351 research outputs found
Supplementary_Information – Supplemental material for Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine
No full textSupplemental material, Supplementary_Information for Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine by Femke M. de Man, G.D. Marijn Veerman, Esther Oomen-de Hoop, Maarten J. Deenen, Didier Meulendijks, Caroline M.P.W. Mandigers, Marcel Soesan, Jan H.M. Schellens, Esther van Meerten, Teun van Gelder and Ron H.J. Mathijssen in Therapeutic Advances in Medical Oncology</p
Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy
Get PDFTamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate
Factors affecting inter-individual variability in endoxifen concentrations in patients with breast cancer : results from the prospective TOTAM trial
Get PDFAbstract: Introduction Endoxifen-the principal metabolite of tamoxifen-is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modeling, we aimed to identify factors that determine the inter-individual variability. Our purpose was to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure (endoxifen < 16 nmol/L) and thus potential failure of therapy. Methods Tamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation. Results Key predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI 0.49-0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen (< 16 nmol/L) were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI 0.86-0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule. Conclusion The inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. The model showed a sensitivity and specificity of 66 and 98%, respectively, indicating a high probability of (misclassification) error for the patients with subtherapeutic endoxifen concentrations (< 16 nmol/L). The remaining unexplained inter-individual variability is still high and therefore model-informed tamoxifen dosing should be accompanied by therapeutic drug monitoring
Nivolumab for Squamous-Cell Cancer of Head and Neck
No full textTo the Editor: Ferris et al. report promising results from a large, phase 3 trial in which nivolumab outperformed standard therapy in patients with platinum-refractory squamous-cell cancer of the head and neck. However, the monotherapies that were identified as standard treatment led to varied overall survival. Moreover, the median difference of 1.7 months in overall survival between docetaxel and nivolumab treatment was equal to the difference between docetaxel and cetuximab. This finding is further reflected in the nonsignifican difference between nivolumab and docetaxel in the hazard ratio for death.Therefore, we believe that it is not correct to conclude that nivolumab is superior to all three drugs that are used in patients with platinumrefractory squamous-cell cancer of the head and neck. Because the overall survival benefit was especially prominent in patients who had not received cetuximab previously, this subgroup is likely to be biologically different from patients who were pretreated with cetuximab. Since the comparison between nivolumab and docetaxel is likely to be underpowered in this study, we believe that this cohort should be expanded to detect the true additive value of nivolumab in this line of treatment.<br/
Cross-resistance and drug sequence in prostate cancer
Get PDFThe treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed
Obesity alters endoxifen plasma levels in young breast cancer patients: pharmacometric simulation approach
Get PDFEndoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing
Blood-based PD-L1 analysis in tumor-derived extracellular vesicles: Applications for optimal use of anti-PD-1/PD-L1 axis inhibitors
No full textMonoclonal antibodies that inhibit the programmed cell death protein 1 axis (anti-PD-1/PD-L1) are part of a new pharmacological strategy aimed at reinforcing the immune response to cancer. Despite the success in several cancer types, a significant percentage of patients do not benefit from treatment with these drugs due to intrinsic or acquired resistance or the occurrence of immune-related adverse reactions. Assessment of PD-L1 expression in tumor tissues is currently used to predict drug response in the clinics; however, there is a growing interest in identifying blood-based biomarkers that, owing to the minimally-invasive nature, can allow a dynamic monitoring of drug response in daily clinical practice. In the current review article, we discuss whether the assessment of PD-L1 mRNA and protein levels in circulating extracellular vesicles may have the potential to predict the likelihood of tumor response to anti-PD-1/PD-L1 antibodies
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