The Role of CYP2D6 Polymorphisms in Determining Response to Tamoxifen in Metastatic Breast Cancer Patients: Review and Egyptian Experience

Malash, Ibrahim; Mansour, O.; Shaarawy, Sabry; Abdellateif, Mona S.; Omar, Anan; Gaafer, Rabab; Zekri, Abdel-Rhaman N; Ahmed, Ola; Bahnassy, Abeer A.

doi:10.31557/apjcp.2020.21.12.3619

Cited by 6 publications

(3 citation statements)

References 29 publications

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“…A prospective cohort study in 157 Egyptian metastatic breast cancer patients investigated the influence of CYP2D6 polymorphisms on tamoxifen response after 6 months of tamoxifen treatment. Thirty carriers of CYP2D6 variant alleles had progression within 6 months after the start of tamoxifen treatment, whereas fourteen patients achieved good clinical tamoxifen response after 6 months [88]. This suggests that patients with metastatic breast cancer carrying certain CYP2D6 variant alleles have worse 6-month prognosis after tamoxifen treatment.…”

Section: Positive Association Cyp2d6 Genotype and Outcomementioning

confidence: 98%

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

Mulder

With

et al. 2021

Cancers

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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.

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Section: Positive Association Cyp2d6 Genotype and Outcomementioning

confidence: 98%

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

Mulder

With

et al. 2021

Cancers

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“…The remaining studies on OS were not included in the meta-analysis because they did not provide HR (Ref. 49 ) or with different comparing groups (Refs 25 , 40 , 41 , 67 , 73 ). In which, significant shorter OS was found in PMs compared with EMs ( P = 0.01), and in CYP2D6*10 variant genotype (T/T) carriers compared with wild genotype (C/C) plus heterozygous genotype (C/T) carriers ( P = 0.015) (Ref.…”

Section: Resultsmentioning

confidence: 99%

Association between genetic polymorphisms in cytochrome P450 enzymes and survivals in women with breast cancer receiving adjuvant endocrine therapy: a systematic review and meta-analysis

Chan

Xiao

et al. 2022

Expert Rev. Mol. Med.

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Tamoxifen is commonly prescribed for preventing recurrence in patients with breast cancer. However, the responses of the patients on tamoxifen treatment are variable. Cytochrome P450 genetic variants have been reported to have a significant impact on the clinical outcomes of tamoxifen treatment but no tangible conclusion can be made up till now. The present review attempts to provide a comprehensive review on the associative relationship between genetic polymorphisms in cytochrome P450 enzymes and survival in breast cancer patients on adjuvant tamoxifen therapy. The literature search was conducted using five databases, resulting in the inclusion of 58 studies in the review. An appraisal of the reporting quality of the included studies was conducted using the assessment tool from the Effective Public Health Practice Project (EPHPP). Meta-analyses were performed on CYP2D6 studies using Review Manager 5.3 software. For other studies, descriptive analyses were performed. The results of meta-analyses demonstrated that shorter overall survival, disease-free survival and relapse-free survival were found in the patients with decreased metabolisers when compared to normal metabolisers. The findings also showed that varying and conflicting results were reported by the included studies. The possible explanations for the variable results are discussed in this review.

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“…75 A recent study on Egyptian patients with metastatic breast cancer and treated with tamoxifen demonstrated that patients who were refractory to tamoxifen therapy had CYP2D6 *3 and *4 polymorphisms whereas patients carrying the variants *10/*10 and *10/*3 of CYP2D6 were more common in the responders to the treatment with tamoxifen. 22…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Cyp2d6*4 and Its Possible Relation to Therapeutic Outcomes of Adjuvant Tamoxifen Therapy in Egyptian Premenopausal Women With Breast Cancer

Hareedy

Taha²,

Ibrahim³

et al. 2022

Bulletin of Pharmaceutical Sciences. Assiut

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Background: Although tamoxifen is a main adjuvant therapy in estrogen positive breast cancer especially in premenopausal women, reliance on genetic polymorphisms of its CYP2D6 metabolizing enzyme and/or therapeutic drug monitoring of its active metabolite, endoxifen to determine tamoxifen-therapeutic outcomes is debatable. Objective: The goal of the study was to investigate the prevalence of CYP2D6*4 and possible association between its nonfunctional allele (A) and both tamoxifen-induced adverse effects and cancer relapse in premenopausal breast cancer patients. Method:Polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) analysis was applied for detection of CYP2D6*4 (1846 G>A) genotypes. Results:Genotyping analysis of CYP2D6*4 showed a minimal allele frequency of 23%. Increased endometrial thickness in mm was significantly correlated with CYP2D6*4 GA and AA genotypes in comparison with GG genotypes (P< 0.01). No other relations were found between CYP2D6*4 alleles and other tamoxifen adverse effects (P > 0.9) or cancer relapse (P= 0.7). Conclusion: The prevalence of CYP2D6*4 polymorphism in Egyptian premenopausal females with breast cancer who are given tamoxifen is similar to that in Caucasians. The nonfunctional allele (A-allele) of CYP2D6*4 showed a significant association with increased endometrial thickness possibly related to tamoxifen, but no association with other drug adverse effects or cancer relapse.

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The Role of CYP2D6 Polymorphisms in Determining Response to Tamoxifen in Metastatic Breast Cancer Patients: Review and Egyptian Experience

Cited by 6 publications

References 29 publications

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

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

Association between genetic polymorphisms in cytochrome P450 enzymes and survivals in women with breast cancer receiving adjuvant endocrine therapy: a systematic review and meta-analysis

Prevalence of Cyp2d6*4 and Its Possible Relation to Therapeutic Outcomes of Adjuvant Tamoxifen Therapy in Egyptian Premenopausal Women With Breast Cancer

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