RESUMO
BACKGROUND: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. METHODS: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed. RESULTS: Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). CONCLUSIONS: Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).
Assuntos
Androstadienos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstadienos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias Ósseas/secundário , Neoplasias da Mama/química , Intervalo Livre de Doença , Receptores ErbB/análise , Everolimo , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pós-Menopausa , Recidiva , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Estomatite/induzido quimicamenteRESUMO
BACKGROUND: Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC. METHODS: This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned. RESULTS: Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy's law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0-15.6). CONCLUSION: The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.
Assuntos
Androstadienos/uso terapêutico , Compostos de Anilina/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , Androstadienos/efeitos adversos , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Nitrilas/efeitos adversos , Pós-Menopausa , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoRESUMO
BACKGROUND: Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2- BC. METHODS; Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy. RESULTS: Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy's law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2. CONCLUSION: The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.
Assuntos
Compostos de Anilina/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , Triazóis/uso terapêutico , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Letrozol , Nitrilas/efeitos adversos , Pós-Menopausa , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Triazóis/efeitos adversosRESUMO
The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.
Assuntos
Androstadienos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Sirolimo/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Everolimo , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Sirolimo/administração & dosagemRESUMO
BACKGROUND: The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). METHODS: Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. RESULTS: Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). CONCLUSIONS: In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Androstadienos/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias da Mama/psicologia , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Everolimo , Feminino , Nível de Saúde , Humanos , Pessoa de Meia-Idade , Razão de Chances , Pós-Menopausa , Modelos de Riscos Proporcionais , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease.
RESUMO
The recent development of monoclonal antibodies targeting growth factor receptors in cancer treatment represents a milestone for both researchers and physicians. Advances in the understanding of key molecular pathways for tumour growth and survival have facilitated the development of these targeted therapies, in particular in breast cancer. This review focuses on the three most important recombinant humanised monoclonal antibodies that have shown activity in women with breast cancer: trastuzumab, pertuzumab and bevacizumab. Trastuzumab, an anti-erbB2 (human epidermal growth factor receptor) monoclonal antibody, is currently routinely used in both the metastatic and adjuvant settings for patients with erbB2-positive tumours. Pertuzumab, a monoclonal antibody binding to a different epitope on erbB2 than trastuzumab, is under early clinical evaluation. This drug has been developed for breast cancer patients, whether overexpressing erbB2 or not. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, is being evaluated in the metastatic setting for its antiangiogenic properties, and is showing promising results.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/efeitos dos fármacos , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Bevacizumab , Ensaios Clínicos como Assunto , Feminino , Humanos , Receptor ErbB-2/metabolismo , TrastuzumabRESUMO
BACKGROUND: EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel. METHODS: HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. RESULTS: Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04). CONCLUSIONS: The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01537536.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Terapia Combinada , Ciclofosfamida/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Quimioterapia de Indução , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Receptor ErbB-2/metabolismo , Resultado do TratamentoRESUMO
PURPOSE: To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. PATIENTS AND METHODS: Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated. RESULTS: Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues. CONCLUSION: The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Everolimo/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Inibidores da Aromatase/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Mutação/genética , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Pós-Menopausa , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: Following ionizing radiation exposure, intestinal crypt regeneration is possible but it is still not known if regenerating crypts give rise to differentiated functional epithelial cells on villi. The aim of this study was to demonstrate that irradiated progeny of enterocytic precursor cells are capable of proliferation and subsequent differentiation using the HT-29?cell line. MATERIALS AND METHODS: Cells were cultured, irradiated (5 Gy or 10 Gy) and incubated in the presence or absence of butyrate (5 mM). Cell numbers, cell cycle parameters, alkaline phosphatase (ALP) activity, occludin labelling and gene expression were determined at different times post-exposure. RESULTS: Butyrate-induced inhibition of cell growth and arrest in G0 phase was comparable in both sham and irradiated cells in addition to similar development of ALP activity and expression. Cells also formed a monolayer with tight junctions post-irradiation. Butyrate-stimulated modulation of integrin expression during differentiation was unchanged after radiation exposure. Genes known to be implicated in differentiation mechanisms, i.e., growth and transcription factors (vascular Epidermal Growth Factor, v-EGF ; Activating Transcription Factor 4, ATF4), cell cycle genes (Cyclin-Dependent Kinase Inhibitor 1A, CDKN1A/p21(Cip1/waf1)), were studied. Most responded similarly to the differentiation stimulus whether irradiated or not. CONCLUSION: These results demonstrate that irradiated HT-29 cells still respond to butyrate to form a differentiated, functional epithelium.
