scholarly journals Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer

2021 ◽  
Vol 11 (3) ◽  
pp. 201
Author(s):  
Thomas Helland ◽  
Sarah Alsomairy ◽  
Chenchia Lin ◽  
Håvard Søiland ◽  
Gunnar Mellgren ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tamoxifen Treatment ◽  
Prediction Algorithm ◽  
Endocrine Treatment ◽  
Cyp2d6 Genotype ◽  
Active Metabolites ◽  
Metabolic Resistance ◽  
Metabolite Concentrations ◽  
Tamoxifen Efficacy ◽  
Endoxifen Concentration

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.

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.

Perspectives of pharmacogenetics approach to personalized tamoxifen therapy

2017 ◽  
Vol 1 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Marina I. Savelyeva ◽  
Julia S. Panchenko ◽  
Irina A. Urvantseva ◽  
Anna K. Ignatova ◽  
Irina V. Poddubnaya
Keyword(s):  
Breast Cancer ◽  
Current Data ◽  
Tamoxifen Treatment ◽  
Individual Response ◽  
Active Metabolites ◽  
Tamoxifen Metabolites ◽  
High Interindividual Variability ◽  
Genes Encoding ◽  
Personalized Approach ◽  
Success Of Treatment

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used in the treatment of ER(+) breast cancer and substantially decreases the risks of recurrence and disease progression. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is metabolized by cytochrome P450, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. The effectiveness and success of treatment depends largely on concentrations of the active tamoxifen metabolites in blood plasma. Polymorphisms in the genes encoding these enzymes are proposed to influence on pharmacokinetics and pharmacodynamics of tamoxifen. Therefore, pharmacogenetic approach may form the basis of personalized treatment of breast cancer. In this systematic review, we analyze all current data about the potential use of genotyping of CYP2D6, CYP3A4/5, CYP2B6 to predict an individual response on tamoxifen treatment.

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.

Dextromethorphan As a Phenotyping Test to Predict Endoxifen Exposure in Patients on Tamoxifen Treatment

2011 ◽  
Vol 29 (24) ◽  
pp. 3240-3246 ◽  
Author(s):  
Anne-Joy M. de Graan ◽  
Sebastiaan F. Teunissen ◽  
Filip Y.F.L. de Vos ◽  
Walter J. Loos ◽  
Ron H.N. van Schaik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Active Metabolite ◽  
Tamoxifen Treatment ◽  
Strongly Correlated ◽  
Single Patient ◽  
Time Curve ◽  
Concentration Time ◽  
Probe Drug ◽  
Dosing Strategies ◽  
Endoxifen Concentration

Purpose Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. Methods In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. Results A strong and highly significant correlation (r = −0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration–time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = −0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Conclusion Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.

Weight change associated with anastrozole and tamoxifen treatment in postmenopausal women with breast cancer or at high risk of developing it.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 165-165
Author(s):  
I. Sestak ◽  
M. Harvie ◽  
A. Howell ◽  
J. F. Forbes ◽  
M. Dowsett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Weight Gain ◽  
High Risk ◽  
Postmenopausal Women ◽  
Weight Change ◽  
Tamoxifen Treatment ◽  
Endocrine Treatment ◽  
High Risk Women ◽  
Treatment And Prevention

165 Background: Weight gain is commonly reported by patients with breast cancer. Aromatase inhibitors are being tested in the preventive setting in high risk women and it is important to evaluate the association between treatment and weight change as this may effect the patient’s decision to continue to take the drug. Methods: Weight change in postmenopausal women from three large clinical trials (ATAC, IBIS-I, IBIS-II) investigating endocrine treatment for the treatment and prevention of breast cancer have been analysed. The objective of this retrospective study was to assess the effects of anastrozole and tamoxifen on weight change in postmenopausal women. Results: In the ATAC trial, a mean increase of 1.4 kg was observed after 12 months of follow-up and no statistically significant differences between treatment arms (anastrozole vs. tamoxifen) were found. The majority of women kept their weight stable and only 11.2% gained more than 5 kg within this time period. Significant baseline predictors for gaining more than 5 kg of weight after 12 months of follow-up were being younger than 60 years old at entry, smoking at entry, and mastectomy. Results for the two prevention studies IBIS-I and IBIS-II were quite similar. In the IBIS-II trial, the overall mean weight change after 12 months of follow-up was 0.5 kg. In the IBIS-I study women gained an average of 0.9 kg within the first 12 months of follow up. In both studies no differences between treatment and placebo (IBIS-I: tamoxifen vs. placebo; IBIS-II: anastrozole vs. placebo) were observed. Overall, women in the adjuvant setting gained more than 5 kg of weight (11.2%) after 12 months of follow up compared to those in the preventive setting (5.3% IBIS-I, 5.7% IBIS-II), but similar overall weight gain was seen after 60 months of follow up in both settings (5.7% IBIS-I vs. 6.1% ATAC). Conclusions: All three trials have demonstrated that weight gain occurs primarily within the first 12 months of active treatment and are similar to those on placebo. Weight stabilises after 12 months of follow up and major weight gain was rare in all trials, and unrelated to treatment.

