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1.
Yonsei Med J ; 61(4): 317-322, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32233174

RESUMO

PURPOSE: To evaluate factors associated with endometrial pathology during tamoxifen use in premenopausal breast cancer (BC) patients. MATERIALS AND METHODS: We reviewed the medical records of premenopausal BC patients treated with tamoxifen who underwent endometrial biopsy with or without hysteroscopy. Clinical characteristics were compared between women with endometrial pathology (endometrial hyperplasia or cancer) and those with normal histology or endometrial polyps. RESULTS: Among 284 endometrial biopsies, endometrial hyperplasia was diagnosed in 7 patients (2.5%), endometrial cancer was diagnosed in 5 patients (1.8%), normal histology was noted in 146 patients (51.4%), and endometrial polyp was present in 114 patients (40.1%). When comparing women with endometrial cancer (n=5) to women with normal histology, abnormal uterine bleeding was more common (p=0.007), and endometrial thickness was greater (p=0.007) in women with endometrial cancer. Chemotherapy for BC was also more common in patients with endometrial cancer (p=0.037). When comparing women with endometrial polyps and those with endometrial hyperplasia or cancer, the presence of abnormal uterine bleeding was more common in patients with endometrial hyperplasia or cancer (p<0.001); however, tamoxifen duration and endometrial thickness did not differ significantly between the two groups. CONCLUSION: In premenopausal BC patients treated with tamoxifen, abnormal uterine bleeding, increased endometrial thickness, and chemotherapy for BC were associated with the occurrence of endometrial cancer. These findings may provide useful information for gynecologic surveillance and counseling during tamoxifen treatment in premenopausal BC patients.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hiperplasia Endometrial/induzido quimicamente , Neoplasias do Endométrio/induzido quimicamente , Endométrio/efeitos dos fármacos , Pólipos/induzido quimicamente , Pré-Menopausa , Tamoxifeno/efeitos adversos , Adulto , Antineoplásicos Hormonais/uso terapêutico , Biópsia , Hiperplasia Endometrial/diagnóstico por imagem , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Endométrio/diagnóstico por imagem , Endométrio/patologia , Feminino , Humanos , Histeroscopia , Pessoa de Meia-Idade , Pólipos/diagnóstico por imagem , Pólipos/patologia , Fatores de Risco , Tamoxifeno/uso terapêutico , Fatores de Tempo , Doenças Uterinas , Neoplasias Uterinas/induzido quimicamente , Neoplasias Uterinas/patologia
2.
Medicine (Baltimore) ; 99(8): e19083, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080081

RESUMO

BACKGROUND: Breast cancer is the most prevalent cancer in females and disease recurrence remains a significant problem. To prevent recurrence, tamoxifen is prescribed for at least 5 years. However, among patients who receive tamoxifen, individual responses are highly variable. These responses are affected by the type, frequency, and severity of endocrine symptoms, as well as adherence rates. Polymorphisms in genes involved in the metabolism of tamoxifen (ie, CYP3A4, CYP2D6) may influence responses to tamoxifen. In this study, the inter-relationships among endocrine symptoms, drug adherence, and genetic polymorphisms in Chinese breast cancer patients receiving tamoxifen therapy will be examined. We hypothesize that patients with more severe endocrine symptoms will be less likely to adhere to tamoxifen treatment. In addition, we hypothesize that a relationship will exist between the severity of tamoxifen-induced symptoms and allelic variations in tamoxifen metabolism-related genes. Although many association studies have determined that select genotypes influence the efficacy of tamoxifen, very few studies have investigated for associations between tamoxifen-induced endocrine symptoms and these polymorphisms. OBJECTIVES: The aim of this study was to characterize genetic polymorphisms in tamoxifen metabolism-associated genes in Chinese women with breast cancer and to explore the inter-relationships between genetic polymorphisms, endocrine symptoms, and adherence to tamoxifen. METHOD: We will conduct a prospective cohort study that follows 200 Chinese women over 18 months and assess treatment-related symptoms and genetic variations. Endocrine symptoms and drug adherence will be determined through interview-administered standardized questionnaires. Polymorphisms in drug metabolism genes will be determined using real-time polymerase chain reaction based genotyping method. Data will be analyzed to determine associations between allelic variations, endocrine symptoms, and adherence. DISCUSSION: The proposed study will evaluate for polymorphisms in gene(s) that are associated with tamoxifen-related endocrine symptoms and adherence with tamoxifen. We will explore the relationships between genotypes, endocrine symptoms, and drug adherence in Chinese breast cancer patients. Findings from this study may assist clinicians to identify patients at higher risk for a worse symptom experience and lower adherence rates and enable them to initiate appropriate interventions. In the long term, the findings from this study may be used to develop and test tailored symptom management interventions for these patients.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Doenças do Sistema Endócrino/induzido quimicamente , Tamoxifeno/efeitos adversos , Alelos , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/epidemiologia , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Cooperação do Paciente , Polimorfismo de Nucleotídeo Único , Prevalência , Estudos Prospectivos , Índice de Gravidade de Doença , Tamoxifeno/metabolismo , Tamoxifeno/uso terapêutico
3.
Chemosphere ; 239: 124705, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31479913

