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The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Cetonas/administração & dosagem , Lapatinib/administração & dosagem , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Terapia de Salvação , Taxa de Sobrevida , Trastuzumab/administração & dosagemRESUMO
BACKGROUND: We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy. METHODS: In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554. FINDINGS: Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group. INTERPRETATION: This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy. FUNDING: GlaxoSmithKline, Roche, and Sanofi-Aventis.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/uso terapêutico , Idoso , Antraciclinas/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Quinazolinas/efeitos adversos , Receptor ErbB-2/metabolismo , Taxoides/uso terapêutico , Trastuzumab , Adulto JovemRESUMO
The purpose of the StaPlaRes project was to evaluate two innovative techniques of urea fertiliser application and to quantify greenhouse gas (GHG) emissions. All GHG emissions, as well as other gaseous emissions, agronomic and environmental variables were collected for three years (2016/2017-2018/2019) at three experimental field sites in Germany. All management activities were consistently documented. Multi-variable data sets of gas fluxes (N2O and NH3), crop parameters (grain and straw yield, N content, etc.), soil characteristics (NH4-N, NO3-N, etc.), continuously recorded meteorological variables (air and soil temperatures, radiation, precipitation, etc.), management activities (sowing, harvest, soil tillage, fertilization, etc.), were documented and metadata (methods, further information about variables, etc.) described. Additionally, process-related tests were carried out using lab (N2 emissions), pot and lysimeter experiments (nitrate leaching). In total, 2.5 million records have been stored in a Microsoft Access database (StaPlaRes-DB-Thuenen). The database is freely available for (re)use by others (scientists, stakeholders, etc.) on the publication server and data repository OpenAgrar for meta-analyses, process modelling and other environmental studies.
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Recently, we have shown that the new G-protein-coupled estrogen receptor GPR30 plays an important role in the development of tamoxifen resistance in vitro. This study was undertaken to evaluate the correlation between GPR30 and tamoxifen resistance in breast cancer patients. GPR30 protein expression was evaluated by immunohistochemical analysis in 323 patients with primary operable breast cancer. The association between GPR30 expression and tamoxifen resistance was confirmed in a second cohort of 103 patients treated only with tamoxifen. Additionally, we evaluated GPR30 expression in 33 primary tumors and in recurrent tumors from the same patients. GPR30 expression was detected in 56.7% of the breast cancer specimens investigated and it correlated with overexpression of HER-2 (P = 0.021), EGFR (P = 0.024) and lymph node status (P = 0.047). In a first cohort, survival analysis showed that GPR30 was negatively correlated with relapse-free survival (RFS) only in patients treated with tamoxifen (tamoxifen with or without chemotherapy). GPR30 expression was associated with shorter RFS (HR = 1.768; 95% CI, 1.156-2.703; P = 0.009). In a subset of patients treated only with tamoxifen, multivariate analysis revealed that GPR30 expression is an independent unfavorable factor for RFS (HR = 4.440; 95% CI, 1.408-13.997; P = 0.011). In contrast, GPR30 tended to be a favorable factor regarding RFS in patients who did not receive tamoxifen. In 33 paired biopsies obtained before and after adjuvant therapy, GPR30 expression significantly increased only under tamoxifen treatment (P = 0.001). GPR30 expression in breast cancer independently predicts a poor RFS in patients treated with tamoxifen.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptores Acoplados a Proteínas G/metabolismo , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Progressão da Doença , Receptores ErbB/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Receptores de Estrogênio , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To investigate a modified technique for arterial port placement that uses a suture-mediated closure system with the aim to reduce delays caused by intraprocedural oozing around the catheter. MATERIALS AND METHODS: Forty consecutive patients (age, 63.9 y ± 11.8) stratified for regional arterial infusion chemotherapy were prospectively randomized to undergo conventional or modified port implantation. Time for device placement, total procedure time, number of catheters, size of largest and final catheters placed, duration of bleeding from puncture site, procedural delays, and time until hemostasis was achieved were recorded. RESULTS: Time for device placement was 3.7 minutes ± 1.1, with no complications encountered. Total procedure times were 133.0 minutes ± 62.8 for conventional port implantation and 100.0 minutes ± 49.5 for modified implantation (P = .13). No differences were found in the number of catheters or size of largest or final catheter used. Duration of groin bleeding necessitating manual compression was 21.8 minutes ± 24.4 for conventional port implantation, resulting in a mean procedural delay of 6.2 minutes ± 7.0. Hemostasis was achieved after a mean of 17.1 minutes ± 20.9. Groin hematoma was observed in three patients. In contrast, with the modified technique, mean duration of oozing and intraprocedural delays were only 0.2 minutes ± 0.6 and 0.1 minutes ± 0.5, respectively (both P < .0001 vs conventional technique). Hemostasis was achieved within 3.2 minutes ± 4.1 (P < .0001), with no cases of hematoma found. CONCLUSIONS: Use of a suture-mediated closure system facilitated arterial port implantation by effective prevention of groin bleeding while allowing the use of a sheath.
