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1.
Eur J Cancer ; 169: 74-81, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35504244

RESUMO

BACKGROUND: Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. METHODS: NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. RESULTS: Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). CONCLUSION: Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.


Assuntos
Segunda Neoplasia Primária , Tumores Neuroendócrinos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1 , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos
3.
Gynecol Oncol ; 153(2): 304-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30792002

RESUMO

OBJECTIVES: Conducting clinical trials in rare malignancies is challenging due to the limited number of patients and differences in biologic behavior. We investigated the feasibility and clinical utility of using genomic profiling for rare gynecologic malignancies. METHODS: Rare epithelial gynecologic cancer patients were analyzed for somatic variants through an institutional molecular profiling program using the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel on the MiSeq platform. Clinical trial outcomes by RECIST 1.1, and time on treatment were evaluated. RESULTS: From March 2012 to November 2015, 767 gynecologic patients were enrolled and 194 (27%) were classified as rare epithelial malignancies. At least one somatic mutation was identified in 72% of patients, most commonly in TP53 (39%), KRAS (28%) and PIK3CA (27%). A total of 14% of patients were treated on genotype-matched trials. There were no significant differences in overall response rate between genotype-matched versus unmatched trials, nor in median time on treatment between genotype trials and the immediate prior systemic standard treatment. Among 13 evaluable Low Grade Serous ovarian cancer patients treated on genotype-matched trials with MEK inhibitor-based targeted combinations, there were four partial responses. CONCLUSIONS: Somatic molecular profiling is feasible and enables the identification of patients with rare gynecologic cancers who are candidates for genotype-matched clinical trials. Genotype-matched trials, predominantly MEK-based combinations in KRAS and/or NRAS mutant Low Grade Serous ovarian cancer patients, and genotype-unmatched trials, have shown potential clinical activity. Prospective trials with integrated genotyping are warranted to assess the clinical utility of next generation sequencing tests as a standard clinical application in rare malignancies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Técnicas de Genotipagem/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Feminino , Neoplasias dos Genitais Femininos/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Estudos Prospectivos , Doenças Raras/genética , Critérios de Avaliação de Resposta em Tumores Sólidos , Adulto Jovem
4.
Gynecol Oncol ; 152(2): 270-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30551885

RESUMO

OBJECTIVES: The hallmarks of germline(g) and/or somatic(s) BRCA1/2 mutation ovarian cancer (BMOC) patients are increased sensitivity to platinum-based chemotherapy (PCT) and PARP inhibitors (PARPi). There is little information on the effectiveness of chemotherapy in heavily pretreated (≥3 CT lines) g/sBMOC patients. METHODS: g/sBMOC patients who received CT from 2006 to 2016 at 4 cancer centers in Spain were selected. Overall survival (OS) and time to progression (TTP) were calculated with Kaplan Meier and Cox models. RESULTS: 135 g/sBMOC patients were identified (6% sBRCA1/2 mutations). The median number of chemotherapy lines was 2 (1-7). The 6-years OS rate was 69.4% and 71% in BRCA1 or BRCA2 mutation carriers (p = 0.98). A total of 57 (42%) patients had ≥3 CT lines (3-7), which encompassed a total of 155 treatments. The median overall TTP across all treatment lines beyond 2nd line was 10.2 months (CI 95% 8.4-11.9 months). In the platinum-sensitive setting, TTP was improved with PCT plus PARPi (17.1 m), PCT (12.6 m) or PARPi (12.4 m) versus non-PCT (4.9 m; p < 0.001 all comparisons). In the platinum-resistant setting, these differences in TTP were not statistically significant. A multivariate model confirmed that primary platinum-free interval (PFI) > 12 months and exposure to PCT and PARPi associated with improved outcomes. PARPi exposure did not compromise benefit of subsequent CT beyond 2nd relapse. CONCLUSIONS: Heavily pretreated g/sBMOC demonstrated CT sensitivity, including for non-PCT choices. Primary platinum-free interval (PFI) >12 months and exposure to both platinum-based chemotherapy and PARPi associate with improved prognosis in heavily pretreated g/sBMOC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Feminino , Humanos , Compostos Organoplatínicos/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Estudos Retrospectivos
5.
Clin. transl. oncol. (Print) ; 20(1): 38-46, ene. 2018. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-170466

RESUMO

Gestational trophoblastic disease (GTD) is a rare but curable disease. Recent improvements in diagnosis and molecular biology have resulted in changes in staging and treatment. These guidelines provide evidence-based recommendation on how to manage GTD (AU)


No disponible


Assuntos
Humanos , Doença Trofoblástica Gestacional/diagnóstico , Doença Trofoblástica Gestacional/terapia , Neoplasias Trofoblásticas/diagnóstico , Neoplasias Trofoblásticas/terapia , Fatores de Risco , Vilosidades Coriônicas/patologia , Coriocarcinoma/patologia , Gonadotropina Coriônica/análise , Guias de Prática Clínica como Assunto
6.
Clin Transl Oncol ; 20(1): 38-46, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29149431

RESUMO

Gestational trophoblastic disease (GTD) is a rare but curable disease. Recent improvements in diagnosis and molecular biology have resulted in changes in staging and treatment. These guidelines provide evidence-based recommendation on how to manage GTD.


