Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
Eur Urol ; 68(6): 959-67, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26238431

RESUMO

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. OBJECTIVE: To discover and validate biomarkers predictive of response to NAC for MIBC. DESIGN, SETTING, AND PARTICIPANTS: Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. RESULTS AND LIMITATIONS: Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets. CONCLUSIONS: Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. PATIENT SUMMARY: Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Reparo do DNA , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Prognóstico , Estudos Prospectivos , Neoplasias da Bexiga Urinária/patologia
2.
J Clin Oncol ; 32(18): 1895-901, 2014 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-24821881

RESUMO

PURPOSE: Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls. PATIENTS AND METHODS: Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity. RESULTS: Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non-muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity. CONCLUSION: AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/química , Carcinoma de Células de Transição/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Terapia Neoadjuvante/métodos , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Medula Óssea/efeitos dos fármacos , Carcinoma de Células de Transição/patologia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Filgrastim , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Polietilenoglicóis , Estudos Prospectivos , Substâncias Protetoras/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Vimblastina/administração & dosagem
3.
Genome Med ; 5(5): 49, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23718828

RESUMO

BACKGROUND: Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach. METHODS: Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings. RESULTS: HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors. CONCLUSION: These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.

4.
Mol Syst Biol ; 3: 82, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17299418

RESUMO

There is a need to identify genetic mediators of solid-tumor cancers, such as prostate cancer, where invasion and distant metastases determine the clinical outcome of the disease. Whole-genome expression profiling offers promise in this regard, but can be complicated by the challenge of identifying the genes affected by a condition from the hundreds to thousands of genes that exhibit changes in expression. Here, we show that reverse-engineered gene networks can be combined with expression profiles to compute the likelihood that genes and associated pathways are mediators of a disease. We apply our method to non-recurrent primary and metastatic prostate cancer data, and identify the androgen receptor gene (AR) among the top genetic mediators and the AR pathway as a highly enriched pathway for metastatic prostate cancer. These results were not obtained on the basis of expression change alone. We further demonstrate that the AR gene, in the context of the network, can be used as a marker to detect the aggressiveness of primary prostate cancers. This work shows that a network biology approach can be used advantageously to identify the genetic mediators and mediating pathways associated with a disease.


Assuntos
Redes Reguladoras de Genes , Neoplasias da Próstata/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Metástase Neoplásica/genética , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...