RESUMO
BACKGROUND: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. PATIENTS AND METHODS: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. RESULTS: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). CONCLUSION: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. IMPLICATIONS FOR PRACTICE: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.
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Neoplasias Esofágicas , Amplificação de Genes , Neoplasias Gástricas , Adulto , Idoso , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Junção Esofagogástrica , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Massachusetts , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-met , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Glutaratos/sangue , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/mortalidade , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: In nongastric gastrointestinal (GI) cancers, HER2-positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2-targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially. MATERIALS AND METHODS: We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty-four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH. RESULTS: A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017). CONCLUSION: In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue. IMPLICATIONS FOR PRACTICE: HER2 amplification is a well-known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2-directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias Gastrointestinais/patologia , Receptor ErbB-2/genética , Adulto , Idoso , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Feminino , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Amplificação de Genes , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first-line gemcitabine/platinum-based chemotherapy. A single-arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma. METHODS: Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule). The primary endpoint was progression-free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated. RESULTS: The study enrolled 19 patients with cholangiocarcinoma (female, 68%; median age, 67 years; intrahepatic vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95% confidence interval, 1.6-5.4 months), and the median overall survival (OS) was 5.2 months (95% confidence interval, 2.7-10.5 months). Grade 3/4 adverse events occurred in 89% of the patients and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistulas (5%), and hypertension (11%). One patient with 3 + MET expression in the tumor stayed on treatment for 278 days, but the MET expression did not correlate with the outcomes in the overall study population. Plasma vascular endothelial growth factor, placental growth factor, and stromal cell-derived factor 1α increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values < .01). Plasma tissue inhibitor of matrix metalloproteinase 1 was inversely correlated with PFS, and soluble MET (sMET) and interleukin 6 were inversely correlated with OS. CONCLUSIONS: In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, 1 patient with a MET-high tumor had a prolonged benefit from treatment. Baseline plasma soluble MET was associated with OS. Any further development of this drug in cholangiocarcinoma should include a dose reduction and a biomarker-driven approach. Cancer 2017;123:1979-1988. © 2017 American Cancer Society.
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Anilidas/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Idoso , Angiopoietina-2/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Quimiocina CXCL12/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Intervalo Livre de Doença , Epistaxe/induzido quimicamente , Feminino , Humanos , Hiperbilirrubinemia/induzido quimicamente , Hipertensão/induzido quimicamente , Interleucina-6/metabolismo , Fístula Intestinal/induzido quimicamente , Perfuração Intestinal/induzido quimicamente , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Fator de Crescimento Placentário/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Taxa de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. METHODS: In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. RESULTS: We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. CONCLUSION: Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. IMPLICATIONS FOR PRACTICE: Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.
Assuntos
Biomarcadores Tumorais/urina , Glioma/urina , Glutaratos/urina , Isocitrato Desidrogenase/genética , Adulto , Idoso , Feminino , Genótipo , Glioma/sangue , Glioma/genética , Glioma/patologia , Glutaratos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
PURPOSE: It is now recognized that Crohn's disease (CD), similar to ulcerative colitis (UC), carries an up to 20-fold higher cancer risk, and the development of colorectal carcinoma (CRC) is a major long-term complication. Once CRC is present, molecular profiling is one of the components in selecting appropriate treatment strategies; however, in contrast to UC, genetic alterations in Crohn's colitis-associated CRC are poorly understood. METHODS: In a series of 227 patients with Crohn's colitis, we identified 33 cases of CRC (~14 %) and performed targeted mutational analysis of BRAF/KRAS/NRAS and determined microsatellite status as well as immunophenotype of the tumors. RESULTS: In the CRC cohort, the median age at time of cancer diagnosis was 58 (range 34-77 vs. 59.5 in sporadic; P = 0.81) and the median CD duration was 29 years (range 6-45). As a group, CRC complicating Crohn's colitis is BRAF (97 %) and NRAS (100 %) wild type and the vast majority is microsatellite stable (94 %); KRAS-mutations were found in six cases (18 %). Stage grouping, anatomic distribution, and overall survival were similar to sporadic CRC; however, long-standing CD (≥25 years) as well as gastric-immunophenotype (MUC5AC+) was associated with significantly shorter overall survival (P = 0.0029; P = 0.036, respectively). CONCLUSION: In summary, the clinicopathological and molecular profile of CD-associated CRC is similar to that observed in sporadic CRC.
Assuntos
Neoplasias Colorretais/complicações , Doença de Crohn/complicações , Adulto , Idoso , Neoplasias Colorretais/genética , Doença de Crohn/patologia , Metilação de DNA/genética , Feminino , Seguimentos , GTP Fosfo-Hidrolases/genética , Estudos de Associação Genética , Humanos , Imunofenotipagem , Masculino , Proteínas de Membrana/genética , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Mutação , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de SobrevidaRESUMO
BACKGROUND: Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. METHODS: Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. RESULTS: Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. CONCLUSION: The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. IMPLICATIONS FOR PRACTICE: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date. The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study.
Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Isocitrato Desidrogenase/genética , Adulto , Idoso , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa. MATERIALS AND METHODS: With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000 and 2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression. RESULTS: We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8RF/mm2 was observed in 53% (n=54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p<0.001). CONCLUSIONS: These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa.