Assuntos
Diferenciação Celular/efeitos da radiação , Enterócitos/efeitos da radiação , Fosfatase Alcalina/metabolismo , Butiratos/farmacologia , Enterócitos/citologia , Fase G1/efeitos dos fármacos , Células HT29 , Humanos , Fase de Repouso do Ciclo Celular/efeitos dos fármacosRESUMO
AIM: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a phase I, dose-escalation trial. METHODS: Twenty-seven patients in four cohorts received docetaxel on day 1 (cohorts 1 and 4: 75 mg/m2; cohorts 2 and 3: 100 mg/m2) plus sorafenib on days 2-19 (cohorts 1 and 2: 200 mg twice-daily (bid); cohorts 3 and 4: 400 mg bid) in 21-day cycles. RESULTS: Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration-time curve (AUC)(0-24) increased by 5% (cohort 1), 54% (cohort 2), 36% (Cohort 3) and 80% (cohort 4) with docetaxel plus sorafenib, while C(max) increased by 16-32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. CONCLUSION: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for phase II.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/farmacocinética , Estudos de Coortes , Progressão da Doença , Docetaxel , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Piridinas/farmacocinética , Sorafenibe , Taxoides/efeitos adversos , Taxoides/farmacocinética , Resultado do TratamentoRESUMO
AKT1 is frequently up-regulated in sporadic breast cancer, whereas BRCA1 is frequently mutated in familial breast cancer. Because BRCA1 is involved in homologous recombination (HR), we addressed whether AKT1 also has an effect on this process. We showed that AKT1 repressed HR through cytoplasmic retention of BRCA1 and RAD51 proteins, resulting in a BRCA1-deficient-like phenotype. This process does not require direct BRCA1 phosphorylation by AKT1. The cytoplasmic retention of BRCA1 and RAD51 correlated with activated AKT1 in tumor cell lines and in biopsies from sporadic breast cancers. Under nonpathologic conditions, fibroblast growth factor, which activates AKT1 and stimulates proliferation in fibroblasts, impaired excessive HR without fully inhibiting it, promoting genome stability. Our study reveals that the regulation of BRCA1 and RAD51 is altered in a high frequency of sporadic breast cancers and highlights the role of extracellular AKT signaling-dependent regulation of HR and genome stability.
Assuntos
Proteína BRCA1/metabolismo , Citoplasma/metabolismo , Proteínas Proto-Oncogênicas c-akt/fisiologia , Rad51 Recombinase/metabolismo , Recombinação Genética , Transporte Ativo do Núcleo Celular , Proteína BRCA1/análise , Neoplasias da Mama , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/farmacologia , Conversão Gênica , Instabilidade Genômica , Humanos , FosforilaçãoRESUMO
OBJECTIVES: The prognosis of patients with platinum refractory disease is dismal. We present data from heavily pretreated patients to whom the folinic acid, 5-fluorouracil and oxaliplatin (Folfox) regimen was administered. The objectives were to assess response rate and to evaluate the safety profile. METHODS: Patients with recurrent, resistant or refractory pretreated ovarian carcinoma were eligible for oxaliplatin (85 mg/m(2)) and leucovorin (200 mg/m(2)), both given as a 2-h infusion on day 1, followed by a 48-h infusion of 5FU 2,600 mg/m(2) every 2 weeks. RESULTS: Fourteen patients were treated. Median age: 56 years (49-70). Median number of previous chemotherapy regimens: 5 (3-10) and previous platinum-based regimens: 2 (1-3). Median chemotherapy-free interval (interval since the completion of the last-line chemotherapy before the administration of the Folfox regimen): 9.5 weeks (1-39). Median number of administered cycles of Folfox/patient: 8 (2-11 cycles). Two (14.5%) patients had a disease complete response, 2 (14.5%)-partial response, 4 (29%)-stable disease and 6 (43%)-progressive disease. Four (29%) patients had a CA-125 complete response, 2 (14.5%)-CA-125 partial response, 5 (35.5%)-stable CA-125 levels and 3 (21%)-progressive CA-125 levels. There were no grade 4 adverse events or deaths due to the treatment. No dose modifications were required due to toxicity. CONCLUSIONS: Folfox seems to be a valuable option for heavily pre-treated patients with ovarian cancer, with an overall response rate, according to RECIST criteria, of 29% and disease stabilization in an additional 29% of patients, with a manageable toxicity profile. These results support further assessment of Folfox as salvage treatment for patients with carcinoma of the ovary or fallopian tube.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Estudos de Coortes , Intervalo Livre de Doença , Neoplasias das Tubas Uterinas/patologia , Feminino , Fluoruracila/efeitos adversos , Humanos , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Neoplasias Ovarianas/patologia , Oxaliplatina , Resultado do TratamentoRESUMO
Over the last decades, the introduction of several new agents into clinical practice has significantly improved disease control and obtained some, albeit rare, survival benefits in metastatic breast cancer (MBC). Despite these results, the choice of treatment for the majority of patients is still empirically based, since the only two predictive factors with level 1 evidence for clinical use are hormonal receptor status for endocrine therapy and HER-2 status for trastuzumab therapy. Important improvements in the endocrine therapy of both pre- and postmenopausal women with hormone-responsive disease have been achieved. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogs combined with tamoxifen has become the standard treatment, although aromatase inhibitors plus ovarian function suppression are under evaluation. In postmenopausal patients, aromatase inhibitors have proved to be superior to standard endocrine therapies in either first- or second-line treatment and a novel antiestrogen compound, fulvestrant, has been introduced in clinical practice. Chemotherapy remains the treatment of choice for hormone unresponsive or resistant patients. Anthracyclines and taxanes have been used either alone or in combination as first-line chemotherapy, but with the more frequent use of these agents in the adjuvant setting, new standards are needed for first-line chemotherapy, and new and more efficacious treatments are required. In the subgroup of patients with tumors that overexpress HER-2, the use of trastuzumab alone or in combination with chemotherapy has modified the natural history of these tumors, even if only about one out of two patients obtains a clinical response. In this review we summarize the main achievements and the currently available treatment options for patients with MBC.