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Oral endocrine therapies (OET) for breast cancer treatment need to be taken over a long period of time and are associated with considerable side effects. Therefore, adherence to OET is an important issue and of high clinical significance for breast cancer patients’ caregivers. We hypothesized that a new bioanalytical strategy based on liquid chromatography and high-resolution mass spectrometry might be suitable for unbiased adherence monitoring (AM) of OET. Four different biomatrices (plasma, urine, finger prick blood by volumetric absorptive microsampling (VAMS), oral fluid (OF)) were evaluated regarding their suitability for AM of the OET abemaciclib, anastrozole, exemestane, letrozole, palbociclib, ribociclib, tamoxifen, and endoxifen. An analytical method was developed and validated according to international recommendations. The analytical procedures were successfully validated in all sample matrices for most analytes, even meeting requirements for therapeutic drug monitoring. Chromatographic separation of analytes was achieved in less than 10 min and limits of quantification ranged from 1 to 1000 ng/mL. The analysis of 25 matching patient samples showed that AM of OET is possible using all four matrices with the exception of, e.g., letrozole and exemestane in OF. We were able to show that unbiased bioanalytical AM of OET was possible using different biomatrices with distinct restrictions. Sample collection of VAMS was difficult in most cases due to circulatory restraints and peripheral neuropathy in fingers and OF sampling was hampered by dry mouth syndrome in some cases. Although parent compounds could be detected in most of the urine samples, metabolites should be included when analyzing urine or OF. Plasma is currently the most suitable matrix due to available reference concentrations.

Purpose Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limited evidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM® (BR-DIM) with tamoxifen. Methods Women prescribed tamoxifen ( n  = 130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint was change in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed. Results Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (−0.7 [−1.7, 0.8], P  < 0.001). Serum SHBG increased with BR-DIM compared to placebo (+25 ± 22 and +1.1 ± 19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N -desmethyl-tamoxifen) were reduced in women receiving BR-DIM versus placebo ( P  < 0.001). Minimal adverse events were reported and did not differ by treatment arm. Conclusion In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether BR-DIM associated decreases in tamoxifen metabolites, including effects on endoxifen levels, attenuates the clinical benefit of tamoxifen. Trial Registration: ClinicalTrials.gov NCT01391689.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N -desmethyltamoxifen (DM-Tam)/ (Z)- endoxifen and CYP2D6 phenotype significantly correlated across ethnicities ( R 2 : 53%, P <10 −77 ). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively ( P <0.001). DM-Tam was influenced by body mass index ( P <0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam /(Z)- endoxifen ( P =0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P =0.013). Low (<14 n M ) compared with high (>35 n M ) endoxifen concentrations were associated with shorter DRFS (univariate P =0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P =0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Tamoxifen is essential in treating estrogen receptor-positive (ER+) breast cancer, primarily through its active metabolite, endoxifen. Emerging research suggests potential interactions between tamoxifen and gut microbiota. This study investigates the effects of tamoxifen on gut microbiota composition in postmenopausal ER+ and human epidermal growth factor receptor 2 negative (HER2−) breast cancer patients and explores correlations between gut microbiota and endoxifen plasma levels. This prospective observational study included postmenopausal ER+/HER2− breast cancer patients. Fecal and blood samples were collected before and during 6–12 weeks of tamoxifen therapy. Gut microbiota composition was analyzed using 16S rRNA amplicon sequencing of the hypervariable V4 gene region, and plasma endoxifen levels were measured using liquid chromatography-mass spectrometry. Changes in microbial diversity and composition were assessed, with correlations to endoxifen levels. A total of 62 patients were included. Tamoxifen significantly increased microbial richness ( p  = 0.019), although overall community structure remained consistent between pre- and during-treatment samples. Notable changes were observed in specific microbial taxa, with significant increases in genera such as Blautia ( p adjusted  = 0.003) and Streptococcus ( p adjusted  = 0.010), and decreases in Prevotella_9 ( p adjusted  = 0.006). No significant correlations between gut microbiota and endoxifen levels were identified after multiple comparisons. Tamoxifen therapy increases gut microbial diversity in postmenopausal ER+/HER2− breast cancer patients, though overall microbial community structure remains stable. The absence of significant correlations with endoxifen levels suggests that while tamoxifen affects the gut microbiota, its role in endoxifen metabolism requires further study. More comprehensive research is needed to understand the relationship between tamoxifen, gut microbiota, and therapeutic outcomes.

