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.

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 Opportunities of the pharmacogenetic approach to personalized tamoxifen breast cancer therapy: case reports

2019 ◽  
Vol 21 (1) ◽  
pp. 24-30
Author(s):  
Marina I Savelyeva ◽  
Irina A Dudina ◽  
Juliya S Zaharenkova ◽  
Anna K Ignatova ◽  
Kristina A Ryzhikova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Effects ◽  
Case Reports ◽  
Tamoxifen Resistance ◽  
Premenopausal Women ◽  
Individual Response ◽  
Clinical Effects ◽  
Active Metabolites ◽  
Clinical Value ◽  
Luminal A

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used for treatment of premenopausal women with ER(+) breast cancer likewise for postmenopausal women with treatment contraindications to aromatase inhibitors. Tamoxifen is a prodrug which is metabolized by cytochrome P450 (CYP): CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19 to active metabolites. There is high variability in the CYP genes therefore differences in tamoxifen metabolism, tamoxifen individual response and efficacy are observed among patients. This article presents two clinical case reports. Both patients have breast cancer luminal A subtype, similar prognosis and are administered tamoxifen but they have diverse clinical effects. Patients responded to the survey questionnaire, then samples of buccal epithelium were taken for genetic analysis of CYP2D6*4, CYP3A5*3, CYP3A4*17, CYP2C9*2,3, CYP2C19*2,3, ABCB1 gene mutations by use of real time PCR. In patient A samples were detected significant mutations in CYP2D6 (*1/*4), CYP3A5 (*3/*3) и CYP2С9 (*2/*3), but there were no mutations detected in patient B. It is interesting that patient B has had prominent tamoxifen adverse effects, such as flushes, ostealgia, faintness, after 1 month of tamoxifen therapy. Patient A has taken tamoxifen for 19 months without any adverse effects. Also there is a review in this article about clinical value of different CYP2D6, CYP3A5, CYP2C9 polymorphisms. Additionally, we make a suggestion about the role of polymorphisms in tamoxifen adverse effects and the way of solution for problems of tamoxifen resistance. We suppose that routine genetic study before tamoxifen administration would help to predict individual intolerance and increase the efficacy of treatment.

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.

Spices with Breast Cancer Chemopreventive and Therapeutic Potentials: A Functional Foods Based-Review

2018 ◽  
Vol 18 (2) ◽  
pp. 182-194 ◽  
Author(s):  
Aliyu Muhammad ◽  
Mohammed Auwal Ibrahim ◽  
Ochuko Lucky Erukainure ◽  
Ibrahim Malami ◽  
Auwal Adamu
Keyword(s):  
Breast Cancer ◽  
Urban Areas ◽  
Cancer Chemoprevention ◽  
Biologically Active ◽  
Active Metabolites ◽  
Rural And Urban Areas ◽  
Anticancer Properties ◽  
Rural And Urban ◽  
Breast Cancer Chemoprevention ◽  
Biologically Active Metabolites

Background: Cancer is a multifaceted metabolic disease that affects sizeable dwellers of rural and urban areas. Among the various types of cancer, mammary cancer is one of the most frequently diagnosed cancers in women. Its menace can be curbed with locally consumed spices due to their multiple bioactive phytochemicals. Aims: This review focuses on the breast cancer chemopreventive and therapeutic potentials of locally consumed spices. Methods/Results: The most commonly consumed spices with breast cancer chemopreventive and chemotherapeutic phytochemical include pepper, onions, ginger, garlic, curry and thyme containing many biologically active metabolites ranging from vitamins, fatty acids esters, polyphenols/phenolics, sulfurcontaining compounds and anthraquinones with proven antioxidant, anti-inflammatory, immuno-modulatory, antitumor and anticancer properties against breast cancer/carcinogenesis. Therefore, extracts and active principles of these spices could be explored in breast cancer chemoprevention and possibly therapeutically which may provide an avenue for reducing the risk and prevalence of breast cancer.

Adenosarcoma of the uterus following tamoxifen treatment for breast cancer

1998 ◽  
Vol 8 (2) ◽  
pp. 168-171 ◽  
Author(s):  
Mourits ◽  
Hollema ◽  
Willemse ◽  
de Vries ◽  
Aalders ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tamoxifen Treatment

scholarly journals Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Andrea DeCensi ◽  
Harriet Johansson ◽  
Thomas Helland ◽  
Matteo Puntoni ◽  
Debora Macis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Low Dose ◽  
Cancer Recurrence ◽  
Phase Iii ◽  
Cyp2d6 Genotype ◽  
Phase Iii Trial ◽  
Reactive Protein ◽  
Non Invasive ◽  
Tamoxifen Metabolites ◽  
Dose Trial

AbstractLow-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.

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.

Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients

2001 ◽  
Vol 11 (4) ◽  
pp. 272-276 ◽  
Author(s):  
N. Nishimura ◽  
T. Hachisuga ◽  
T. Saito ◽  
T. Kawarabayashi
Keyword(s):  
Breast Cancer ◽  
Endometrial Carcinoma ◽  
Cancer Patients ◽  
Myometrial Invasion ◽  
Tamoxifen Treatment ◽  
Adjuvant Tamoxifen ◽  
Serous Carcinoma ◽  
Breast Cancer Patients ◽  
Two Stage ◽  
Endometrial Carcinomas

Abstract.Nishimura N, Hachisuga T, Saito T, Kawarabayashi T. Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients.This study aimed to detail the clinicopathologic features of endometrial carcinomas that developed in Japanese patients receiving adjuvant tamoxifen treatment for breast cancer patients. Ten endometrial carcinomas in tamoxifen-treated breast cancer patients were collected from two medical centers. The endometrial carcinomas included two stage Ia, four stage Ib, two stage Ic and two stage IIIc. Three tumors were Grade 1, six were Grade 2, and one was Grade 3. The tumor was limited to the endometrium in two cases. Myometrial invasion was limited to the inner half of the myometrium in five cases and involved the outer half in three. A mild degree of lymphovascular space invasion was identified in five cases. Deep cervical invasion was recognized in one case. The cell types comprised nine endometrioid adenocarcinomas and one serous carcinoma. Five of eight postmenopausal endometrial carcinomas were associated with polypoid endometrial lesions composed of cystically dilated atrophic and proliferative glands widely separated by fibrotic stroma. Two patients with retroperitoneal lymph node metastases died of endometrial cancer. One patient developed a contralateral breast cancer during tamoxifen treatment. No patient died of breast cancer. We did not demonstrate a higher frequency of either high-grade tumors or unfavorable histologic subtypes in tamoxifen-treated Japanese breast cancer patients.

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