RESUMO
Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/epidemiologia , Quimioterapia Adjuvante/efeitos adversos , Terapia Neoadjuvante/efeitos adversos , Adulto , Idoso , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Cardiotoxicidade/etiologia , Quimioterapia Adjuvante/métodos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Receptor ErbB-2/genética , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc. Here we show that a Myc-associated transcription factor, Miz-1, arrests cells in G1 phase and inhibits cyclin D-associated kinase activity. Miz-1 upregulates expression of the cyclin-dependent kinases (CDK) inhibitor p15INK4b by binding to the initiator element of the p15INK4b promoter. Myc and Max form a complex with Miz-1 at the p15 initiator and inhibit transcriptional activation by Miz-1. Expression of Myc in primary cells inhibits the accumulation of p15INK4b that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15INK4b expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization.
Assuntos
Proteínas de Transporte/biossíntese , Proteínas de Ciclo Celular , Inibidor p16 de Quinase Dependente de Ciclina , Proteínas de Ligação a DNA/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor , Dedos de Zinco , Células 3T3 , Animais , Inibidor de Quinase Dependente de Ciclina p15 , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Células HeLa , Humanos , Fatores de Transcrição Kruppel-Like , Camundongos , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/genéticaRESUMO
Mad proteins are transcriptional repressors that antagonize transcriptional activation and transformation by Myc oncoprotein; recent findings suggest that they repress transcription by recruiting histone deacetylases to target sites on DNA.
Assuntos
Histona Desacetilases/metabolismo , Fatores de Transcrição , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Fatores de Transcrição de Zíper de Leucina Básica , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Modelos Biológicos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/metabolismo , Transcrição GênicaRESUMO
Although USF-1 and -2 are the major proteins that bind to Myc-regulated E-box (CACGTG) elements in many cells, there is no clear role for USF during Myc-dependent gene regulation. Using dominant negative alleles of USF-1 we now show that DNA binding by USF at a Myc-regulated E-box limits the ability of another E-box binding factor, TFE-3, to activate a target gene of Myc in vivo and to stimulate S phase entry in resting fibroblasts. Similarly, dominant negative alleles of USF-1 relieve the restriction that prevents activation of the IgH enhancer by TFE-3 in non B-cells. DNA binding activity of USF complexes is abundant in primary human B-cells and is significantly downregulated during B-cell immortalization. Re-expression of USF-1 in immortalized B-cells retards proliferation. Our data establish an essential role for USF in restricting E-box dependent gene activation in vivo and suggest that this control is relaxed during cellular immortalization.
Assuntos
Proteínas de Ligação a DNA , DNA/metabolismo , Genes myc , Fatores de Transcrição/metabolismo , Células 3T3 , Animais , Sítios de Ligação/genética , DNA/genética , Regulação da Expressão Gênica , Células HeLa , Sequências Hélice-Alça-Hélice , Humanos , Zíper de Leucina , Camundongos , Ligação Proteica , Fatores de Transcrição/genética , Ativação Transcricional , Fatores Estimuladores UpstreamRESUMO
Myc oncoproteins promote cell cycle progression in part through the transcriptional up-regulation of the cyclin D2 gene. We now show that Myc is bound to the cyclin D2 promoter in vivo. Binding of Myc induces cyclin D2 expression and histone acetylation at a single nucleosome in a MycBoxII/TRRAP-dependent manner. Down-regulation of cyclin D2 mRNA expression in differentiating HL60 cells is preceded by a switch of promoter occupancy from Myc/Max to Mad/Max complexes, loss of TRRAP binding, increased HDAC1 binding, and histone deacetylation. Thus, recruitment of TRRAP and regulation of histone acetylation are critical for transcriptional activation by Myc.
Assuntos
Proteínas de Bactérias , Ciclinas/genética , Regulação da Expressão Gênica , Regiões Promotoras Genéticas/fisiologia , Proteínas Proto-Oncogênicas c-myc/fisiologia , Proteínas Repressoras , Acetilação , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Fatores de Transcrição de Zíper de Leucina Básica , Ciclina D2 , Proteínas de Ligação a DNA/fisiologia , Células HL-60 , Histonas/metabolismo , Humanos , RNA Mensageiro/biossíntese , Proteínas de Ligação a RNA/fisiologia , Fatores de Transcrição/fisiologiaRESUMO
The c-myc gene has been implicated in three distinct genetic programs regulating cell proliferation: control of cyclin E-cdk2 kinase activity, E2F-dependent transcription and cell growth. We have now used p27(-/-) fibroblasts to dissect these downstream signalling pathways. In these cells, activation of Myc stimulates transcription of E2F target genes, S-phase entry and cell growth without affecting cyclin E-cdk2 kinase activity. Both cyclin D2 and E2F2, potential direct target genes of Myc, are induced in p27(-/-) MycER cells. Ectopic expression of E2F2, but not of cyclin D2, induces S-phase entry, but, in contrast to Myc, does not stimulate cell growth. Our results show that stimulation of cyclin E-cdk2 kinase, of E2F-dependent transcription and of cell growth by Myc can be genetically separated from each other.