Background: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. Methods: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. Results: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. Conclusions: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

Background The plasma concentration of endoxifen, the active metabolite of tamoxifen, might be affected by different CYP2D6 genotypes in patients with breast cancer, but solid evidence is still lacking in Asian patients. This prospective study aimed to investigate the relationship between CYP2D6 genetic polymorphisms and endoxifen plasma concentrations among Chinese patients with breast cancer treated with tamoxifen. Methods From August 2015 to June 2018, 110 patients with breast cancer were enrolled. CYP2D6 variant alleles and endoxifen plasma concentration were determined using Sanger sequencing and high-performance liquid chromatography-tandem mass spectrometry, respectively. Results The most frequent allele of CYP2D6 was *10 (56.4%). The most frequent genotype of CYP2D6 was *10/*10 (33%), *1/*10(28.2%) and *2/*10(14.5%). Sixty-four patients (58.2%) were Normal Metabolizers (NM), while 46 (41.8%) were Intermediate Metabolizers (IM). All patients except two had endoxifen concentrations above the threshold of 5.9ng/ml. The median endoxifen plasma concentrations for patients with CYP2D6 genotypes *1/*2 and *1/10 were higher compared to other genotypes ( p =  0.012). The median endoxifen plasma concentration was higher in NM than in IM (18ng/ml vs. 13ng/ml, p  = 0.0077). Patients with CYP2D6*10(T/T) had lower endoxifen concentrations than those with *10(C/T) and *10(C/C) but the difference was not significant. There were no significant differences in adverse events between patients in the NM and IM groups or between patients with the CYP2D6*10 (T/T) genotype and non-*10 (T/T) genotype. Conclusion Only CYP2D6 IMs and NMs were identified in this study. Almost all patients had the endoxifen concentrations above the threshold. The endoxifen plasma concentration was lower in CYP2D6 IMs than in NMs, but these variants did not compromise the adverse effects of tamoxifen in Asian patients with breast cancer. Trial registration The study protocol was approved by the institutional review boards of Sun YatSen University Cancer Center (Ethics approval number, B201506501,20160115).

Background Pharmacogenetic profiling and therapeutic drug monitoring (TDM) have both been proposed to manage inter-individual variability (IIV) in drug exposure. However, determining the most effective approach for estimating exposure for a particular drug remains a challenge. This study aimed to quantitatively assess the circumstances in which pharmacogenetic profiling may outperform TDM in estimating drug exposure, under three sources of variability (IIV, inter-occasion variability [IOV], and residual unexplained variability [RUV]). Methods Pharmacokinetic models were selected from the literature corresponding to drugs for which pharmacogenetic profiling and TDM are both clinically considered approaches for dose individualization. The models were used to simulate relevant drug exposures (trough concentration or area under the curve [AUC]) under varying degrees of IIV, IOV, and RUV. Results Six drug cases were selected from the literature. Model-based simulations demonstrated that the percentage of patients for whom pharmacogenetic exposure prediction is superior to TDM differs for each drug case: tacrolimus (11.0%), tamoxifen (12.7%), efavirenz (49.2%), vincristine (49.6%), risperidone (48.1%), and 5-fluorouracil (5-FU) (100%). Generally, in the presence of higher unexplained IIV in combination with lower RUV and IOV, exposure was best estimated by TDM, whereas, under lower unexplained IIV in combination with higher IOV or RUV, pharmacogenetic profiling was preferred. Conclusions For the drugs with relatively low RUV and IOV (e.g., tamoxifen and tacrolimus), TDM estimated true exposure the best. Conversely, for drugs with similar or lower unexplained IIV (e.g., efavirenz or 5-FU, respectively) combined with relatively high RUV, pharmacogenetic profiling provided the most accurate estimate for most patients. However, genotype prevalence and the relative influence of genotypes on the PK, as well as the ability of TDM to accurately estimate AUC with a limited number of samples, had an impact. The results could be used to support clinical decision making when considering other factors, such as the probability for severe side effects.

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4 *22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4 *22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4 *22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using 13 C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer. Clinical Trial Identification: EudraCT No 2017-000641-44.

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. 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.MethodsData 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.ResultsNone 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, p value: 0.074; 3.3 ng/ml threshold: HR: 0.728; 95% CI 0.421–1.258, p value: 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, p value: 0.248) and the risk for tamoxifen discontinuation (OR: 1.006 95% CI 0.961–1.053, p value: 0.798) with endoxifen concentrations.ConclusionOur 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.