RESUMO

Tamoxifen is a clinical drug for estrogen receptor (ER)-positive breast cancer. Recently, it has been detected in aquatic environment. The residual drugs will produce certain biological activity and create a risk to aquatic organism when they enter the water environment. Therefore, it has great significance to study the ecotoxicity of tamoxifen. In the study, we used zebrafish as a model of aquatic to investigate the ecotoxic mechanism of tamoxifen to aquatic. We found that tamoxifen induced liver lipid accumulation in zebrafish, which showed a significant hepatotoxicity with smaller liver area and bigger yolk area. Though biochemical and pathologic measurement, tamoxifen treated group showed higher transaminase and lipid content. The elevated liver lipid synthesis might due to the increase of lipid metabolism related gene Srebf1, Srebf2 and Fasn. Moreover, inflammatory cytokine Tnf-α, Il-1ß And Il-6 were increased. This result confirmed the toxicity of tamoxifen to aquatic, suggested liver injury was the main characteristic of its ecotoxicity. This study indicated it is important to avoid tamoxifen discharging into the aquatic ecology and provided a theoretical basis of prevention tamoxifen-induced ecotoxicity to aquatic.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inflamação/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Tamoxifeno/efeitos adversos , Animais , Citocinas/metabolismo , Ecotoxicologia , Feminino , Humanos , Inflamação/complicações , Fígado/metabolismo , Fígado/patologia , Tamoxifeno/química , Poluentes Químicos da Água/efeitos adversos , Peixe-Zebra/metabolismo
4.
Urology ; 137: 84-90, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31877313

RESUMO

OBJECTIVE: To investigate the influence of CYP2D6 polymorphisms on outcomes and health-related quality of life of patients with retroperitoneal fibrosis (RPF) receiving tamoxifen (TMX). TMX is an effective alternative to corticosteroids for patients with RPF. Conversion of TMX to more potent endoxifen is dependent on enzyme activity of CYP2D6. MATERIALS AND METHODS: CYP2D6 genotyping and phenotype prediction of all patients treated with TMX between 02/2007 and 01/2018 was assessed using multiplex polymerase chain reaction (PCR). Groups were classified by phenotype: extensive (EM) vs poor and intermediate (PM + IM) vs ultrarapid metabolizer (UM). Retrospective evaluation of outcome (including magnetic resonance imaging and positron emission tomography-computed tomography) and health-related quality of life using the SF-36 was performed. RESULTS: A total of 63/194 patients received TMX, 40/63 with complete follow-up were sequenced: Twenty-nine patients with EM phenotype, 8 PM + IM and 3 UM. The median therapy duration was 364.5 days with a mean follow-up of 62.9 months. Seven therapy terminations occurred due to lack of response (17.5%), including all UM patients (P <.001). Magnetic resonance imagings showed a regression of fibrosis for EM and PM + IM in 69% and 62.5% of cases and a progression for UM in 100% (P = .004). In positron emission tomography-computed tomography, glucose utilization of RPF decreased significantly for EM and PM + IM. The physical sum-score of SF-36 improved for EM and PM + IM and decreased for UM (P <.05). The removal of DJ-stents was successful for EM, PM + IM, and UM in 48.3%, 75%, and 0% of cases (P = .0581). CONCLUSION: Contrary to expectations, UM showed the lowest success rate, which concludes that genotyping of RPF-patients may be useful in the sense of a tailored-therapy.