scholarly journals New opportunities of pharmacogenetics approach to personalized tamoxifen therapy (updated systematic review)

2020 ◽  
pp. 42-56
Author(s):  
M. I. Savelyeva ◽  
I. V. Poddubnaya
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Current Data ◽  
Tamoxifen Treatment ◽  
Individual Response ◽  
Active Metabolites ◽  
Tamoxifen Metabolites ◽  
High Interindividual Variability ◽  
Genes Encoding ◽  
Personalized Approach

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used in the treatment of ER(+) breast cancer and substantially decreases the risks of recurrence and disease progression. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is metabolized by cytochrome P450, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. The effectiveness and success of treatment depends largely on concentrations of the active tamoxifen metabolites in blood plasma. Polymorphisms in the genes encoding these enzymes are proposed to influence on pharmacokinetics and pharmacodynamics of tamoxifen. Therefore, pharmacogenetic approach may form the basis of personalized treatment of breast cancer. In the updated systematic review, we analyze all current data about the potential use of genotyping of CYP2D6, CYP2С19, CYP3A4/5, CYP2B6 to predict an individual response on tamoxifen treatment.

scholarly journals Relation of EGFR/PI3K/AKT signaling components with tamoxifen efficacy in patients with estrogen-dependent breast cancer

2018 ◽  
Vol 5 (3) ◽  
pp. 40-50 ◽  
Author(s):  
T. A. Dronova ◽  
N. N. Babyshkina ◽  
M. V. Zavyalova ◽  
S. V. Patalyak ◽  
E. M. Slonimskaya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Tamoxifen Resistance ◽  
Progression Free Survival ◽  
Expression Level ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Tamoxifen Efficacy ◽  
Signaling Components

Background. It is generally accepted that crosstalk between the growth factor receptor and ER pathways implicated in tamoxifen resistance. The aim of the study was to examine the relationship between mRNA level, protein expression and gene polymorphism of the EGFR/PI3K/AKT signaling components with tamoxifen efficacy in patients with estrogen-dependent breast cancer. Materials and methods. The study included 95 breast cancer patients who had received adjuvant tamoxifen, of which 31 patients developed recurrence/metastasis after tamoxifen treatment (tamoxifen resistance group), 64 patients did not develop any diseases progression (tamoxifen sensitive group) during the 5 years of follow-up. Genotypes for ESR1 (rs2077647, rs2228480, rs1801132), EGFR (rs1468727, rs2227983), AKT1 (rs1130233) and PTEN (rs11202592) were analyzed using a TaqMan assay. Using reverse transcription-PCR, the relative expression of mRNA for ESR1, EGFR, AKT1 and PTEN was determined. ERα, EGFR, Akt (pS473) and PTEN expression level was evaluated using immunohistochemistry. Progression-free survival (PFS) was estimated by Kaplan – Meier analysis. Results. The minor allele of ESR1 rs2077647 was more prevalent in tamoxifen sensitive tumors compared to tamoxifen resistant tumors (p = 0.044). We found high AKT1 mRNA expression level in tamoxifen sensitive group compared with tamoxifen resistance patients (7.27 ± 5.29 and 0.02 ± 0.01, respectively, p = 0.014). ESR1 rs2228480 was significantly associated with tamoxifen resistance (p = 0.028). EGFR and Akt (pS473) protein expression level was significantly higher in the tamoxifen resistance group compared to tamoxifen sensitive breast cancer patients (p = 0.006 and 0.037, respectively). Patients carrying mutant genotypes of ESR1 rs2228480 had a poorer progression-free survival than those carrying wild and heterozygous variants (log rank p = 0.043). Positive EGFR tumor expression as well as positive Akt (pS473) expression were significantly associated with shorter PFS (log rank p = 0.014 and 0.048, respectively). Conclusion. Polymorphic sites of the ESR1 gene, AKT1 mRNA expression, EGFR expression level and Akt (pS473) protein expression can be potential molecular markers associated with tumor sensitivity/resistance to tamoxifen treatment.