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Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Virilha/irrigação sanguínea , Hemorragia/prevenção & controle , Técnicas Hemostáticas/instrumentação , Técnicas de Sutura/instrumentação , Idoso , Catéteres , Quimioterapia do Câncer por Perfusão Regional/instrumentação , Desenho de Equipamento , Feminino , Alemanha , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pressão , Estudos Prospectivos , Punções , Fatores de Tempo , Resultado do TratamentoRESUMO
The aim of the current study was to investigate the role of promoter methylation of adenomatous polyposis coli (APC) and epithelial cadherin (E-cadherin) genes in endometrial tumorigenesis. The methylation status of both genes was investigated in 43 cases of normal endometrium, 21 simple hyperplasia, 17 atypical hyperplasia, and 86 endometrial carcinoma (EC). Additionally, the methylation pattern of both genes was analyzed in 24 primary ECs and their corresponding metastases. DNA methylation of the APC gene increased from atypical hyperplasia (23.5%) to endometrial carcinoma, reaching its highest level of 77.4% in early stage cancer (FIGO I and II) and decreasing stepwise to 24.2% in advanced stage carcinomas (FIGO III and IV). No methylation of APC was found in normal endometrium or simple hyperplasia. Methylation of E-cadherin was found only in EC (22.1%). The mean age of the patients with aberrant APC methylation was 68.8 years and was significantly higher compared to the mean age (60.9 years) of the patients without methylation of APC promoter (P = 0.02). APC promoter methylation significantly correlated with decreased protein expression of APC (P = 0.039), with increased expression of the Ki-67 proliferative marker (P = 0.006) and decreased metastatic potential (P = 0.002). There was no correlation between APC and E-cadherin methylation patterns and the other clinicopathologic features, nor with patient outcome. Our results suggest that hypermethylation of APC promoter region is an early event in endometrial tumorigenesis.
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Metilação de DNA , Neoplasias do Endométrio/genética , Genes APC , Regiões Promotoras Genéticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Caderinas/genética , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: This study was undertaken to evaluate the potential role of G-protein-coupled estrogen receptor in endometrial pathology associated with tamoxifen treatment of breast cancer patients. STUDY DESIGN: We investigated whether G-protein-coupled estrogen receptor plays a role in mediating proliferating effect of tamoxifen in endometrial carcinoma cells. These results were compared with the G-protein-coupled estrogen receptor expression pattern in endometrial tissue from a cohort of 95 breast cancer patients, who received tamoxifen or another adjuvant therapy. RESULTS: In vitro tamoxifen significantly stimulated the mitogen-activated protein kinase phosphorylation and cell proliferation of endometrial cell lines via G-protein-coupled estrogen receptor. In vivo, there was a significant correlation between G-protein-coupled estrogen receptor expression and the tamoxifen-induced endometrial pathology (P = .006). Moreover, G-protein-coupled estrogen receptor positivity was predictive of an earlier development of symptoms, such as bleeding or suspect endometrial thickness, induced by tamoxifen therapy (P = .019). CONCLUSION: G-protein-coupled estrogen receptor plays an important role in tamoxifen-induced endometrial abnormalities.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias do Endométrio/induzido quimicamente , Neoplasias do Endométrio/patologia , Receptores Acoplados a Proteínas G/metabolismo , Tamoxifeno/efeitos adversos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Valores de Referência , Sensibilidade e Especificidade , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
BACKGROUND: Little is known about proper interval periods between the flushings of totally implantable access ports after completion of chemotherapy. Manufacturer guidelines recommend flushing catheters every 4 weeks. METHODS: This retrospective study examined whether flushing less than every 4 weeks conferred any benefit. RESULTS: 349 totally implanted access ports were divided into four groups based on the different durations of the intervals between flushings. Sixteen (4.6%) complications were observed in the study population. CONCLUSION: Our results demonstrate that extending the flushing interval to up to 4 months remains medically safe and drastically reduces the costs.