Assuntos
Citocromo P-450 CYP2D6/genética , Qualidade de Vida , Fibrose Retroperitoneal , Tamoxifeno , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Fibrose Retroperitoneal/diagnóstico por imagem , Fibrose Retroperitoneal/tratamento farmacológico , Fibrose Retroperitoneal/genética , Fibrose Retroperitoneal/psicologia , Espaço Retroperitoneal/diagnóstico por imagem , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
5.
Pharm Res ; 37(1): 7, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31845095

RESUMO

PURPOSE: Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. METHODS: Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. RESULTS: The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8-23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4-33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4-20.6 ms; P < 0.01) and citalopram (20.7 ms; 95%CI:0.7-40.7 ms; P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms. CONCLUSIONS: Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Inibidores de Captação de Serotonina/efeitos adversos , Tamoxifeno/efeitos adversos , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/complicações , Citalopram/farmacologia , Feminino , Humanos , Síndrome do QT Longo/induzido quimicamente , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/farmacologia , Tamoxifeno/farmacologia
6.
BMJ Case Rep ; 12(8)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31473640

RESUMO

Tamoxifen is a selective oestrogen receptor modulator widely used in breast cancer treatment, with good survival rates. Its partial agonist action on other tissues such as the uterus, however, promotes the development of endometrial hyperplasia and cancer. It appears that tamoxifen does not alter the age of menopause and women may still get pregnant while on tamoxifen. We present the case of a 47-year-old Chinese woman with breast cancer on tamoxifen, who presented with one episode of heavy per vaginal bleeding after 2 years of amenorrhoea. Her urine pregnancy test was negative and the ultrasound scan was suspicious for malignancy. She underwent a hysteroscopic evaluation for abnormal bleeding on tamoxifen. Histopathology confirmed products of conception. This case illustrates the importance of understanding the rise and decline of human chorionic gonadotropin in pregnancy, as well as the pivotal role of contraception despite having amenorrhoea on tamoxifen.


Assuntos
Aborto Espontâneo/induzido quimicamente , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fertilização/efeitos dos fármacos , Tamoxifeno/efeitos adversos , Feminino , Humanos , Histeroscopia , Pessoa de Meia-Idade , Gravidez
7.
JAMA ; 322(9): 868-886, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479143

RESUMO

Importance: Medications to reduce risk of breast cancer are effective for women at increased risk but also cause adverse effects. Objective: To update the 2013 US Preventive Services Task Force systematic review on medications to reduce risk of primary (first diagnosis) invasive breast cancer in women. Data Sources: Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013, to February 1, 2019); manual review of reference lists. Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; randomized clinical trials of tamoxifen, raloxifene, and aromatase inhibitors for primary breast cancer prevention; studies of medication adverse effects. Data Extraction and Synthesis: Investigators abstracted data on methods, participant characteristics, eligibility criteria, outcome ascertainment, and follow-up. Results of individual trials were combined by using a profile likelihood random-effects model. Main Outcomes and Measures: Probability of breast cancer in individuals (area under the receiver operating characteristic curve [AUC]); incidence of breast cancer, fractures, thromboembolic events, coronary heart disease events, stroke, endometrial cancer, and cataracts; and mortality. Results: A total of 46 studies (82 articles [>5 million participants]) were included. Eighteen risk assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55-0.65). In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials [n = 28 421]), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials [n = 17 806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials [n = 8424]) were associated with a lower incidence of invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in 1 trial after long-term follow-up (RR, 1.24 [95% CI, 1.05-1.47]; n = 19 747). Raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53-0.73]; 2 trials [n = 16 929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45-0.98]; 1 trial [n = 13 388]) compared with placebo. Tamoxifen and raloxifene were associated with increased thromboembolic events compared with placebo; tamoxifen was associated with more events than raloxifene. Tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo. Symptomatic effects (eg, vasomotor, musculoskeletal) varied by medication. Conclusions and Relevance: Tamoxifen, raloxifene, and aromatase inhibitors were associated with lower risk of primary invasive breast cancer in women but also were associated with adverse effects that differed between medications. Risk stratification methods to identify patients with increased breast cancer risk demonstrated low accuracy.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Área Sob a Curva , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Mutação , Guias de Prática Clínica como Assunto , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco/métodos , Fatores de Risco , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos
8.
J Cancer Res Ther ; 15(3): 722-724, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169251

