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1.
Breast Cancer Res ; 19(1): 120, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29137653

RESUMO

BACKGROUND: The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) pN0 patients not treated with chemotherapy. METHODS: Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995-1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). RESULTS: Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2- patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2- patients) yielded strong prognostic information. Among the HR+/HER2- pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2- pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2- population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). CONCLUSIONS: The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias/métodos , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Medição de Risco
2.
Acta Oncol ; 53(9): 1180-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24697744

RESUMO

UNLABELLED: Approximately 50% of patients with high-grade soft tissue sarcoma (STS) will develop pulmonary metastasis. This is the most frequent cause of death and improving treatment is warranted. Preoperative chemotherapy is used for selected patients, usually those with less favorable prognosis and mainly outside clinical trials. The predicted value of histological and radiological response to preoperative chemotherapy on outcome was the main focus for this investigation. PATIENTS AND METHODS: This retrospective study comprises 93 patients with metachronous lung metastasis from STS who underwent complete metastasectomy alone (n = 41) or metastasectomy following preoperative chemotherapy (n = 52). Clinical data, histological and radiological responses to chemotherapy were recorded and survival analyses performed. RESULTS: The time from initial STS diagnosis to the appearance of metastasis was shorter in the preoperative chemotherapy group than in those treated with surgery alone (p = 0.02). However, no statistical differences in post-metastasis disease-specific survival (DSS) or progression-free survival (PFS) between the groups were demonstrated. Patients in the preoperative chemotherapy group with good (complete) histological response had improved PFS compared with poor responders (p = 0.04). Radiological partial response was an independent, favorable prognostic factor for improved PFS and DSS (p = 0.003). CONCLUSION: Despite having unfavorable disease characteristics, some patients may benefit from preoperative chemotherapy. Both histological and radiological responses to preoperative chemotherapy seem to be prognostic in STS patients undergoing complete pulmonary metastasectomy.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Metastasectomia , Sarcoma/tratamento farmacológico , Sarcoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Radiografia , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem , Sarcoma/secundário , Neoplasias de Tecidos Moles , Análise de Sobrevida , Toracotomia/estatística & dados numéricos , Resultado do Tratamento , Adulto Jovem
3.
Cancer ; 119(5): 1013-22, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23165797

RESUMO

BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53(Wt) ) tumors had improved survival (P < .001) and TP53(Wt) was an independent prognostic factor (hazard ratio = 0.41; 95% confidence interval = 0.23-0.74; P = .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P = .07), which was strongest with doxorubicin/ifosfamide-based regimens (P = .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53(Wt) background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53(Wt) tumors harboring the R72 variant. MDM2 overexpression in TP53(Wt) tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to systemic therapy are recommended.


Assuntos
Genes p53 , Proteínas Proto-Oncogênicas c-mdm2/genética , Sarcoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Criança , Feminino , Genótipo , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Resultado do Tratamento , Adulto Jovem
4.
BMC Cancer ; 11: 211:1-11, 2011 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-21624110

RESUMO

BACKGROUND: Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified MDM2 gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy. METHODS: A panel of sarcoma cell lines with different TP53 and MDM2 status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined. RESULTS: Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type TP53 and amplified MDM2, or with Methotrexate in both MDM2 normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated TP53, but inhibited the effect of Methotrexate. CONCLUSION: The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.


Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Imidazóis/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
5.
PLoS One ; 5(11): e15378, 2010 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-21085701

