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.

Bleomycin electrochemotherapy in elderly metastatic breast cancer patients: clinical outcome and management considerations

2014 ◽  
Vol 140 (9) ◽  
pp. 1557-1565 ◽  
Author(s):  
Luca G. Campana ◽  
Sara Galuppo ◽  
Sara Valpione ◽  
Antonella Brunello ◽  
Cristina Ghiotto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Metastatic Breast ◽  
Breast Cancer Patients

CYP2D6 genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 634-634 ◽  
Author(s):  
H. Lim ◽  
H. Lee ◽  
K. Lee ◽  
E. Lee ◽  
I. Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Plasma Concentrations ◽  
Cancer Center ◽  
Cyp2d6 Genotype ◽  
Active Metabolites ◽  
Fluorescence Detector ◽  
Wilcoxon Rank Sum Test ◽  
Center Hospital ◽  
State Plasma

634 Background: Tamoxifen is a prodrug that is metabolized to active metabolites, Z-4-hydroxy-N-desmethyltamoxifen (BX) and Z-4-hydroxy-tamoxifen (4OH) where CYP2D6 plays a major role in the conversion. Genetic polymorphisms of CYP2D6 by ethnicities are well known with CYP2D6*10 in Asians (up to 50% in Koreans), and CYP2D6 *2 and *4 in American Whites as major variant alleles. We analyzed the steady state plasma concentrations of tamoxifen and its metabolites in patients (pts) with breast cancer to evaluate their associations with various CYP2D6 genotypes. Methods: Blood samples were collected from 219 pts on tamoxifen, 20 mg daily as adjuvant therapy for more than 3 months at National Cancer Center, Korea. Plasma tamoxifen, N-desmethyltamoxifen, BX, 4OH were measured by validated HPLC with fluorescence detector, and analyzed according to CYP2D6 genotype groups by Wilcoxon rank sum test. CYP2D6*10, CYP2D6*5 and CYP2D6*2×2 were identified by PCR-RFLP methods, and the rests were classified as CYP2D6*1 (wild type). This study was approved by IRB at National Cancer Center Hospital (NCCNHS04–033) and conducted after informed consent obtained by the patients. Results: Thus far, we measured plasma concentration of tamoxifen and its metabolites for 158 pts among 198 pts genotyped. 59 pts (29.8%) carried CYP2D6*1/*1, 84 pts (42.4%) *1/*10 and 49 pts (24.7%) *10/*10. Other types were CYP2D6*1/*5 (8.6%), *5/*5 (1.0%), *1/*2×2 (2.5%). Pts with CYP2D6 *10/*10 (n=40) demonstrated significantly lower steady state plasma concentrations of BX and 4OH than those with other genotypes (n=118) (BX: 7.9 vs.19.2. ng/ml [95 % CI; 5.5–10.4 vs. 15.8–22.7 ng/ml] p<0.0001; 4OH: 1.5 vs. 2.8 ng/ml [95 % CI; 1.1–2.0 vs. 2.3–3.3 ng/ml] p<0.0001), whereas there were no differences with *1/*10 (n=64) vs. without *10 allele (n=54) (BX: 20.6 vs. 18.1 ng/ml; 4OH: 2.9 vs. 2.7 ng/ml). Basically no significant differences in BX/4OH or other compounds by various CYP2D6*2 ×2 and *5 alleles were observed. Conclusions: The steady state plasma concentrations of BX and 4OH were significantly low with CYP2D6 *10/*10 genotype, and their clinical implications need to be explored.(Supported by a grant NCC-0410590). No significant financial relationships to disclose.

First-Line Efficacy of Anti-HER2 Treatments in Previously Treated HER2-Positive Metastatic Breast Cancer Patients: A Retrospective Observational Study Investigating the Efficacy of Re-Exposure to Anti-HER2 Therapy for HER2-Positive Metastatic Breast Cancer Patients in Comparison with Naïve Patients

Breast Care ◽  
2021 ◽  
pp. 1-7
Author(s):  
Barliz Waissengrin ◽  
Roni Levin ◽  
Ido Wolf ◽  
Eliya Shachar ◽  
Amir Sonnenblick
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Outcome ◽  
Metastatic Breast ◽  
Line Treatment ◽  
Previous Exposure ◽  
Breast Cancer Patients ◽  
First Line ◽  
Her2 Positive ◽  
First Line Treatment

<b><i>Background:</i></b> Most patients with HER2-positive metastatic breast cancer (MBC) receive first-line treatment with anti-HER2 agents and have already received anti-HER2 therapy as adjuvant or neoadjuvant therapy in the local setting of their disease presentation. Despite that, they constitute only a minority among clinical trials, and their response to reintroduction to anti-HER2 treatments is inconclusive based upon conflicting studies. We aimed to examine if previous exposure influences the clinical outcome of patients treated with anti-HER2 treatments compared to patients who were naïve to anti-HER2 agents. <b><i>Methods:</i></b> We conducted a retrospective observational study of HER2-positive MBC patients who were treated with trastuzumab and pertuzumab from 2014 to 2018. We collected and analyzed data including patients’ demographic characteristic as well as extracted data of previous treatment regimens and the efficiency of the anti-HER2 therapy measured by response rate (RR), time to tumor progression (TTP), and overall survival (OS). <b><i>Results:</i></b> Eighty patients met the inclusion criteria, 26 (32.5%) of them were previously exposed to anti-HER2 treatments and 54 (67.5%) were not previously exposed to anti-HER2 therapy. No significant differences were detected in RR after 3 months of treatment (<i>p</i> = 0.684). TTP was significantly better among patients with no previous exposure in comparison with patients with previous exposure to anti-HER2 therapy (21 vs. 14 months, <i>p</i> = 0.044) and we noted a trend in better OS (<i>p</i> = 0.056). <b><i>Conclusion:</i></b> Our analysis suggests that previous exposure to anti-HER2 agents might influence the clinical outcome of first-line treatment in metastatic HER2 patients. These findings justify further exploration of the benefit of reintroduction of anti-HER2 treatment enabling the optimal treatment for patients with previous anti-HER2 therapy exposure.

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.

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