RESUMO

Tamoxifen-induced ocular complications including cataracts, keratopathies, retinopathy, impaired visual acuity, ocular irritation, optical neuritis, and retinal vein occlusion are uncommonly reported in the literature. Herein, we report on a premenopausal patient with right-side breast carcinoma who received adjuvant tamoxifen therapy (20 mg/day) for 1.5 years and developed sudden visual loss. Fundal examination revealed an obstruction in the branch of the retinal vein. The diagnosis was confirmed by fluorescein angiography and optical coherence tomography. Thus, tamoxifen was switched to an aromatase inhibitor. Tamoxifen-induced ocular complications should be kept in mind when visual symptoms are seen in patients undergoing tamoxifen therapy. In such cases, a complete ocular examination should be performed.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/etiologia , Tamoxifeno/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Feminino , Angiofluoresceinografia , Humanos , Pessoa de Meia-Idade , Tamoxifeno/uso terapêutico , Tomografia de Coerência Óptica
9.
Breast Cancer ; 26(6): 766-775, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31172425

RESUMO

BACKGROUND: Icariin is a major component isolated from Epimedium brevicornum Maxim and has been reported to exhibit anti-tumor activity. However, whether icariin could reverse the acquired drug resistance in breast cancer remains largely unclear. Therefore, this study was designed to explore the antitumor effects of icariin and its underlying mechanisms in a tamoxifen-resistant breast cancer cell line MCF-7/TAM. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Lactate dehydrogenase (LDH) assay were performed to determine the effects of icariin on cell viability and cell death. Cell cycle progression and apoptosis were detected by flow cytometry analysis. Transmission electron microscopy (TEM) assay was utilized to observe cell autophagy. The downstream protein levels were measured using western blotting. RESULTS: Here, we observed that icariin treatment not only inhibited the growth of MCF-7 but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Moreover, icariin significantly induced cell cycle G0/G1 phase arrest and apoptosis, as well as suppressed autophagy. At molecular levels, icariin treatment remarkably down-regulated the expression levels of CDK2, CDK4, Cyclin D1, Bcl-2, LC3-1, LC3-II, AGT5, Beclin-1, but upregulated the expression levels of caspase-3, PARP and p62. Most importantly, we found inhibition of autophagy via 3-MA treatment could significantly enhance the effects of icariin on cell viability and apoptosis. Enhanced autophagy via autophagy related 5 (ATG5) overexpression could partially reverse the effects of icariin on cell viability and apoptosis. CONCLUSION: These results revealed that icariin might potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen through suppression of autophagy in vitro and provide insight into the therapeutic potential of icariin for the treatment of chemo-resistant breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Tamoxifeno/efeitos adversos , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Neoplasias da Mama/tratamento farmacológico , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Epimedium/química , Feminino , Humanos , Células MCF-7 , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/uso terapêutico , Transfecção
10.
Breast Cancer Res Treat ; 177(1): 185-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144152

RESUMO

PURPOSE: Tamoxifen is an important targeted endocrine therapy in breast cancer. However, side effects and early discontinuation of tamoxifen remains a barrier for obtaining the improved outcome benefits of long-term tamoxifen treatment. Biomarkers predictive of tamoxifen side effects remain unidentified. The objective of this prospective population-based study was to investigate the value of tamoxifen metabolite concentrations as biomarkers for side effects. A second objective was to assess the validity of discontinuation rates obtained through pharmacy records with the use of tamoxifen drug monitoring. METHODS: Longitudinal serum samples, patient-reported outcome measures and pharmacy records from 220 breast cancer patients were obtained over a 6-year period. Serum concentrations of tamoxifen metabolites were measured by LC-MS/MS. Associations between metabolite concentrations and side effects were analyzed by logistic regression and cross table analyses. To determine the validity of pharmacy records we compared longitudinal tamoxifen concentrations to discontinuation rates obtained through the Norwegian Prescription database (NorPD). Multivariable Cox regression models were performed to identify predictors of discontinuation. RESULTS: At the 2nd year of follow-up, a significant association between vaginal dryness and high concentrations of tamoxifen, Z-4'-OHtam and tam-NoX was identified. NorPD showed a tamoxifen-discontinuation rate of 17.9% at 5 years and drug monitoring demonstrated similar rates. Nausea, vaginal dryness and chemotherapy-naive status were significant risk factors for tamoxifen discontinuation. CONCLUSIONS: This real-world data study suggests that measurements of tamoxifen metabolite concentrations may be predictive of vaginal dryness in breast cancer patients and verifies NorPD as a reliable source of adherence data.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Monitoramento de Medicamentos , Tamoxifeno/efeitos adversos , Tamoxifeno/farmacocinética , Vagina/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida , Feminino , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Prognóstico , Inquéritos e Questionários , Tamoxifeno/uso terapêutico , Espectrometria de Massas em Tandem , Vagina/fisiopatologia , Adulto Jovem
12.
Breast ; 46: 52-57, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082762

