BackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study ... Show moreBackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS).Results668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R-2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R-2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96-1.04, p = 0.84) or CYP polymorphisms.ConclusionSerum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients. Show less
New drugs for use as tuberculosis (TB) treatment are needed due to the constrains of classical antibiotics against TB and the rise of antibiotic-resistant strains, making TB a harder and harder... Show moreNew drugs for use as tuberculosis (TB) treatment are needed due to the constrains of classical antibiotics against TB and the rise of antibiotic-resistant strains, making TB a harder and harder disease to treat. This thesis is focused on using the in vivo whole animalzebrafish embryo model for TB to evaluate potential anti-TB host-directed therapeutics (HDTs) arising from in vitro screens. Although in vitro screens for HDTs using cellular models can be performed at high throughput, a limiting step is the validation in whole animal models and translation of results to clinical applications. Due to the complex infection dynamics of mycobacteria, the use of whole animal models is indispensable in research into TB and the zebrafish model has contributed key findings about host-pathogen dynamics during mycobacterial infection. One of the most promising host targets of HDTs is autophagy, which is recognized as an important host-protective pathway. Boosting autophagy levels using HDTs could be a way to overcome the pathogen’s autophagy evasion strategies and could therefore be a promising therapeutic route. For this thesis we took advantage of the possibilities of the zebrafish embryo model for TB and the zebrafish toolkit to study several autophagy-modulating HDTs as potential anti-TB drugs. Show less
For more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide... Show moreFor more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide variability in response to therapy is still observed since disease recurrence happens in nearly 30 % of breast cancer patients. Tamoxifen has a complex metabolism and it is mainly metabolized by CYP2D6 enzyme, among others, into endoxifen, the most active metabolite of tamoxifen.In the search of a manner in order to individualize endocrine therapy with tamoxifen, CYP2D6 genotyping and therapeutic drug monitoring based on endoxifen serum concentrations were proposed as potential manners to individualize tamoxifen efficacy. Both approaches have been an ongoing discussion and many studies have been published claiming both negative and positive associations. This thesis mainly focusses on CYP2D6 genotyping and endoxifen concentrations and their impact on clinical survival outcome in early breast cancer patients treated with tamoxifen. Show less
Background Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most... Show moreBackground Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most commonly used dietary supplements among breast cancer patients. EGCG may alter the metabolism of tamoxifen. Therefore, the aim of this study was to investigate the influence of green tea supplements on the pharmacokinetics of endoxifen; the most relevant active metabolite of tamoxifen. Methods In this single-center, randomized cross-over trial, effects of green tea capsules on endoxifen levels were evaluated. Patients treated with tamoxifen for at least 3 months were eligible for this study. After inclusion, patients were consecutively treated with tamoxifen monotherapy for 28 days and in combination with green tea supplements (1 g twice daily; containing 300 mg EGCG) for 14 days (or vice versa). Blood samples were collected on the last day of monotherapy or combination therapy. Area under the curve (AUC(0-24h)), maximum concentration (C-max) and minimum concentration (C-trough) were obtained from individual plasma concentration-time curves. Results No difference was found in geometric mean endoxifen AUC(0-24h)in the period with green tea versus tamoxifen monotherapy (- 0.4%; 95% CI - 8.6 to 8.5%;p = 0.92). Furthermore, no differences inC(max)(- 2.8%; - 10.6 to 5.6%;p = 0.47) norC(trough)(1.2%; - 7.3 to 10.5%;p = 0.77) were found. Moreover, no severe toxicity was reported during the whole study period. Conclusions This study demonstrated the absence of a pharmacokinetic interaction between green tea supplements and tamoxifen. Therefore, the use of green tea by patients with tamoxifen does not have to be discouraged. Show less