Assuntos
Doença Trofoblástica Gestacional/diagnóstico , Doença Trofoblástica Gestacional/patologia , Doença Trofoblástica Gestacional/terapia , Feminino , Humanos , Gravidez
7.
Clin. transl. oncol. (Print) ; 14(7): 512-515, jul. 2012. tab
Artigo em Espanhol | IBECS | ID: ibc-126944

RESUMO

Endometrial cancer (EC) is the most common gynaecological tumour in developing countries. Most patients with EC are diagnosed at an early stage with a low risk of relapse and overall survival at 5 years greater than 85%. Nevertheless, there is a subgroup of patients with a very poor prognosis due to the pathological features and molecular characteristics. Until now there has been no consensus regarding adjuvant treatment in EC patients, with many open questions: In which patients is it indicated? Which is the best approach: chemotherapy, radiotherapy or both? What is the right timing? Relevant clinical trials are in progress in order to answer these questions. Unfortunately, the survival of patients with metastatic or recurrent EC is quite short due to the poor responses to standard first-line chemotherapy and the lack of second lines of treatment (AU)


Assuntos
Humanos , Feminino , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/terapia , Guias de Prática Clínica como Assunto , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Oncologia/legislação & jurisprudência , Oncologia/organização & administração , Prognóstico , Recidiva , Espanha , Sociedades Médicas/legislação & jurisprudência , Sociedades Médicas/organização & administração
8.
Clin. transl. oncol. (Print) ; 14(7): 516-519, jul. 2012. tab
Artigo em Inglês | IBECS | ID: ibc-126945

RESUMO

Cervical cancer (CC) is the second most common cancer worldwide, with a well known origin, infection by high-risk human papilloma virus. Although screening programmes have led to a relevant reduction in the incidence and mortality due to CC in developed countries, it is still an important cause of mortality in young women in undeveloped countries. Clinical stage is the most relevant prognostic factor in CC and the standard of care is still based on it. In early stages, the primary treatment is surgery or radiotherapy, whereas concomitant chemo-radiotherapy is the conventional approach in locally advanced stage. In the setting of recurrent or metastatic CC the treatment is largely palliative, so it is important to develop new therapeutic strategies (AU)


Assuntos
Humanos , Feminino , Carcinoma/terapia , Guias de Prática Clínica como Assunto , Neoplasias do Colo do Útero/terapia , Carcinoma/diagnóstico , Carcinoma/patologia , Seguimentos , Oncologia/legislação & jurisprudência , Metástase Neoplásica , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Espanha
9.
Lung Cancer ; 77(1): 192-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22459204

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM. PATIENTS AND METHODS: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis. RESULTS: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8). CONCLUSIONS: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.


Assuntos
Mesotelioma/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Pleurais/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ciclo Celular , Intervalo Livre de Doença , Feminino , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Mesotelioma/diagnóstico , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Análise Multivariada , Fosfoproteínas/metabolismo , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/mortalidade , Prognóstico , Estudos Retrospectivos , Proteínas Quinases S6 Ribossômicas/metabolismo , Estatísticas não Paramétricas
10.
Clin Transl Oncol ; 12(4): 261-70, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20462835

RESUMO

Systemic therapies available for treatment of colorectal cancer have increased in recent years, leading to improved clinical outcomes. However, a significant proportion of patients fail to derive meaningful benefits, whereas others suffer from unacceptable toxicities. Therefore, not only does the search for novel and effective anticancer agents continue, there is also a pressing need to optimise the use of all treatments in the therapeutic armamentarium. In addition to knowledge gleaned from well-designed and relevant clinical trials, increasing effort is being invested into biomarkers. The identification and implementation of validated biomarkers has the potential to further our understanding of the biology of colorectal cancer and also to greatly improve the efficiency with which cancer treatments are administered.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Animais , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos
11.
Clin. transl. oncol. (Print) ; 12(4): 261-270, abr. 2010. tab
Artigo em Inglês | IBECS | ID: ibc-124068

RESUMO

Systemic therapies available for treatment of colorectal cancer have increased in recent years, leading to improved clinical outcomes. However, a significant proportion of patients fail to derive meaningful benefits, whereas others suffer from unacceptable toxicities. Therefore, not only does the search for novel and effective anticancer agents continue, there is also a pressing need to optimise the use of all treatments in the therapeutic armamentarium. In addition to knowledge gleaned from well-designed and relevant clinical trials, increasing effort is being invested into biomarkers. The identification and implementation of validated biomarkers has the potential to further our understanding of the biology of colorectal cancer and also to greatly improve the efficiency with which cancer treatments are administered (AU)


No disponible


Assuntos
Humanos , Animais , Masculino , Feminino , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Biomarcadores Tumorais , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos
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