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Anticoagulantes/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Cateterismo Venoso Central/métodos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Cateterismo Venoso Central/efeitos adversos , Cateteres de Demora , Esquema de Medicação , Feminino , Humanos , Estudos RetrospectivosRESUMO
Metastasis to the central nervous system (CNS), including neoplastic meningitis (NM), is a devastating complication of systemic cancer. With the improved survival of cancer patients, the incidence of CNS metastasis is rising, especially among those with breast or lung carcinoma. New therapies that effectively treat these primary tumors outside of the CNS have underscored the significance of CNS metastases; they have become a significant clinical issue and a therapeutic challenge. This review discusses clinical situations in which treatment or chemoprophylaxis of CNS metastases and NM from breast or lung cancer may play an important role. Potential clinical trials to assess these assumptions also will be proposed.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/secundário , Ensaios Clínicos como Assunto , Feminino , Humanos , Injeções Espinhais , Carcinomatose Meníngea/prevenção & controle , Análise de SobrevidaRESUMO
OBJECTIVE: The aim of this study was to investigate the role of p16 in tumorigenesis of endometrial carcinoma (EC). METHODS: Expression of p16 protein was analyzed using immunohistochemistry. The methylation status of p16 promoter region was determined by methylation-specific PCR. Deletion analysis of the p16 gene was performed by PCR-analyses. RESULTS: Aberrant protein expression of p16 was observed in 18 of 46 (39.2%) ECs and correlated significantly with p16 alterations, including gene deletions in 26 of 46 (56.5%) ECs and promoter hypermethylation in 8 of 46 (17.4%) ECs (p<0.001). A significant increase in the frequency of p16 alterations from early stage (I-II) to advanced stage (III-IV) ECs was observed (p=0.002). There was no significant correlation between p16 protein expression and the clinico-pathological features of EC. The development of metastases correlated significantly with the frequency of p16 alterations: p16 alterations were detected in 14 of 15 (93.3%) PTs with metastases and in only 18 of 31 (58.1%) PTs without metastases (p=0.018). The genetic comparison of 15 primary ECs and their paired metastases revealed that in most of the cases the deleted region of p16 gene remains the same or becomes larger during the progression from primary tumor to its corresponding metastases. CONCLUSION: Our results suggest that p16 alterations and particularly p16 gene deletions in ECs are associated with increased incidence of metastases.
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Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Genes p16 , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina , Metilação de DNA , Feminino , Deleção de Genes , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Regiões Promotoras GenéticasRESUMO
We present a case of high-risk metastatic gestational trophoblastic neoplasia treated successfully with methotrexate monotherapy after severe toxicity from the combination chemotherapy: etoposide, dactinomycin, methotrexate, vincristine, and cyclophosphamide.
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Antibióticos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dactinomicina/administração & dosagem , Etoposídeo/administração & dosagem , Metotrexato/administração & dosagem , Neoplasias Trofoblásticas/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Gravidez , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Antineoplastic agents directly targeting tumor cells have represented the major strategy of systemic anticancer therapy for many years. Nevertheless, overcoming resistance mechanisms remains a great challenge because treatment options are limited in many cases. From this point of view, immunotherapeutic approaches seem promising in a broad spectrum of solid tumors. These include in particular the currently available inhibitors directed against immune checkpoints leading to a significant T-cell activation. To date, the programmed death receptor 1 (PD-1) and its ligand are the most prominent targets in this context. However, the role of checkpoint inhibitors in the treatment of breast cancer is still being debated, and the main focus is on triple-negative breast cancer patients as a target population in many ongoing trials. Moreover, the potential superiority of combinations with other anticancer drugs such as cytotoxics and targeted agents will be discussed.
