RESUMO
BACKGROUND: The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility. PATIENTS AND METHODS: VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes. RESULTS: A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib. CONCLUSIONS: ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.
Assuntos
Antineoplásicos , DNA Tumoral Circulante , Tumores do Estroma Gastrointestinal , Humanos , Trifosfato de Adenosina/uso terapêutico , Antineoplásicos/uso terapêutico , DNA Tumoral Circulante/genética , Progressão da Doença , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/diagnóstico , Mesilato de Imatinib , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Receptores Proteína Tirosina Quinases/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/uso terapêuticoRESUMO
BACKGROUND: Gastrointestinal stromal tumors (GISTs) and desmoid tumors (DTs) are two rare mesenchymal tumor. Anecdotal reports of individuals with both diseases led us to make the hypothesis that the association is a nonrandom event as the probability would be extremely low to observe such cases if they were independent events. PATIENTS AND METHODS: We evaluated the existence of patients with GIST and DT in a large multicenter cohort at 10 institutions in the United States, Australia and Europe. Data on gender, age at diagnosis, KIT, PDGFRA, CTNNB1 mutation status and follow-up time after diagnosis were collected. RESULTS: We identified 28 patients diagnosed with both tumors. DT was diagnosed after GIST in 75% of patients and concomitantly in 21%. In only one case (4%), GIST was diagnosed after DT. KIT or PDGFRA mutations were detected in 12 of 14 GIST, 9 in KIT exon 11, 2 in KIT exon 9 and 1 in PDGFRA. CONCLUSION: A statistical analysis of these 28 cases suggests a nonrandom association between GIST and DT. Further studies may be able to elucidate the underlying biology responsible for this association.
Assuntos
Fibromatose Agressiva/complicações , Fibromatose Agressiva/epidemiologia , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The objective of the study was to describe patterns of care of patients with gastrointestinal stromal tumors (GISTs) in the United States in the tyrosine kinase inhibitor (TKI) era. PATIENTS AND METHODS: From November 2004 through March 2009, data were collected regarding demographics, diagnostic history, treatment, relapse, and survival of 882 patients with GIST from 122 community and academic medical practices. RESULTS: The most common first-line treatment for the 719 patients presenting with localized GIST was surgery (87%). Use of adjuvant imatinib increased after June 2007; 47% of patients enrolled in the registry considered by the investigator to be at high risk for recurrence received adjuvant imatinib after June 2007 versus 18% before. Overall, 56% of patients received imatinib and 11% received sunitinib. The utilization of targeted therapy increased over time (45% and 0.4% of patients received imatinib and sunitinib, respectively, in 2006 versus 56% and 11%, respectively, in 2009). CONCLUSIONS: These are the first GIST registry data from the TKI era. The use of targeted therapy for GIST has increased in accordance with updated treatment guidelines. Diagnosis of GIST has evolved with increased use of KIT testing. The duration of targeted therapy in the adjuvant therapy setting is similar in community and academic practices.
Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Padrões de Prática Médica , Centros Médicos Acadêmicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/epidemiologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/epidemiologia , Hospitais Comunitários , Humanos , Mesilato de Imatinib , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sistema de Registros , Sunitinibe , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: We sought to investigate the characteristics and survival rate of patients with gastrointestinal stromal tumor (GIST) associated with other primary malignancies. PATIENTS AND METHODS: A total of 783 patients with GIST were identified from 1995 to 2007. Additional primaries included tumors not considered metastasis, invasion, or recurrence of GIST, nor non-melanoma skin cancer. Data on gender, age at diagnosis, follow-up time after diagnosis, and death were collected. RESULTS: Of the 783 patients with GIST, 153(20%) were identified with at least one additional primary. Patients with additional primaries were more often men (M : F 1.5 versus 1.3) and older (66 versus 53 years). More patients had another cancer diagnosed before (134) than after (52) GIST. Primaries observed before GIST were cancers of the prostate (25), breast (12), esophagus (9), and kidney (7) and melanoma (6). Lung (5) and kidney (5) primaries were the most frequent after GIST. The 5-year survival was 68% for patients with primaries before GIST, 61% for patients with primaries after GIST, 58% for patients with GIST only, and 49% for patients with two or more primaries in addition to GIST (P = 0.002). CONCLUSIONS: Approximately 20% of patients with GIST develop other cancers. Inferior median 5-year survival was observed in patients with GIST with two or more other cancers. The etiology and clinical implications of other malignancies in patients with GIST should be investigated.
Assuntos
Tumores do Estroma Gastrointestinal/mortalidade , Neoplasias Primárias Múltiplas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Gastrointestinal stromal tumors (GIST) contain tumor-infiltrating immune cells and their presence provides an opportunity and rationale for developing effective forms of immunotherapy. The types of tumor-infiltrating inflammatory cells and relevant immune checkpoint inhibitors are the focus of active investigation. The most numerous tumor-infiltrating inflammatory cells are tumor-associated macrophages (TAMs) and CD3+ T cells. Studies have shown that patients with GISTs that harbor increased numbers of CD3+ T cells have better outcomes. However, the clinical behavior of GIST has not been shown to correlate with the number of TAMs. The biological significance of other less frequent tumor-infiltrating immune cells including tumor-infiltrating neurtrophils (TINs), natural killer cells (NKs), B cells, dendritic cells (DCs) remains unclear. The immune checkpoint inhibitors CTLA-4, PD1/PDL1 and TIM3/galectin-9 are molecules that can be targeted by synthesized antibodies. Clinical and pre-clinical trials using this approach against immune checkpoint inhibitors, anti-KIT antibody and the generation of chimeric antigen receptor (CAR) T-cells have shown promising results. The treatment of GIST with immunotherapy is complex and evolving; this article reviews its current status for patients with GISTs.