RESUMO

OBJECTIVES: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM. MATERIALS AND METHODS: Twenty patients with severe HFs on 20 mg TAM had CYP2D6genotype, trough level tamoxifen and metabolites measured with Loprinzi HF scores (HFS) derived before and after DR of tamoxifen to 10 mg. Other data collected included demographics, smoking, alcohol, menstrual and breast cancer history, previous chemotherapies, concurrent medications, BMI and other tamoxifen toxicities. RESULTS: At the 20 mg tamoxifen dose, endoxifen levels were 25.6, 0-91.9 nM (median, range) with HFS 131, 22-1482 (median, range). Upon DR to 10 mg, median endoxifen level fell to 14.1, 0.6-71.9 nM (difference in means p = 0.11, two-tailed T test) with HFS 47, 5-864 (difference in means p = 0.24, two-tailed T test). Despite lacking statistical significance, 85% of patients reported subjective improvement of HFs with DR. After DR, the proportion of patients with endoxifen level <15 nM increased from 20% to 50%. HFS did not correlate with any other parameter. CONCLUSION: DR of tamoxifen from 20 mg to 10 mg daily resulted in halving of endoxifen levels and subjective improvement of HF. While half the dose-reduced patients were below a potential therapeutic level of endoxifen, other recent studies suggest that low endoxifen levels may not indicate reduced effectiveness of tamoxifen.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fogachos/induzido quimicamente , Tamoxifeno/análogos & derivados , Tamoxifeno/efeitos adversos , Adulto , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6 , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Tamoxifeno/administração & dosagem , Tamoxifeno/sangue , Resultado do Tratamento
14.
Thromb Res ; 177: 51-58, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851629

RESUMO

Platelet-tumour cell interaction is implicated in the initiation of breast cancer-associated thrombosis, with hormone-therapy (Tamoxifen/Anastrozole), increasing this risk. However, recent in vitro research indicates that Tamoxifen inhibits platelet activation, while the effects of Anastrozole on platelet activation are not well characterised. This study investigated platelet activation caused by Tamoxifen or Anastrozole-treated breast cancer cells in vitro. MCF7 and T47D cells were pre-treated with Tamoxifen or Anastrozole to mimic the effects of the drugs in vivo, and co-cultured with whole blood. Platelet activation was determined using flow cytometry. Platelet (CD41a+CD62P+) was determined using an interval gating strategy. Platelet morphology was visualised using scanning electron microscopy. Our results support clinical findings, showing that hormone-therapy is associated with platelet activation. Tamoxifen-treated MCF7 cells increased P-selectin expression, with ultrastructural analysis showing fully spread platelets. Conversely, Tamoxifen-treated T47D cells decreased P-selectin expression with platelets showing signs of early aggregation. Anastrozole pre-treatment decreased P-selectin expression, with treated MCF7 cells inducing platelet membrane folds and lamellipodia extension, and treated T47D cells inducing platelet aggregation and fibrin network formation indicating hypercoagulation. The findings support clinical studies. Hormone-therapy augments tumour cell-induced platelet activation, which may be linked to cell phenotype. This may have clinical implications for treatment strategies.


