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1.
Ann Oncol ; 33(7): 702-712, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35550723

RESUMO

BACKGROUND: The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments. METHODS: An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients' representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs. RESULTS: The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations. CONCLUSIONS: ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.


Assuntos
Neoplasias , Qualidade de Vida , Ensaios Clínicos como Assunto , Humanos , Oncologia , Neoplasias/diagnóstico , Neoplasias/terapia , Estudos Prospectivos , Estudos Retrospectivos
3.
Ann Oncol ; 29(3): 654-660, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29293876

RESUMO

Background: Homologous recombination deficiency (HRD)-causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313. Patients and methods: In total, 425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing, and BRCA1 PM were carried out on DNA isolated from formalin-fixed paraffin-embedded tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation or a pre-defined HRD score ≥42. Markers were tested for prognostic value on disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment and nodal status. Results: HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD positive (27% with tBRCA mutation, 40% tBRCA-negative but HRD score ≥42). HRD-positive status was associated with a better DFS [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.51-1.00; P = 0.049] and non-significant trend toward better OS (HR = 0.71; 95% CI 0.48-1.03; P = 0.073). High HRD score (≥42) in tBRCA-negative patients (n = 274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; P = 0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; P = 0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; P = 0.25). Conclusions: HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC-based chemotherapy and should be evaluated further in prospective studies. Clinical Trials Number: Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Instabilidade Genômica/genética , Reparo de DNA por Recombinação/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Proteína BRCA1/genética , Quimioterapia Adjuvante/métodos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade
5.
Ann Oncol ; 28(8): 1700-1712, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28838210

RESUMO

The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.


Assuntos
Neoplasias da Mama/terapia , Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico , Áustria , Neoplasias da Mama/patologia , Terapia Combinada , Diagnóstico Precoce , Feminino , Humanos , Terapia Neoadjuvante , Radioterapia , Procedimentos Cirúrgicos Operatórios
6.
Breast Cancer Res Treat ; 166(1): 85-94, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28717852

RESUMO

PURPOSE: Elevated S100A8 expression has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8 is expressed by breast cancer cells as well as by infiltrating immune and myeloid cells. Here we investigate the association of elevated S100A8 protein expression in breast cancer cells and in breast tumor stroma with survival outcomes in a cohort of breast cancer patients. PATIENTS AND METHODS: Tissue microarrays (TMA) were constructed from breast cancer specimens from 417 patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004 and 2006. Representative regions of non-necrotic tumor and distant normal tissue from each patient were used to construct the TMA. Automated quantitative immunofluorescence (AQUA) was used to measure S100A8 protein expression, and samples were scored for breast cancer cell and stromal S100A8 expression. S100A8 staining intensity was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations between breast cancer cell and stromal S100A8 expression with disease-free survival and overall survival were determined using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: High breast cancer cell S100A8 protein expression (as indicated by AQUA scores), as a continuous measure, was a significant prognostic factor for OS [univariable hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.00-1.55, p = 0.05] in this patient cohort. Exploratory analyses identified optimal S100A8 AQUA score cutoffs within the breast cancer cell and stromal compartments that significantly separated survival curves for the complete cohort. Elevated breast cancer cell and stromal S100A8 expression, indicated by higher S100A8 AQUA scores, significantly associates with poorer breast cancer outcomes, regardless of estrogen receptor status. CONCLUSIONS: Elevated breast cancer cell and stromal S1008 protein expression are significant indicators of poorer outcomes in early stage breast cancer patients. Evaluation of S100A8 protein expression may provide additional prognostic information beyond traditional breast cancer prognostic biomarkers.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Calgranulina A/metabolismo , Células Estromais/metabolismo , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Calgranulina A/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Feminino , Imunofluorescência , Humanos , Estimativa de Kaplan-Meier , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Estrogênio/metabolismo , Células Estromais/patologia , Análise Serial de Tecidos , Microambiente Tumoral
7.
Pharmacogenomics J ; 17(6): 521-527, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-27549341

RESUMO

Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% greater exemestane concentration (P<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index and had not received chemotherapy (all P<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (P<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.