Assuntos
Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/terapia , Imunoterapia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Vacinas Anticâncer/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Combinada , Citocinas/metabolismo , Citocinas/uso terapêutico , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação/efeitos dos fármacos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Microambiente Tumoral/imunologiaRESUMO
A paradigm shift has occurred in the last decade from chemotherapy to targeted therapy for the management of many patients with advanced sarcoma. This work identifies a combination of targeted agents and doxorubicin that are effective against small cell sarcoma cell lines. Three small cell sarcoma cell lines were studied: RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma). Each cell line was exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (HSP90 inhibitor), abacavir (anti-telomerase) or sorafenib (tyrosine kinase inhibitor) alone, combined with one another, or combined with doxorubicin. Cell viability, cell cycle analysis and apoptosis were assessed by MTS assay, propidium iodide-Annexin V staining, and caspase 3/7 activity, respectively. The Chou and Talalay combination index (CI) was used to determine whether the effects were additive (CI = 1), synergistic (CI < 1) or antagonistic (CI > 1). In monotherapy, targeted agents achieved 30-90% reductions in viability, with the exception of abacavir. Dual-targeted combination therapies with vorinostat, sorafenib and 17-DMAG demonstrated synergy. Abacavir was antagonistic with every other drug and was not further studied. Both vorinostat and 17-DMAG synergized with doxorubicin, achieving 60% cell killing compared to 12% with doxorubicin alone. No synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17-DMAG and doxorubicin did not show synergy, but increased the subG1 population at 24H, from 30% to 70% compared to monotherapies with an increase in apoptosis. This work provides evidence of synergy of combinations of vorinostat, 17-DMAG and sorafenib in small cell sarcoma. In addition to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations.
Assuntos
Doxorrubicina/farmacologia , Sarcoma de Células Pequenas/metabolismo , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Ácidos Hidroxâmicos/farmacologia , Lactamas Macrocíclicas/farmacologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Sarcoma de Células Pequenas/tratamento farmacológico , Sorafenibe , VorinostatRESUMO
Activating oncogenic mutations of BRAF have been described in patients with gastrointestinal stromal tumor (GIST), but treatment of GIST with BRAF inhibitors and mechanisms of mediating the emergence of resistance in GIST have not been reported. Dabrafenib is a potent ATP-competitive inhibitor of BRAF kinase and is highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. We report prolonged antitumor activity in the first patient with V600E BRAF-mutated GIST who was treated with a BRAF inhibitor. Whole exome sequencing performed in tumor tissue obtained at the time of progressive disease demonstrated a somatic gain-of-function PIK3CA mutation (H1047R) as well as a CDKN2A aberration, which may have contributed to eventual resistance to treatment.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Imidazóis/uso terapêutico , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases , Exoma , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismoRESUMO
We present the radiographic, computed tomographic (CT), and magnetic resonance (MR) findings in a woman with constrictive pericarditis due to an embolized hypodermic needle. The chest films revealed pleural effusions but no foreign body. The CT showed pericardial thickening and a linear foreign body of metallic attenuation in the right ventricular apex, and MR imaging revealed a signal void with magnetic susceptibility artifact. This case illustrates the capabilities and limitations of CT and MR imaging in hypodermic needle-induced constrictive pericarditis.
Assuntos
Reação a Corpo Estranho/diagnóstico , Reação a Corpo Estranho/etiologia , Agulhas/efeitos adversos , Pericardite Constritiva/diagnóstico , Pericardite Constritiva/etiologia , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Feminino , Seguimentos , Reação a Corpo Estranho/terapia , Humanos , Imageamento por Ressonância Magnética/métodos , Pericardite Constritiva/terapia , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios XRESUMO
Tumor necrosis factor (TNF) exerts cytotoxicity on many types of tumor cells but not on normal cells. The molecular events leading to cell death triggered by TNF are still poorly understood. Our previous studies have shown that enforced expression of an activated H-ras oncogene converted non-tumorigenic, TNF-resistant C3H 10T1/2 fibroblasts into tumorigenic cells that also became very sensitive to TNF-induced apoptosis. This finding suggested that Ras activation may play a role in TNF-induced apoptosis. In this study we investigated whether Ras activation is an obligatory step in TNF-induced apoptosis. Introduction of two different molecular antagonists of Ras, the rap1A tumor suppressor gene or the dominant-negative rasN17 gene, into H-ras-transformed 10TEJ cells inhibited TNF-induced apoptosis. Similar results were obtained with L929 cells, a fibroblast cell line sensitive to TNF-induced apoptosis, which does not have a ras mutation. While Ras is constitutively activated in TNF-sensitive 10TEJ cells, TNF treatment increased Ras-bound GTP in TNF-sensitive L929 cells but not in TNF-resistant 10T1/2 cells. Moreover, RasN17 expression blocked TNF-induced Ras-GTP formation in L929 cells. These results demonstrate that Ras activation is required for TNF-induced apoptosis in mouse fibroblasts.