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Tamoxifen is increasingly used in adjuvant endocrine therapy for postsurgery breast cancer patients and in chemoprevention for high-risk patients. We present a case of bilateral ovarian cyst development with consecutive unilateral cyst torsion and elevated serum estradiol in a premenopausal patient treated with tamoxifen after breast-conserving surgery.
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Neoplasias da Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Cistos Ovarianos/induzido quimicamente , Síndrome de Hiperestimulação Ovariana/induzido quimicamente , Tamoxifeno/efeitos adversos , Adulto , Estradiol/sangue , Feminino , Humanos , Cistos Ovarianos/diagnóstico por imagem , Anormalidade Torcional , UltrassonografiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/administração & dosagem , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagemRESUMO
The presence of occult micrometastases in bone marrow (BM) of patients with early breast cancer increases the risk of relapse. Detection of circulation tumor cells in peripheral blood (PB) may also influence the patient's prognosis. Few data are available on the correlation between tumor cell dissemination in BM and PB in solid epithelial tumors. Twenty-milliliter blood samples were collected from PB of 42 patients with advanced breast cancer and centrifuged using the density gradient OncoQuick (OncoQuick Greiner BioOne, Frickenhausen, Germany). The BM aspirates available from 11 of the 42 patients were centrifuged using density centrifugation Ficoll. Tumor cell detection was performed by microscopy after cytospin preparation and immunocytochemical staining with the monoclonal antibody A45-B/B3. Cytokeratin-positive cells were detected in 23 patients (55%) in the PB and in three patients (27%) in the BM. A cohort with bone lesions as the only metastatic side showed a correlation as follows: 7 of the 11 patients (64%) had negative findings in BM and PB, whereas cytokeratin-positive cells in PB were present in 3 of these 11 patients (27%). The presence of visceral metastases was associated with the detection of cytokeratin-positive cells in the PB in 20 of the 31 patients (65%) in this subgroup. The density gradient OncoQuick in combination with immunocytochemical staining allows the detection of cytokeratin-positive cells in PB of patients with advanced breast cancer. The immunocytochemical detection of cytokeratin-positive cells in PB seems to be associated with the site of metastatic manifestation.
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Neoplasias da Medula Óssea/secundário , Medula Óssea/patologia , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Células da Medula Óssea , Neoplasias da Mama/sangue , Feminino , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Metástase Neoplásica , Pós-Menopausa , Prognóstico , Resultado do TratamentoRESUMO
Endocrine therapy is the corner stone treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Besides tamoxifen and many older agents, recently developed endocrine agents for the treatment of MBC include the third generation aromatase inhibitors (AI) - anastrozole, exemestane, letrozole - and the pure oestrogen receptor antagonist fulvestrant. As treatment of breast cancer evolves, both tamoxifen and the AIs are being increasingly used in the adjuvant setting. As such, a significant proportion of patients with hormone receptor-positive MBC will have previously received tamoxifen, an AI or both, as adjuvant treatment. This has changed the metastatic landscape and has an impact on treatment choices for patients with hormone receptor-positive MBC. In this review, we evaluate the available evidence supporting the use of endocrine therapy for the treatment of hormone receptor-positive MBC. Additionally, we consider the effect of prior adjuvant therapy on treatment choice in the metastatic setting and the optimal treatment sequence. Finally, we discuss endocrine-responsive HER2 positive tumours and the ongoing research initiatives which aim to improve outcomes for patients with MBC.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/patologia , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Feminino , Fulvestranto , Humanos , Metástase Neoplásica , Neoplasias Hormônio-Dependentes/patologia , Pós-Menopausa , Tamoxifeno/uso terapêuticoRESUMO
PURPOSE: Everolimus has shown to stop formation and activity of osteoclasts. Breast cancer patients with bone metastases only are candidates for effective but low toxic treatment. PATIENTS AND METHODS: We evaluated everolimus in a double-blind, placebo-controlled, phase II, randomized discontinuation study in breast cancer patients with HER2 negative breast cancer patients with bone metastases only. After being stable on 8 weeks of everolimus 10 mg/day, patients were randomized to everolimus-continuation or placebo. Primary outcome was time (from randomization) to progression (TTP). Seventy-six patients would have had to be randomized to show a hazard ration (HR) of 0.5 for everolimus-continuation. RESULTS: Eighty-nine patients were enrolled in 4 years. Thirty-nine patients with SD after 8 weeks on everolimus were randomized to everolimus-continuation or placebo. TTP in patients with everolimus-continuation was 37.0 (95 % CI 16.7-40.3) versus 12.6 weeks (95 % CI 7.1-17.9) with placebo [HR 0.554 (95 % CI 0.282-1.09) p = 0.0818], adjusted for endocrine therapy [HR 0.464 (95 % CI 0.226-0.954) p = 0.037]. TTP in everolimus responders (n = 6) was 86 weeks. CONCLUSION: The RADAR study is mainly hypothesis generating. It suggests that everolimus has single-agent activity, and patients with bone metastases only may retrieve long-term benefit from everolimus if they do not progress within 8 weeks of treatment.