Assuntos
Androstadienos/sangue , Antineoplásicos/sangue , Neoplasias da Mama/genética , Citocromo P-450 CYP3A/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Androstadienos/administração & dosagem , Androstadienos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Feminino , Técnicas de Genotipagem , Humanos , Pessoa de Meia-Idade , Testes Farmacogenômicos , Pós-Menopausa , Medicina de Precisão , Valor Preditivo dos Testes
8.
J Comp Pathol ; 155(4): 299-304, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27567927

RESUMO

Epithelial cell adhesion molecule (EpCAM) is expressed in most human normal and neoplastic tissues of epithelial derivation and may have an association with tumour cell aggressiveness, a stem cell-like phenotype and clinical outcome. Antibody-based strategies for the targeting and capture of EpCAM-expressing tumour cells are showing promise, both as diagnostic tools and potential therapies. The aim of this study was to assess EpCAM expression in canine tumours. EpCAM expression was assessed in tumour cell lines via gene expression profiling and in formalin-fixed and paraffin wax-embedded tissues from canine carcinomas representing various anatomical sites by immunohistochemistry. EpCAM mRNA expression was higher in cell lines from carcinomas than those derived from sarcomas or haemopoietic tumours. EpCAM was expressed by >2/3 of tumour cells in 71% of canine carcinomas evaluated, irrespective of histotype, with the exception of carcinomas of the adrenal gland. Canine sarcomas and haemopoietic tumours were uniformly negative. Most canine carcinomas express EpCAM and so could be suitable for the study of EpCAM-directed diagnostics and therapeutics.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/veterinária , Doenças do Cão/patologia , Molécula de Adesão da Célula Epitelial/biossíntese , Animais , Western Blotting , Cães , Molécula de Adesão da Célula Epitelial/análise , Imuno-Histoquímica , Análise Serial de Tecidos
9.
Breast Cancer Res Treat ; 158(3): 485-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27393622

RESUMO

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Albuminas/uso terapêutico , Bevacizumab/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
Pharmacogenomics J ; 14(3): 241-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23999597

RESUMO

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.


Assuntos
Aldeído Desidrogenase/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Família Aldeído Desidrogenase 1 , Neoplasias da Mama/genética , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Retinal Desidrogenase
11.
Br J Cancer ; 109(9): 2331-9, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24084768

RESUMO

BACKGROUND: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. METHODS: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. RESULTS: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ≥20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. CONCLUSION: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Mama/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstadienos/uso terapêutico , Aromatase/genética , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Estrogênios/metabolismo , Feminino , Humanos , Letrozol , Mamografia/métodos , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/genética , Pós-Menopausa/metabolismo , Estudos Prospectivos , Triazóis/uso terapêutico
12.
J Intern Med ; 274(2): 137-43, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23844916

RESUMO

Tumour heterogeneity is a major barrier to cure breast cancer. It can exist between patients with different intrinsic subtypes of breast cancer or within an individual patient with breast cancer. In the latter case, heterogeneity has been observed between different metastatic sites, between metastatic sites and the original primary tumour, and even within a single tumour at either a metastatic or a primary site. Tumour heterogeneity is a function of two separate, although linked, processes. First, genetic instability is a hallmark of malignancy, and results in 'fixed' genetic changes that are almost certainly carried forward through progression of the cancer over time, with increasingly complex additional genetic changes in new metastases as they arise. The second type of heterogeneity is due to differential but 'plastic' expression of various genes important in the biology and response to various therapies. Together, these processes result in highly variable cancers with differential response, and resistance, to both targeted (e.g. endocrine or anti-human epithelial growth receptor type 2 (HER2) agents) and nontargeted therapies (e.g. chemotherapy). Ideally, tumour heterogeneity would be monitored over time, especially in relation to therapeutic strategies. However, biopsies of metastases require invasive and costly procedures, and biopsies of multiple metastases, or serially over time, are impractical. Circulating tumour cells (CTCs) represent a potential surrogate for tissue-based cancer and therefore might provide the opportunity to monitor serial changes in tumour biology. Recent advances have enabled accurate and reliable quantification and molecular characterization of CTCs with regard to a number of important biomarkers including oestrogen receptor alpha and HER2. Preliminary data have demonstrated that expression of these markers between CTCs in individual patients with metastatic breast cancer reflects the heterogeneity of the underlying tumours. Future studies are designed to determine the clinical utility of these novel technologies in either research or routine clinical settings.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Células Neoplásicas Circulantes/patologia , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/genética , Biópsia por Agulha , Feminino , Heterogeneidade Genética , Humanos , Imuno-Histoquímica , Prognóstico , Receptor ErbB-2/genética
13.
Ann Oncol ; 24(8): 2011-6, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23613476