Purpose Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy.... Show morePurpose Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy. Three endoxifen thresholds have been suggested (5.9 ng/ml, 5.2 ng/ml and 3.3 ng/ml) for therapeutic drug monitoring (TDM). Our aim was to validate these thresholds and to examine endoxifen exposure with clinical outcome in early-breast cancer patients using tamoxifen. Methods Data from 667 patients from the CYPTAM study (NTR1509) were available. Patients were stratified (above or below), according to the endoxifen threshold values for tamoxifen efficacy and tested by Cox regression. Logistic regressions to estimate the probability of relapse and tamoxifen discontinuation were performed. Results None of the thresholds showed a statistically significant difference in relapse-free survival: 5.2 ng/ml threshold: hazard ratio (HR): 2.545, 95% confidence interval (CI) 0.912-7.096,pvalue: 0.074; 3.3 ng/ml threshold: HR: 0.728; 95% CI 0.421-1.258,pvalue: 0.255. Logistic regression did not show a statistically significant association between the risk of relapse (odds ratio (OR): 0.971 (95% CI 0.923-1.021,pvalue: 0.248) and the risk for tamoxifen discontinuation (OR: 1.006 95% CI 0.961-1.053,pvalue: 0.798) with endoxifen concentrations. Conclusion Our findings do not confirm the endoxifen threshold values for TDM nor does it allow definition of a novel threshold. These findings indicate a limited value of TDM to guide tamoxifen efficacy. Show less
Hellemond, I.E.G. van; Smorenburg, C.H.; Peer, P.G.M.; Swinkels, A.C.P.; Seynaeve, C.M.; Sangen, M.J.C. van der; ... ; Dutch Breast Canc Res Grp BOOG 2020
Purpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the... Show morePurpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. Methods We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan-Meier methods and Cox proportional hazards models were used for analyses. Results Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45-1.49), osteoporosis HR 1.10 (95% CI 0.26-4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40-1.42), osteoporosis HR 1.86 (95% CI 0.43-8.01)]. Moreover, bisphosphonate use did not impact DRFS. Conclusion No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS. Show less
Although the survival of breast cancer has improved the past decades, there is still major over- and undertreatment for the majority of patients. The aim of this research was to identity the most... Show moreAlthough the survival of breast cancer has improved the past decades, there is still major over- and undertreatment for the majority of patients. The aim of this research was to identity the most optimal adjuvant endocrine therapy, with regard to the optimal duration of therapy and the selection of subgroups who require selected therapy. Show less
Upon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients... Show moreUpon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients express this hormonal receptor. These patients are often treated with tamoxifen, which competitively inhibits the proliferative effects of estrogen in breast cancer cells. While tamoxifen inhibits the tumor growth of breast cancer, its effects in other Estrogen Receptor-positive tissues vary, as reviewed in chapter 1. Its most adverse side-effect is that it increases the risk for endometrial cancer. Chapters 2 and 3 describe the effects of tamoxifen on the DNA binding sites of the Estrogen Receptor in tamoxifen-associated endometrial cancer, and the similarities of these binding sites with those found in breast cancer. Unfortunately, there are Estrogen Receptor-positive breast cancer patients who do not respond to hormonal treatment. Chapter 4 reveals a key-role for activating transcription factor 2 on tamoxifen’s inhibitory response on cell proliferation. Chapter 5 discusses components of the Estrogen Receptor pathway and highlights their potential as biomarkers in hormonal response therapy. Finally, chapter 6 provides new questions invoked by this thesis, and discusses the importance of unraveling the Estrogen Receptor pathway in multiple tissues in order to develop tailor-made treatments. Show less
Blok, E.J.; Derks, M.G.M.; Hoeven, J.J.M. van der; Velde, C.J.H. van de; Kroep, J.R. 2015
Not all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by... Show moreNot all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by formation of the metabolite endoxifen, which is mainly catalyzed by the enzyme CYP2D6. In this thesis, we studied the variation in tamoxifen metabolism in relation to endoxifen serum concentration, tamoxifen efficacy and side effects, focusing on CYP2D6 activity and pharmacogenetics. The importance of good methodology for genotyping and endoxifen measurement was exemplified. In a large trial population, no association between CYP2D6 genotype and disease free survival or the occurence of hot flashes was found, although polymorphisms in the estrogen receptor-1 and UGT2B15 might be related to clinical outcome. Adherence, but not the concomitant use of CYP2D6 inhibiting medication was associated with breast cancer recurrence. CYP2D6 genotype and endoxifen-guided tamoxifen dose escalation led to an increase in endoxifen serum levels and a new 13C-Dextromethorphan breath test was used for phenotyping CYP2D6, which correlated well with CYP2D6 genotype and endoxifen levels. Finally, the CYP2D6 phenotype and endoxifen serum levels are currently prospectively related to breast cancer recurrence. This may lead to therapeutic drug monitoring and selection of patients who benefit most from tamoxifen. Show less
Dezentje, V.O.; Schaik, R.H.N. van; Vletter-Bogaartz, J.M.; Straaten, T. van der; Wessels, J.A.M.; Kranenbarg, E.M.K.; ... ; Guchelaar, H.J. 2013
Molecular understanding of estrogen receptor signalling, phosphorytion and its role in resistance to endocrine (tamoxifen) therapy in breast cancer patients