scholarly journals Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

2010 ◽  
Vol 17 (1) ◽  
pp. 215-230 ◽  
Author(s):  
Ton van Agthoven ◽  
Anieta M Sieuwerts ◽  
Danielle Meijer ◽  
Marion E Meijer-van Gelder ◽  
Thecla L A van Agthoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Clinical Relevance ◽  
Advanced Disease ◽  
Tamoxifen Treatment ◽  
Endocrine Treatment ◽  
Mrna Levels ◽  
Tumor Aggressiveness ◽  
Breast Cancer Patients ◽  
Genetic Screens

Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

CYP2D6 genotype related to tamoxifen efficacy: An analysis with exclusion of potential false CYP2D6 genotype assignment caused by loss of heterozygosity in tumor tissue.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 597-597
Author(s):  
Vincent O. Dezentje ◽  
Ron H.N. van Schaik ◽  
Judith M. Vletter - Bogaartz ◽  
Tahar van der Straaten ◽  
Judith A.M. Wessels ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Microsatellite Markers ◽  
Cancer Patients ◽  
Loss Of Heterozygosity ◽  
Early Breast Cancer ◽  
Tumor Tissue ◽  
Cyp2d6 Genotype ◽  
Breast Cancer Patients ◽  
Genotype Assignment ◽  
Tamoxifen Efficacy

597 Background: The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Methods: Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in the Tamoxifen Exemestane Adjuvant Multinational trial (TEAM) were genotyped for 5 CYP2D6 variant alleles. CYP2D6 genotypes and phenotypes were related to disease free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing three microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. Results: Analysis of the CYP2D6 alleles and the microsatellite markers demonstrated heterozygosity for at least one of the CYP2D6 alleles or microsatellite markers in 97.7% of patients with a specified CYP2D6 phenotype. The 14 patients (2.3%) with a homozygous CYP2D6 genotype in which no heterozygosity could be demonstrated for the microsatellite markers were excluded from the analysis. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t. Conclusions: In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype was associated with DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded.

scholarly journals Tumorigenic Effects of Tamoxifen on the Female Genital Tract

2008 ◽  
Vol 1 ◽  
pp. CPath.S487 ◽  
Author(s):  
Kaei Nasu ◽  
Noriyuki Takai ◽  
Masakazu Nishida ◽  
Hisashi Narahara
Keyword(s):  
Breast Cancer ◽  
Endometrial Cancer ◽  
Side Effects ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Tamoxifen Treatment ◽  
Endocrine Treatment ◽  
Gynecological Examination ◽  
Increased Risk ◽  
Female Genital

Tamoxifen is widely used for endocrine treatment and breast cancer prevention. It acts as both an estrogen antagonist in breast tissue and an estrogen agonist in the female lower genital tract. Tamoxifen causes severe gynecologic side effects, such as endometrial cancer. This review focuses on the effects of prolonged tamoxifen treatment on the human female genital tract and considers its tumorigenicity in the gynecologic organs through clinical data analysis. Tamoxifen is associated with an increased incidence of benign endometrial lesions such as polyps and hyperplasia and a two- to four-fold increased risk of endometrial cancer in postmenopausal patients. Moreover, the incidence of functional ovarian cysts is significantly high in premenopausal tamoxifen users. To prevent tamoxifen from having severe side effects in gynecologic organs, frequent gynecological examination should be performed for both premenopausal and postmenopausal patients with breast cancer who are treated with this drug.

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