RESUMO

BACKGROUND: Aromatase inhibitors (AIs) may cause a rise in estrogen levels due to ovarian function recovery in women with clinical chemotherapy-induced ovarian failure (CIOF). We carried out a prospective registry trial to identify predictors of ovarian function recovery during AI therapy. PATIENTS AND METHODS: Women with hormone receptor (HR)-positive breast cancer who remained amenorrheic and had hormonal levels consistent with ovarian failure after adjuvant chemotherapy were enrolled in a multi-institutional clinical trial of anastrozole. Subjects underwent frequent assessment using an ultrasensitive estradiol assay. Multivariable analysis was used to evaluate clinical and biochemical predictors of ovarian function recovery within 48 weeks. RESULTS: Recovery of ovarian function during AI therapy was observed in 13 of 45 (28.9%) assessable subjects after a median 2.1 months (range 0.6-11.9). Median age at chemotherapy initiation was statistically significantly different between those who regained ovarian function (43 years, range 40-51) and those who remained postmenopausal (49 years, range 44-52; P < 0.0001). CONCLUSIONS: A significant proportion of women with CIOF recover ovarian function during AI therapy, including a woman over age 50 at initiation of chemotherapy. Tamoxifen remains the standard of care for women with CIOF. If an AI is used, patients should be monitored frequently with high-quality estradiol assays. CLINICALTRIALS.GOV: NCT00555477.


Assuntos
Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Estradiol/sangue , Ovário/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Adulto , Amenorreia , Anastrozol , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Insuficiência Ovariana Primária/diagnóstico , Estudos Prospectivos , Receptores de Estrogênio , Tamoxifeno/uso terapêutico , Triazóis/uso terapêutico , Hemorragia Uterina/induzido quimicamente
14.
Mol Endocrinol ; 26(2): 220-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22174377

RESUMO

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Quinase 3 da Glicogênio Sintase/metabolismo , Coativador 1 de Receptor Nuclear/genética , Tamoxifeno/efeitos adversos , Sequência de Aminoácidos , Substituição de Aminoácidos , Antineoplásicos Hormonais/uso terapêutico , Desmineralização Patológica Óssea/induzido quimicamente , Desmineralização Patológica Óssea/genética , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama/prevenção & controle , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Feminino , Estudos de Associação Genética , Glicogênio Sintase Quinase 3 beta , Humanos , Dados de Sequência Molecular , Fosforilação , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Receptores de Estrogênio/agonistas , Receptores de Estrogênio/metabolismo , Análise de Sequência de DNA , Tamoxifeno/uso terapêutico
15.
Clin Pharmacol Ther ; 90(5): 693-700, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21975350

RESUMO

The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n≈250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P<0.0001), body mass index (BMI) (P<0.0001), and age (P=0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.


Assuntos
Antineoplásicos/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias da Mama/tratamento farmacológico , Nitrilas/farmacocinética , Pós-Menopausa , Triazóis/farmacocinética , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Androstadienos/uso terapêutico , Antineoplásicos/uso terapêutico , Índice de Massa Corporal , Estudos Cross-Over , Citocromo P-450 CYP2A6 , Citocromo P-450 CYP3A/genética , Feminino , Variação Genética , Genótipo , Humanos , Letrozol , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Farmacogenética , Estudos Prospectivos , Triazóis/uso terapêutico
16.
Clin Pharmacol Ther ; 88(5): 626-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20827267

RESUMO

We previously reported that the ESR1 XbaI genotypes were associated with baseline and tamoxifen-induced serum lipid profiles. The analysis in that study was carried out by PCR followed by restriction-enzyme digestion. After reanalysis using more robust TaqMan assays, the findings related to ~10% of the genotypes for the ESR1 XbaI single-nucleotide polymorphism (SNP) were revised. For the other genotypes (i.e., ESR1 PvuII, ESR2, and CYP2D6), the results were nearly identical to those in the previous study. Upon reanalysis, previously reported associations between the ESR1 Xba1 genotypes and baseline triglyceride and low-density lipoprotein (LDL) cholesterol levels were no longer observed. Previously reported associations between the ESR1 XbaI genotypes and tamoxifen-induced changes in levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were also no longer observed. However, the following observations from the original report did not change: (i) the levels of circulating lipids are lower in women taking tamoxifen; (ii) there is an association between the ESR2-02 genotypes and changes in triglyceride levels; and (iii) neither ESR1 PvuII nor CYP2D6 is associated with any changes in serum lipid concentrations in patients receiving treatment with tamoxifen.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Pré-Menopausa , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Humanos , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/sangue
17.
Br J Cancer ; 103(3): 291-6, 2010 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-20606683

