scholarly journals Predicting steady‐state endoxifen plasma concentrations in breast cancer patients by CYP2D6 genotyping or phenotyping. Which approach is more reliable?

2020 ◽  
Vol 8 (5) ◽  
Author(s):  
Milena Gusella ◽  
Felice Pasini ◽  
Barbara Corso ◽  
Laura Bertolaso ◽  
Giovanni De Rosa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Breast Cancer Patients

Dextromethorphan phenotyping as a test for prediction of tamoxifen (TAM) activation in breast cancer patients receiving adjuvant hormone therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13019-e13019
Author(s):  
Milena Gusella ◽  
Laura Bertolaso ◽  
Felice Pasini ◽  
Yasmina Modena ◽  
Antonio Bononi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Cancer Patients ◽  
Plasma Levels ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Breast Cancer Patients ◽  
Active Metabolites ◽  
Adjuvant Hormone Therapy ◽  
State Plasma

e13019 Background: TAM is mainly metabolized by CYP2D6 to form its most active metabolites, 4hydroxy-tamoxifen (4OH-T) and endoxifen (END). Because of its long half-life, steady state is reached after around 4 months of continuous intake. The wide variable inter-patient activity of CYP2D6 might influence drug efficacy. A multi-institutional study in north Italy is evaluating the relationship between END levels and outcome. As a part of it, we investigated the role of dextromethorphan (DM), a probe drug for CYP2D6 enzymatic activity, as a potential phenotyping test for TAM activation. Methods: Twenty-nine breast cancer patients (75% postmenopausal) on adjuvant TAM therapy (20 mg/die) were investigated. They received a single dose (15 mg) of oral DM before starting TAM and their urines were collected over the10 following hours. Simultaneous quantitative determination of DM and its metabolite dextrorphan (DO) was performed in urines to estimate their log transformed metabolic ratio (LMR=logDM/DO). After 4 months a blood sample was collected to characterize TAM exposure at steady state; plasma levels of TAM, END, 4OH-T and the non active END precursor N-desmethyltamoxifen (NDT) were quantified by HPLC. Linear regression analysis and t test were performed for correlating LMR and drug plasma levels. Results: LMR varied between -2.15 and 0.90 (median: -1.37) while steady state plasma levels of END varied between 1.9 and 15.0 ng/ml (median: 4.36) and 4OH-T between 0.9 to 3.1 ng/ml (median:1.72). A significant correlation (r = 0.56; p= 0.0013) was found between LMR and END plasma concentrations. The patients with high LMR (> median value), compared to patients with low LMR, had lower END (3.7 vs 7.5 ng/ml, p=0.0003), lower 4OH-T (1.6 vs 2.1 ng/ml, p=0.04) and, accordingly, higher NDT (291.2 vs 198.2 ng/ml, p=0.025). Conclusions: DM/DO urine ratio obtained before starting therapy correlates with TAM biotransformation activity and can predict steady state active metabolites exposure in individual patients. This phenotyping test is fast, simple and unexpensive and could contribute to the personalization of adjuvant breast cancer treatment. Funded by Regione Veneto.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen 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.

Genetic variants in human carbonyl reductase 3 (CBR3) and their influence on doxorubicin pharmacokinetics in Asian breast cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2505-2505 ◽  
Author(s):  
L. Fan ◽  
J. Y. Guo ◽  
C. I. Wong ◽  
R. Lim ◽  
H. L. Yap ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Genetic Variants ◽  
Plasma Concentrations ◽  
Female Breast Cancer ◽  
Individual Variability ◽  
Carbonyl Reductase ◽  
Breast Cancer Patients ◽  
Coding Region

