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

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.

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Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

Cancers ◽

10.3390/cancers13040833 ◽

2021 ◽

Vol 13 (4) ◽

pp. 833

Author(s):

Jesús Fuentes-Antrás ◽

Ana Lucía Alcaraz-Sanabria ◽

Esther Cabañas Morafraile ◽

María del Mar Noblejas-López ◽

Eva María Galán-Moya ◽

...

Keyword(s):

Breast Cancer ◽

Drug Development ◽

Gene Mutations ◽

Complete Response ◽

Breast Cancer Patients ◽

Clinical Value ◽

Luminal A ◽

Genomic Alterations ◽

Cancer Hallmarks ◽

Worse Prognosis

The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.

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Tamoxifen-associated eye disease. A review.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.3.1018 ◽

1996 ◽

Vol 14 (3) ◽

pp. 1018-1026 ◽

Cited By ~ 112

Author(s):

S G Nayfield ◽

M B Gorin

Keyword(s):

Breast Cancer ◽

Adverse Effects ◽

Macular Edema ◽

Case Reports ◽

Eye Disease ◽

High Dose ◽

Ocular Toxicity ◽

Early Stage Disease ◽

Clinical Series

PURPOSE The oral antiestrogen tamoxifen has demonstrated efficacy in the treatment of metastatic breast cancer and as adjuvant therapy in early-stage disease. Clinical trials of tamoxifen in chemoprevention of breast cancer among high-risk women have focused attention on potential adverse effects of long-term tamoxifen use, including the possibility of ocular toxicity. This review evaluates the published case reports, clinical series, and clinical trial data on ocular toxicities attributed to tamoxifen. Clinical issues of surveillance, differential diagnosis, and management of tamoxifen-related eye disease are discussed. DESIGN National Library of Medicine online bibliographic services were used to identify case reports and clinical studies of ocular adverse effects that occurred in patients receiving tamoxifen published through the fall of 1994. The medical literature relevant to issues raised by the reports and studies was similarly identified and reviewed. RESULTS Case reports and case series identify crystalline retinal deposits, macular edema, and corneal changes as potential tamoxifen ocular toxicities. Extensive retinal lesions and macular edema with visual impairment have been reported in a few patients receiving high-dose tamoxifen. Less extensive retinal changes may occur in patients receiving low doses for long periods, and isolated retinal crystals may be observed in patients without visual symptoms. CONCLUSION Ocular toxicity is uncommon in the current clinical setting of long-term, low-dose tamoxifen use. Physicians should be aware of the potential for ocular toxicity among patients receiving the drug and should assure appropriate surveillance and prompt evaluation of visual complaints.

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Perspectives of pharmacogenetics approach to personalized tamoxifen therapy

World Journal of Personalized Medicine ◽

10.14341/wjpm9274 ◽

2017 ◽

Vol 1 (1) ◽

pp. 27-35 ◽

Cited By ~ 3

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.

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

Pharmacogenetics and Pharmacogenomics ◽

10.37489/2588-0527-2020-1-42-56 ◽

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.

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Goserelin has greater physical adverse effects than tamoxifen, but there is no difference in anxiety or depression for premenopausal women with breast cancer

Evidence-based Oncology ◽

10.1054/ebon.2001.0136 ◽

2001 ◽

Vol 2 (3) ◽

pp. 157-158

Author(s):

J CJM de Haes

Keyword(s):

Breast Cancer ◽

Adverse Effects ◽

Premenopausal Women

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The Histological Subtypes of Breast Cancer Seen in a Tertiary Hospital in South-East, Nigeria

Global Journal of Health Science ◽

10.5539/gjhs.v12n6p93 ◽

2020 ◽

Vol 12 (6) ◽

pp. 93

Author(s):

Uzoigwe J. Chukwuma ◽

Nzegwu M. Arinze ◽

Onyishi N. Thaddeus ◽

Ekwedigwe C. Kenneth ◽

Edegbe O. Felix ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

In Situ Hybridisation ◽

Premenopausal Women ◽

Tertiary Hospital ◽

Fluorescence In Situ Hybridisation ◽

Breast Cancers ◽

Luminal A ◽

Systematic Analysis ◽

Luminal B

INTRODUCTION: Breast cancer is a disease with heterogeneous nature that may have different prognosis and respond to therapy differently despite similarities in histological type, grade and stage. It is common among women in both developed and developing countries of the world.  MATERIALS AND METHODS: This study was a 2-year retrospective study involving a systematic analysis of all the formalin-fixed paraffin-embedded tissue blocks previously diagnosed as breast cancers. The study occurred at the Department of Morbid Anatomy, University of Nigeria Teaching Hospital, Enugu. We retrieved all the archived tissue blocks and subjected them to further ancillary testing using the immunohistochemistry monoclonal antibodies: (Oestrogen receptors (ER), Progesterone receptors (PR) and Her-2 neu antibodies). RESULTS: Out of 417 cases of breast cancer analysed, four hundred and Ten (410) were females representing 98.3%, seven (7) were males representing 1.7%. The mean age of all subjects in this study was 45.1±10.2 SD (years). The age of patients ranged from20 to 70 years. The age group 31 to 40 years showed the highest number of cases, 133 (32.4%). The cases positive for ER were 157 (37.6%), while 260 (62.4%) were negative. The cases positive for PR were 144 (34.5%) and 273 (65.5%) were negative. Fifty-four cases (12.9%) were HER2-neu positive, 15 (3.6%) were equivocal and could not be further analysed due to lack of the facility to do Fluorescence in-situ hybridisation, and 348 (83.5%) were HER-neu negative. Phenotypic classification based on ER, PR, and Her2 immunohistochemistry showed 113 cases (27.1%) were Luminal A, 45 cases (10.8%) were Luminal B, 23 cases (5.5%) were Her2 Enriched, 236 cases (56.6%) were Basal-like/Triple-negative, and none (0%) was Normal-like. CONCLUSION: In conclusion, this study shows that Basal-like/Triple-negative breast cancers are most common and are seen more in premenopausal women in Enugu.

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