RESUMO

BACKGROUND: Malignant fibrous histiocytomas (MFHs), or undifferentiated pleomorphic sarcomas, are in general high-grade tumours with extensive chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, as well as novel gene targets of potential importance for MFH development and/or progression, we have analysed DNA copy number changes in 33 MFHs using microarray-based comparative genomic hybridisation (array CGH). PRINCIPAL FINDINGS: In general, the tumours showed numerous gains and losses of large chromosomal regions. The most frequent minimal recurrent regions of gain were 1p33-p32.3, 1p31.3-p31.2 and 1p21.3 (all gained in 58% of the samples), as well as 1q21.2-q21.3 and 20q13.2 (both 55%). The most frequent minimal recurrent regions of loss were 10q25.3-q26.11, 13q13.3-q14.2 and 13q14.3-q21.1 (all lost in 64% of the samples), as well as 2q36.3-q37.2 (61%), 1q41 (55%) and 16q12.1-q12.2 (52%). Statistical analyses revealed that gain of 1p33-p32.3 and 1p21.3 was significantly associated with better patient survival (P = 0.021 and 0.046, respectively). Comparison with similar array CGH data from 44 leiomyosarcomas identified seven chromosomal regions; 1p36.32-p35.2, 1p21.3-p21.1, 1q32.1-q42.13, 2q14.1-q22.2, 4q33-q34.3, 6p25.1-p21.32 and 7p22.3-p13, which were significantly different in copy number between the MFHs and leiomyosarcomas. CONCLUSIONS: A number of recurrent regions of gain and loss have been identified, some of which were associated with better patient survival. Several specific chromosomal regions with significant differences in copy number between MFHs and leiomyosarcomas were identified, and these aberrations may be used as additional tools for the differential diagnosis of MFHs and leiomyosarcomas.


Assuntos
Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , DNA de Neoplasias/genética , Histiocitoma Fibroso Maligno/genética , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Histiocitoma Fibroso Maligno/classificação , Histiocitoma Fibroso Maligno/patologia , Humanos , Estimativa de Kaplan-Meier , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada
6.
Genes Chromosomes Cancer ; 48(8): 679-93, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19441093

RESUMO

Osteosarcomas are the most common primary malignant tumor of bone, and almost all conventional osteosarcomas are high-grade tumors with complex karyotypes. We have examined DNA copy number changes in 36 osteosarcoma tumors and 20 cell lines using microarray-based comparative genomic hybridization. The most frequent minimal recurrent regions of gain identified in the tumor samples were in 1q21.2-q21.3 (78% of the samples), 1q21.3-q22 (78%), and 8q22.1 (72%). Minimal recurrent regions in 10q22.1-q22.2 (81%), 6q16.1 (67%), 13q14.2 (67%), and 13q21.1 (67%) were most frequently lost. A small region in 3q13.31 (2.1 Mb) containing the gene limbic system-associated membrane protein (LSAMP) was frequently deleted (56%). LSAMP has previously been reported to be a candidate tumor suppressor gene in other cancer types. The deletion was validated using fluorescence in situ hybridization, and the expression level and promoter methylation status of LSAMP were investigated using quantitative real-time reverse transcription PCR and methylation-specific PCR, respectively. LSAMP showed low expression compared to two normal bone samples in 6/15 tumors and 5/9 cell lines with deletion of 3q13.31, and also in 5/14 tumors and 3/11 cell lines with normal copy number or gain. Partial or full methylation of the investigated CpG island was identified in 3/30 tumors and 7/20 cell lines. Statistical analyses revealed that loss of 11p15.4-p15.3 and low expression of LSAMP (both P = 0.011) were significantly associated with poor survival. Our results show that LSAMP is a novel candidate tumor suppressor gene in osteosarcomas.


Assuntos
Neoplasias Ósseas/genética , Moléculas de Adesão Celular Neuronais/genética , Hibridização Genômica Comparativa/métodos , Genes Supressores de Tumor , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Osteossarcoma/genética , Adolescente , Adulto , Idoso , Neoplasias Ósseas/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Tumoral , Criança , Aberrações Cromossômicas , Análise por Conglomerados , Ilhas de CpG/genética , Metilação de DNA , Interpretação Estatística de Dados , Feminino , Proteínas Ligadas por GPI , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Osteossarcoma/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
Mol Cancer ; 7: 48, 2008 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-18522746