2505 Background: Human carbonyl reductase 3 (CBR3) is one of the main metabolizing enzymes to extensively reduce doxorubicin to its major active metabolite, doxorubicinol in normal and tumor tissues. Recently, the CBR3 958G>A (V244M) genetic variant has been described to alter function in vitro. We postulate that CBR3 genetic variants could contribute to the inter-individual variability of doxorubicin pharmacokinetics in breast cancer patients. Methods: We studied 101 female breast cancer patients (66 Chinese, 26 Malay, 7 Indian and 2 of other ethnic origins) who were treated with doxorubicin at 75mg/m2 every 3 weeks. Comprehensive sequencing of the 3 exons of CBR3, including the splice-site junctions was performed. Plasma concentrations of doxorubicin and doxorubicinol were analyzed during the first doxorubicin cycle. Results: Five CBR3 coding region variants (239G>A, 483C>T, 507C>T, 598G>A and 958G>A) were detected, of which 239G>A, 598G>A and 958G>A were non-synonymous. 598G>A was novel, and was found in 1 Malay patient who was heterozygous. The genotype distributions of 239G>A and 958G>A were 36%/30%/34%, and 40%/36%/24% respectively for GG/AG/AA. The 239GG variant was associated with significantly higher AUC of doxorubicinol and AUC ratio of doxorubicinol to doxorubicin than the AG and AA variants (AUC of doxorubicinol 2.18±1.37ug/ml*h (GG) vs 2.04±2.11ug/ml*h (AG), p=0.05, and 1.55±0.61ug/ml*h (AA), p=0.004; AUC ratio of doxorubicinol to doxorubicin 1.90±1.29 (GG) vs 1.72±1.34 (AG), p=0.025, and 1.45±0.67 (AA), p=0.006). Patients with the 958AA variant had significantly higher AUC of doxorubicinol than those with the 958GG variant (2.29±1.60ug/ml*h vs 1.56±0.60ug/ml*h, p=0.009). The 239GG variant was more common in our population than in Caucasians (36% vs 20%. p=0.027), while the 958AA variant was more common than reported in Caucasians (24% vs 8%, p=0.014) and Japanese (24% vs 7%, p=0.016). Conclusions: CBR3 genetic variants may influence the pharmacokinetics of doxorubicin and its major metabolite doxorubicinol. Inter-ethnic differences in frequencies of CBR3 genetic variants exist and may account for differences in pharmacokinetics and pharmacodynamics of doxorubicin between different populations. No significant financial relationships to disclose.

scholarly journals Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients

2017 ◽  
Vol 165 (3) ◽  
pp. 659-668 ◽  
Author(s):  
Daniel L. Hertz ◽  
Kelly A. Speth ◽  
Kelley M. Kidwell ◽  
Christina L. Gersch ◽  
Zeruesenay Desta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitor ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Breast Cancer Patients ◽  
Post Menopausal

Relationship of MDA Plasma Concentrations to Long-term Survival of Breast Cancer Patients

2014 ◽  
Vol 100 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Janina Didziapetriene ◽  
Giedre Smailyte ◽  
Jaroslav Bublevic ◽  
Birute Kazbariene ◽  
Vytautas Kasiulevicius ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Breast Cancer Patients ◽  
Term Survival ◽  
Long Term Survival ◽  
Relationship Of

The Steady-State Pharmacokinetics of Tamoxifen and its Metabolites in Breast Cancer Patients

1986 ◽  
Vol 14 (3) ◽  
pp. 162-165 ◽  
Author(s):  
Kari Soininen ◽  
Terttu Kleimola ◽  
Inkeri Elomaa ◽  
Matti Salmo ◽  
Pentti Rissanen
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Cancer Patients ◽  
Mammary Cancer ◽  
Dose Interval ◽  
Urine Samples ◽  
Breast Cancer Patients ◽  
Level Curves ◽  
Plasma And Urine Samples ◽  
To Receive

The steady-state pharmacokinetics of tamoxifen and its metabolites was studied in sixteen patients with advanced mammary cancer. Patients were randomized to receive tamoxifen given as Tamofen®, Leiras, or as Nolvadex®, ICI, 20 mg twice daily for 16 weeks in a cross-over study. Plasma and urine samples were analyzed during one dose interval (12 h) after treatment for 8 and 16 weeks. The concentrations of tamoxifen, N-desmethyltamoxifen, N,N-desdimethyltamoxifen, and metabolite Y were determined in plasma and the areas under the plasma level curves were calculated. 4-Hydroxytamoxifen was not found in plasma. In urine samples only tamoxifen and N-desmethyltamoxifen were above the detection limits even though metabolite Y was also analyzed after acid hydrolysis. There were no statistically significant differences in the concentrations of tamoxifen and its metabolites between the two preparations. The results of nonresponders did not differ from those of responders. Liver metastases had no effect on the metabolism of tamoxifen.

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer

2007 ◽  
Vol 25 (25) ◽  
pp. 3837-3845 ◽  
Author(s):  
Hyeong-Seok Lim ◽  
Han Ju Lee ◽  
Keun Seok Lee ◽  
Eun Sook Lee ◽  
In-Jin Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Steady State ◽  
Clinical Outcome ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Pregnane X Receptor ◽  
Cyp2d6 Genotype ◽  
Breast Cancer Patients ◽  
State Plasma

Purpose The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer. Patients and Methods Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes. Results Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032) Conclusion CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.

Sign in / Sign up

Export Citation Format

Share Document