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Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sirolimo/análogos & derivados , Adulto , Idoso , Neoplasias Ósseas/mortalidade , Neoplasias da Mama/mortalidade , Progressão da Doença , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Everolimo , Feminino , Humanos , Pessoa de Meia-Idade , Placebos , Sirolimo/uso terapêuticoRESUMO
Taxanes are regarded as the most effective single agents in the treatment of metastatic breast cancer (MBC). For conventional taxanes, crucial toxicities and impairments in clinical efficacy are related to solvents necessary because of the agents' hydrophobicity. The mandatory premedication with corticosteroids causes additional side effects. Nab-paclitaxel is a solvent-free colloidal suspension of paclitaxel and human serum albumin that exploits the physiological transport properties of albumin. It is registered as monotherapy with a recommended dose of 260 mg/m(2) every 3 weeks for the treatment of patients with MBC, who have failed a first-line treatment of metastatic disease and for whom a standard anthracycline treatment is not indicated. Clinical evidence is available for the registered 3-weekly administration and for alternative weekly schedules in first and further lines of therapy of patients with MBC. During an advisory board meeting, a group of 8 German breast cancer experts reviewed the clinical data of nab-paclitaxel in MBC and discussed how nab-paclitaxel could be used in clinical practice on the basis of the current data.
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PURPOSE: Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here. PATIENTS AND METHODS: Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit. RESULTS: In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates. CONCLUSION: These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Receptor ErbB-2/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Estudos Cross-Over , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Lapatinib , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Qualidade de Vida , Quinazolinas/administração & dosagem , Fatores de Risco , Trastuzumab , Resultado do TratamentoRESUMO
PURPOSE: To investigate whether sunitinib plus docetaxel improves clinical outcomes for patients with human epidermal growth factor receptor 2 (HER2)/neu-negative advanced breast cancer (ABC) versus docetaxel alone. PATIENTS AND METHODS: In this phase III study, patients were randomly assigned to open-label combination therapy (sunitinib 37.5 mg/d, days 2 to 15 every 3 weeks; and docetaxel 75 mg/m(2), day 1 every 3 weeks) or monotherapy (docetaxel 100 mg/m(2) every 3 weeks). Progression-free survival (PFS) was the primary end point. RESULTS: Two hundred ninety-six patients were randomly assigned to combination therapy, and 297 patients were assigned to monotherapy. Median PFS times were 8.6 and 8.3 months with combination therapy and monotherapy, respectively (hazard ratio, 0.92; one-sided P = .265). The objective response rate (ORR) was significantly higher with the combination (55%) than with monotherapy (42%; one-sided P = .001). Duration of response was similar in both arms (7.5 months with the combination v 7.2 months with monotherapy). Median overall survival (OS) times were 24.8 and 25.5 months with combination therapy and monotherapy, respectively (one-sided P = .904). There were 107 deaths with the combination and 91 deaths with monotherapy. The frequency of common adverse events (AEs) was higher with the combination, as were treatment discontinuations caused by AEs. CONCLUSION: The combination of sunitinib plus docetaxel improved ORR but did not prolong either PFS or OS compared with docetaxel alone when given to an unselected HER2/neu-negative cohort as first-line treatment for ABC. Sunitinib combination therapy may also have resulted in AEs that yield an unfavorable risk-benefit ratio. The sunitinib-docetaxel regimen evaluated in this study is not recommended for further use in ABC.