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, and thereby novel gene targets of potential importance for MPNST development and/or progression, we have analyzed DNA copy number changes in seven high-grade MPNSTs using microarray-based comparative genomic hybridization (array CGH). RESULTS: Considerable more gains than losses were observed, and the most frequent minimal recurrent regions of gain included 1q24.1-q24.2, 1q24.3-q25.1, 8p23.1-p12, 9q34.11-q34.13 and 17q23.2-q25.3, all gained in five of seven samples. The 17q23.2-q25.3 region was gained in all five patients with poor outcome and not in the two patients with disease-free survival. cDNA microarray analysis and quantitative real-time reverse transcription PCR were used to investigate expression of genes located within these regions. The gene lysyl oxidase-like 2 (LOXL2) was identified as a candidate target for the 8p23.1-p12 gain. Within 17q, the genes topoisomerase II-alpha (TOP2A), ets variant gene 4 (E1A enhancer binding protein, E1AF) (ETV4) and baculoviral IAP repeat-containing 5 (survivin) (BIRC5) showed increased expression in all samples compared to two benign tumors. Increased expression of these genes has previously been associated with poor survival in other malignancies, and for TOP2A, in MPNSTs as well. In addition, we have analyzed the expression of five micro RNAs located within the 17q23.2-q25.3 region, but none of them showed high expression levels compared to the benign tumors. CONCLUSION: Our study shows the potential of using DNA copy number changes obtained by array CGH to predict the prognosis of MPNST patients. Although no clear correlations between the expression level and patient outcome were observed, the genes TOP2A, ETV4 and BIRC5 are interesting candidate targets for the 17q gain associated with poor survival.


Assuntos
DNA de Neoplasias/análise , Dosagem de Genes , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Bainha Neural/genética , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias de Tecidos Moles/genética , Proteínas E1A de Adenovirus/genética , Adulto , Idoso , Aminoácido Oxirredutases/genética , Antígenos de Neoplasias/genética , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 8 , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasias de Bainha Neural/enzimologia , Neoplasias de Bainha Neural/mortalidade , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias de Tecidos Moles/enzimologia , Neoplasias de Tecidos Moles/mortalidade , Survivina
8.
Cancer Res ; 66(18): 8984-93, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16982739

RESUMO

Leiomyosarcomas are spindle cell tumors showing smooth muscle differentiation. Until recently, most gastrointestinal stromal tumors (GIST) were also classified as smooth muscle tumors, but now GISTs are recognized as a separate entity, defined as spindle cell and/or epithelioid tumors localized in the gastrointestinal tract. Using microarray-based comparative genomic hybridization (array CGH), we have created a detailed map of DNA copy number changes for 7 GISTs and 12 leiomyosarcomas. Considerable gains and losses of chromosomal segments were observed in both tumor types. The most frequent aberration observed in GISTs was loss of chromosomes 14 and 22, with minimal recurrent regions in 14q11.2-q32.33 (71% of the tumors) and 22q12.2-q13.31 (100%). In leiomyosarcomas, frequent loss of chromosome 10 and 13q was observed, with minimal recurrent regions in 10q21.3 (75%) and 13q14.2-q14.3 (75%). Recurrent high-level amplification of 17p13.1-p11.2 was detected in leiomyosarcomas. Expression profiling using cDNA microarrays revealed four candidate genes in this region with high expression (AURKB, SREBF1, MFAP4, and FLJ10847). Altered expression of AURKB and SREBF1 has been observed previously in other malignancies. Hierarchical clustering of all samples separated GISTs and leiomyosarcomas into two distinct clusters. Statistical analysis identified six chromosomal regions, 1p36.11-p13.1, 9q21.11-9q34.3, 14q11.2-q23.2, 14q31.3-q32.33, 15q24.3-q26.3, and 22q11.21-q13.31, which were significantly different in copy number between GISTs and leiomyosarcomas. Our results show the potential of using array comparative genomic hybridization to classify histologically similar tumors such as GISTs and leiomyosarcomas.


Assuntos
Tumores do Estroma Gastrointestinal/genética , Leiomiossarcoma/genética , Adulto , Idoso , Animais , Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Feminino , Dosagem de Genes , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Família Multigênica , Hibridização de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Transplante Heterólogo
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