Assuntos
Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/efeitos adversos , Trombose/etiologia , Adulto , Plaquetas/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Ativação Plaquetária/efeitos dos fármacos , Adulto Jovem
15.
Support Care Cancer ; 27(10): 3813-3822, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30729298

RESUMO

PURPOSE: To clarify the profile of adverse events from endocrine therapies in older patients. METHODS: We surveyed 15 subjective symptoms including hot flashes, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, lethargy, forgetfulness, depressive state, irritated state, genital bleeding, leukorrhea increase, vaginal dryness, bone fracture, and weight gain by a questionnaire among 2044 patients over 55 years old (total number of answered sheets, 8875) and compared the results according to age (56-69 years old vs. ≥ 70 years old) and type of therapy (aromatase inhibitors (AIs) vs. selective estrogen receptor modulators (SERMs)). Among patients 56-69 years old, 6093 and 314 responses were from patients treated with AIs (1477 patients) and SERMs (123 patients), respectively, and 2292 and 176 responses were from those ≥ 70 years old treated with AIs (581 patients) and SERMs (51 patients), respectively. RESULTS: In patients ≥ 70 years old, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, and lethargy were significantly more frequent/severe with AIs than with SERMs. In those aged 56-69, knuckle stiffness and vaginal dryness were significantly more frequent with AIs than with SERMs, but the opposite occurred for hot flashes, leukorrhea increase, genital bleeding, and weight gain. CONCLUSIONS: Among patients ≥ 70 years old, many symptoms were significantly more frequent/severe with AIs than with SERMs, compared with those aged 56-69, which suggests a difference in the profile of adverse events according to the type of endocrine therapy and the patient's age. It is important to consider the benefits and risks of each treatment to optimize endocrine therapy for older patients.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos , Fatores Etários , Idoso , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Artralgia/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Feminino , Fraturas Ósseas/prevenção & controle , Fogachos/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Inquéritos e Questionários , Sudorese/efeitos dos fármacos , Tamoxifeno/uso terapêutico
16.
Support Care Cancer ; 27(4): 1325-1334, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729333

RESUMO

PURPOSE: Vaginal atrophy is one of the most common side effects of using tamoxifen in women with breast cancer. Hormone therapy for vaginal atrophy is prohibited in these women. The present study was conducted to investigate the effect of vitamin D and E vaginal suppositories on vaginal atrophy in women with breast cancer receiving tamoxifen. METHODS: Women under breast cancer management receiving tamoxifen and showing symptoms of vaginal atrophy were randomized triple-blind to an 8-week trial on vaginal suppository vitamin E or vitamin D or placebo administered every night before bedtime. The genitourinary atrophy self-assessment tool was administered, and pH was measured in all three groups before the intervention and at the end of weeks 2, 4, and 8 of the intervention. The Vaginal Maturation Index (VMI) was also measured before the intervention and at the end of the eighth week. Data were analyzed with paired t tests, repeated measures analysis of variance, and chi-square test. RESULTS: Thirty-two patients were randomized in each group. The results obtained showed an increase in the VMI by the end of the eighth week of the intervention in the groups receiving the vitamin D and E vaginal suppositories compared with the placebo group (P < 0.001). The vaginal pH also reduced in both groups compared with that in the placebo group (P < 0.001). The symptoms of self-reported genitourinary atrophy also improved in the two intervention groups compared with those in the placebo group by the end of the eighth week (P < 0.001). CONCLUSION: These data support that vitamin D and E vaginal suppositories were beneficial in improving vaginal atrophy in women with breast cancer receiving tamoxifen. Given the prohibition on hormone therapy in these women, the suppositories can be used as an alternative therapy to improve these symptoms.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/efeitos adversos , Vagina/efeitos dos fármacos , Doenças Vaginais/induzido quimicamente , Doenças Vaginais/tratamento farmacológico , Vitamina D/administração & dosagem , Vitamina E/administração & dosagem , Adulto , Atrofia/induzido quimicamente , Atrofia/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Irã (Geográfico) , Pessoa de Meia-Idade , Pós-Menopausa , Supositórios , Tamoxifeno/administração & dosagem , Vagina/patologia , Vitamina D/farmacologia , Vitamina E/farmacologia
17.
PLoS One ; 14(2): e0212880, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30811469