RESUMO

BACKGROUND: The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers. METHODS: Patients with breast cancer were enrolled in a trial of adjuvant AI therapy. Changes in pain and function during therapy were assessed prospectively. We selected 30 cases with AIMSS and 22 controls without AIMSS, matched for demographics and prior therapy. Serum samples collected at baseline and during treatment were assayed for multiple inflammatory cytokines and lipid mediators using multiplex assays. RESULTS: Before AI therapy, mean serum concentrations of 6 of 36 assayed factors were statistically significantly lower in cases than controls (all P<0.003). No statistically significant changes during AI therapy relative to pre-treatment were observed between cases and controls for any of the inflammatory markers tested. CONCLUSION: AIMSS is probably not associated with a systemic inflammatory response. Pre-treatment cytokine levels may predict for development of AIMSS.


Assuntos
Androstadienos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocinas/sangue , Inflamação/induzido quimicamente , Doenças Musculoesqueléticas/induzido quimicamente , Idoso , Antineoplásicos/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/sangue , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Estudos de Casos e Controles , Estrogênios/deficiência , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Síndrome , Tamoxifeno/uso terapêutico , Taxoides/uso terapêutico
18.
Br J Cancer ; 102(2): 294-300, 2010 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-19953095

RESUMO

BACKGROUND: Tamoxifen, a selective oestrogen receptor (ER) modulator, increases bone mineral density (BMD) in postmenopausal women and decreases BMD in premenopausal women. We hypothesised that inherited variants in candidate genes involved in oestrogen signalling and tamoxifen metabolism might be associated with tamoxifen effects in bone. METHODS: A total of 297 women who were initiating tamoxifen therapy were enrolled in a prospective multicentre clinical trial. Lumbar spine and total hip BMD values were measured using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of tamoxifen therapy. Single-nucleotide polymorphisms (SNPs) in ESR1, ESR2, and CYP2D6 were tested for associations in the context of menopausal status and previous chemotherapy, with a mean percentage change in BMD over 12 months. RESULTS: The percentage increase in BMD was greater in postmenopausal women and in those patients who had been treated with chemotherapy. No significant associations between tested SNPs and either baseline BMD or change in BMD with 1 year of tamoxifen therapy were detected. CONCLUSION: The evaluated SNPs in ESR and CYP2D6 do not seem to influence BMD in tamoxifen-treated subjects.


Assuntos
Antineoplásicos Hormonais/farmacologia , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Tamoxifeno/farmacologia , Absorciometria de Fóton , Adulto , Citocromo P-450 CYP2D6/genética , Receptor beta de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Sistema de Registros
19.
Pharmacogenomics J ; 9(4): 258-64, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19421167

RESUMO

The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen-receptor-positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n=297) were genotyped for CYP2D6 variants and assigned a 'score' based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months was tested. We observed a strong nonlinear correlation between higher CYP2D6 score and increased rates of discontinuation (r(2)=0.935, P=0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Cooperação do Paciente , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Feminino , Humanos , Estudos Prospectivos , Tamoxifeno/efeitos adversos , Tamoxifeno/metabolismo
20.
Clin Pharmacol Ther ; 83(5): 702-10, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17713466

RESUMO

Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5 mg/dl (13.5-33.5 mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene-dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene-dose effect) and high-density lipoprotein (P=0.004; gene-dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Lipídeos/sangue , Tamoxifeno/farmacologia , Adulto , Neoplasias da Mama/sangue , Colesterol/sangue , Estudos de Coortes , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Receptor alfa de Estrogênio/sangue , Receptor beta de Estrogênio/sangue , Feminino , Genótipo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/sangue , Pré-Menopausa/sangue , Estudos Prospectivos
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