifen dosing. Methods: A cost-effectiveness analysis was performed from a Dutch healthcare perspective, using a partitioned survival model and a lifetime horizon. The reduction in subtherapeutic treatment following TDM is modelled as improved rates of recurrence-free survival (RFS) and overall survival (OS) in comparison to standard tamoxifen treatment. A probabilistic sensitivity analysis (PSA) and a series of scenario analyses were performed to assess the robustness of the results. Results: Base-case results estimated a total increase in life years and quality-adjusted life years (QALYs) for TDM of 0.40 and 0.53, respectively. Total costs for TDM and standard tamoxifen treatment are €32,893 and €39,524, respectively. The TDM intervention results in both more QALYs and less healthcare costs, indicating a dominating effect for TDM. The PSA results indicate that the probability of TDM being cost-effective is 92% when using a willingness-to-pay threshold of €20,000. Conclusions: TDM-guided dose optimization of tamoxifen is estimated to save costs and increase QALYs for early breast cancer patients. [ABSTRACT FROM AUTHOR]

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20–30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/− piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0–24h decreased with 7.7% (95%CI: −15.4 to 0.7%; p = 0.07) with curcumin and 12.4% (95%CI: −21.9 to −1.9%; p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0–24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/− piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20–40% of the patients), especially in EM patients. [ABSTRACT FROM AUTHOR]

Tamoxifen is an effective treatment for primary breast cancer but increases the risk for venous thromboembolism. Tamoxifen decreases anticoagulant proteins, including antithrombin (AT), protein C (PC) and tissue factor (TF) pathway inhibitor, and enhances thrombin generation (TG). However, the relation between plasma concentrations of both tamoxifen and its active metabolite endoxifen and coagulation remains unknown. Tamoxifen and endoxifen were measured in 141 patients from the prospective open-label intervention TOTAM-study after 3 months (m) and 6 m of tamoxifen treatment. Levels of AT and PC, the procoagulant TF, and TG parameters were determined at both timepoints if samples were available (n = 53–135 per analysis). Levels of coagulation proteins and TG parameters were correlated and compared between: 1) quartiles of tamoxifen and endoxifen levels, and 2) 3 m and 6 m of treatment. At 3 m, levels of AT, PC, TF and TG parameters were not associated with tamoxifen nor endoxifen levels. At 6 m, median TF levels were lower in patients in the 3rd (56.6 [33] pg/mL), and 4th (50.1 [19] pg/mL) endoxifen quartiles compared to the 1st (lowest) quartile (76 [69] pg/mL) (P= 0.027 and P= 0.018, respectively), but no differences in anticoagulant proteins or TG parameters were observed. An increase in circulating TF levels (3 m: 46.0 [15] versus 6 m: 54.4 [39] pg/mL, P < 0.001) and TG parameters was observed at the 6 m treatment timepoint, while AT and PC levels remained stable. Our results indicate that higher tamoxifen and endoxifen levels are not correlated with an increased procoagulant state, suggesting tamoxifen dose escalation does not further promote hypercoagulability. [Display omitted] • Patients who receive tamoxifen have increased risk of venous thromboembolism (VTE). • Higher tamoxifen or endoxifen levels do not correlate with an enhanced procoagulant state. • This points towards no further increase in VTE risk upon tamoxifen dose escalation. • Tamoxifen may increase tissue factor levels over time which requires further study. [ABSTRACT FROM AUTHOR]

Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose. Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined. A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %. Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %. [Display omitted] • Continuous expression of CYP2D6 activity based on genotype is feasible. • A model-informed dosing strategy for tamoxifen therapy was developed. • The proportion of patients with subtherapeutic levels can be reduced from 21 % to 5 %. • This is the first clinical application for model-informed precision dosing in oncology. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe health-related quality of life (HRQoL) and productivity in Dutch breast cancer patients treated with tamoxifen in an adjuvant setting. Patients who started treatment with a standard dose of tamoxifen and who gave written informed consent, were eligible for participation in this trial. A total of 145 patients were asked to complete a survey at 3 months (T1) and 6 months (T2) after initiation of tamoxifen. HRQoL was measured by the EQ-5D-5L and the FACT-B questionnaire, and productivity by using the iMTA Productivity Costs Questionnaire. At 3 months 137 (95%) and at 6 months 133 (92%) patients responded to the surveys. EQ-5D-5 L utility values for T1 and T2 were 0.81 ± 0.17 and 0.81 ± 0.18, respectively. FACT-B scores for T1 and T2 were 109 ± 17.9 and 108 ± 20.0, respectively. No differences in both EQ-5D-5 L utility and FACT-B scores were found between T1 and T2 (p > 0.05). Age and employment status were statistically significantly associated with FACT-B scores (p = 0.04 and p = 0.03, respectively), indicating that younger and unemployed respondents had lower FACT-B scores. Importantly, both short-term and long-term productivity improved during the first six months of tamoxifen treatment (p < 0.05). Here, short-term productivity losses (consisting of absenteeism, presenteeism and unpaid work) for T1 and T2 were estimated at € 855,- and € 396,-, respectively. Long-term productivity losses (consisting of absenteeism) for T1 and T2 were estimated at € 2876,- and € 1104,-, respectively. In conclusion, this study presents HRQoL scores using different instruments and detailed loss of productivity estimates for breast cancer patients treated with adjuvant endocrine therapy. The results presented here can be used to inform input parameters in health economic evaluations of interventions for patients with breast cancer in the Netherlands and other Western countries and ultimately support decision making. [Display omitted] • Health economic models require input parameters to describe the patient population evaluated. • The EQ-5D-5 L and FACT-B and productivity were assessed in tamoxifen-treated breast cancer patients. • Younger and employed patients had overall better quality of life. • Productivity of patients improved during the first 6 months of treatment with tamoxifen. [ABSTRACT FROM AUTHOR]