RESUMO

Muscles of older animals are more susceptible to injury and regenerate poorly, in part due to a persistent inflammatory response. The janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory signaling and is tightly regulated by the suppressor of cytokine signaling (SOCS) proteins, especially SOCS3. SOCS3 expression is altered in the muscle of aged animals and may contribute to the persistent inflammation and impaired regeneration. To test this hypothesis, we performed myotoxic injuries on mice with a tamoxifen-inducible deletion of SOCS3 specifically within the muscle stem cell compartment. Muscle stem cell-specific SOCS3 deletion reduced muscle mass at 14 days post-injury (-14%, P < 0.01), altered the myogenic transcriptional program, and reduced myogenic fusion based on the number of centrally-located nuclei per muscle fiber. Despite the delay in myogenesis, muscles with a muscle stem cell-specific deletion of SOCS3 were still able to regenerate after a single bout or multiple bouts of myotoxic injury. A reduction in SOCS3 expression in muscle stem cells is unlikely to be responsible for the incomplete muscle repair in aged animals.


Assuntos
Envelhecimento/genética , Deleção de Genes , Regeneração/efeitos dos fármacos , Células-Tronco/citologia , Proteína 3 Supressora da Sinalização de Citocinas/genética , Tamoxifeno/efeitos adversos , Envelhecimento/metabolismo , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Células Musculares/efeitos dos fármacos , Células Musculares/fisiologia , Fator de Transcrição PAX7/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
19.
Int J Cancer ; 145(5): 1325-1333, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30748011

RESUMO

The phase III DATA study investigates the efficacy of adjuvant anastrozole (6 vs. 3 year) in postmenopausal women with breast cancer previously treated with 2-3 years of tamoxifen. This planned side-study assessed patterns of care regarding detection and treatment of osteopenia/osteoporosis, and trends in bone mineral density (BMD) during and after therapy. We registered all BMD measurements and bisphosphonate-use. Time to osteopenia/osteoporosis was analysed by Kaplan Meier methodology. For the trend in T-scores we used linear mixed models with random patients effects. Of 1860 eligible DATA patients, 910 (48.9%) had a baseline BMD measurement. Among patients with a normal baseline BMD (n = 417), osteopenia was observed in 53.5% and 55.4% in the 6- and 3-year group respectively (p = 0.18), during follow-up. Only two patients (3-year group) developed osteoporosis. Of the patients with osteopenia at baseline (n = 408), 24.4% and 20.4% developed osteoporosis respectively (p = 0.89). Three years after randomisation 18.3% and 18.2% used bisphosphonates in the 6- and 3-year groups respectively and 6 years after randomisation this was 23.7% and 20.9% respectively (p = 0.90) of which the majority used oral bisphosphonates. The yearly mean BMD-change during anastrozole in the lumbar spine showed a T-score decline of 0.075. After bisphosphonate addition the decline became less prominent (0.047 (p < 0.001)) and after anastrozole cessation, while continuing bisphosphonates, the mean BMD yearly increased (0.047 (p < 0.001)). In conclusion, extended anastrozole therapy was not associated with a higher incidence of osteoporosis. Anastrozole-use was associated with a BMD decrease; however, the decline was modest and partially reversible after anastrozole cessation.


Assuntos
Anastrozol/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/terapia , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Feminino , Fraturas Ósseas , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
20.
Post Reprod Health ; 25(1): 21-32, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30776968

RESUMO

This guidance document by the British Menopause Society provides an overview of the management of women experiencing estrogen deficiency symptoms and arthralgia following a breast cancer diagnosis. It is now recommended that breast cancer patients are referred to health care professionals with an expertise in menopause for the management of such symptoms, which in turn often involves liaison with patients' breast cancer teams. However, as many women initially present to primary health care professionals for advice, this statement is aimed to support the latter in such consultations by providing information about symptom aetiology, current management strategies and controversies and identifying useful practice points.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Artralgia/terapia , Neoplasias da Mama/terapia , Estrogênios/deficiência , Menopausa Precoce , Inibidores da Aromatase/efeitos adversos , Artralgia/induzido quimicamente , Atrofia/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante/efeitos adversos , Consenso , Feminino , Terapia de Reposição Hormonal , Fogachos/terapia , Humanos , Tamoxifeno/efeitos adversos , Vagina/patologia , Vulva/patologia
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