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Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Receptor ErbB-2/biossíntese , Idoso , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/genética , Feminino , Amplificação de Genes , Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Gradação de Tumores , Inclusão em Parafina , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Receptor ErbB-2/genéticaRESUMO
WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Rabdomiossarcoma Embrionário/genética , Proteínas Supressoras de Tumor/genética , Tumor de Wilms/genética , Adulto , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Deleção de SequênciaRESUMO
BACKGROUND: Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes. METHODS: Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) who underwent clinical tumor genotyping were reviewed. Multiplexed tumor genotyping screened for >150 mutations across 15 commonly mutated cancer genes. The chi-square test was used to assess genotype frequency by tumor site and additional clinical characteristics. Cox multivariate analysis was used to assess the impact of genotype on overall survival. RESULTS: Broad-based tumor genotyping revealed clinical and anatomic differences that could be linked to gene mutations. NRAS mutations were associated with rectal cancer versus colon cancer (12.5% vs 0.6%; P < .001) and with age ≥56 years (7% vs 0.9%; P = .02). Conversely, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations were associated with colon cancer (13% vs 3%; P = .024) and older age (15.8% vs 4.6%; P = .006). TP53 mutations were associated with rectal cancer (30% vs 18%; P = .048), younger age (14% vs 28.7%; P = .007), and men (26.4% vs 14%; P = .03). Lung metastases were associated with PIK3CA mutations (23% vs 8.7%; P = .004). Only mutations in BRAF were independently associated with decreased overall survival (hazard ratio, 2.4; 95% confidence interval, 1.09-5.27; P = .029). CONCLUSIONS: The current study suggests that underlying molecular profiles can differ between colon and rectal cancers. Further investigation is warranted to assess whether the differences identified are important in determining the optimal treatment course for these patients.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Análise Mutacional de DNA , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Retais/genética , Adenocarcinoma/química , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Colo/química , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , GTP Fosfo-Hidrolases/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/análise , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Retais/química , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores de Risco , Proteína Supressora de Tumor p53/genética , Proteínas ras/genéticaRESUMO
Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.
Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Isocitrato Desidrogenase/genética , Neoplasias Hormônio-Dependentes/genética , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adenocarcinoma/urina , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/urina , Feminino , Glutaratos/sangue , Glutaratos/urina , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Hormônio-Dependentes/sangue , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/urinaRESUMO
BACKGROUND: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. METHODS: Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined. RESULTS: The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. CONCLUSIONS: Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.
Assuntos
Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Perfilação da Expressão Gênica , Genômica/métodos , Mutação/genética , Recidiva Local de Neoplasia/genética , Idoso , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glutaratos/metabolismo , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Doença Aguda , Idoso , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Citarabina/administração & dosagem , Análise Mutacional de DNA , Decitabina , Feminino , Glutaratos/sangue , Glutaratos/urina , Células Precursoras de Granulócitos/metabolismo , Humanos , Idarubicina/administração & dosagem , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Fatores de TempoRESUMO
AIMS: BRAF is mutated in 50-60% of melanomas, but BRAF mutation in sarcomas has not been systematically evaluated. Some melanomas are spindled and may show no immunohistochemical evidence of melanocytic differentiation. Similarly, many sarcomas are undifferentiated, i.e. undifferentiated pleomorphic sarcomas (UPS). Diagnosing melanoma versus sarcoma in an undifferentiated spindle cell malignancy can be challenging. Our aim was to evaluate the prevalence of BRAF mutation in sarcomas and the use of BRAF mutational status in the diagnosis of spindle cell malignancies. METHODS AND RESULTS: BRAF mutational analysis was performed on tissue from 104 patients: 90 with sarcoma only (50 UPS) and 14 with sarcoma and melanoma (seven UPS). In the sarcoma-only group, BRAF mutation was absent. In the sarcoma-melanoma group, three sarcomas showed BRAF mutation; all were UPS, occurred after the melanomas and did not stain for melanocytic markers. One melanoma-sarcoma pair showed identical BRAF V600E mutations. CONCLUSIONS: The presence of BRAF mutation in these tumours raises the possibility that poorly differentiated spindle cell malignancies with BRAF mutation may represent melanomas, and BRAF mutational analysis should be considered in a patient with a spindle cell malignancy and a history of melanoma, as a positive result may indicate de-differentiated melanoma.
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Melanoma/genética , Melanoma/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sarcoma/genética , Sarcoma/patologia , Biomarcadores Tumorais/genética , Desdiferenciação Celular/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Melanoma/diagnóstico , Sarcoma/diagnósticoRESUMO
Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
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Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/genética , Neoplasias da Vesícula Biliar/genética , Isocitrato Desidrogenase/genética , Mutação , Adolescente , Adulto , Neoplasias dos Ductos Biliares/enzimologia , Criança , Colangiocarcinoma/enzimologia , Feminino , Neoplasias da Vesícula Biliar/enzimologia , Genótipo , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single-arm, phase 1/2 study of everolimus in patients with advanced HCC. METHODS: Patients with histologically confirmed measurable advanced HCC, 0-2 prior regimens, and adequate hematologic, hepatic, and renal functions received everolimus at 5 mg/day or 10 mg/day orally (6 weeks/cycle). The primary end points were determination of a safe dosage of everolimus (phase 1) and progression-free survival (PFS) at 24 weeks (phase 2). RESULTS: Twenty-eight patients were enrolled and evaluable for efficacy and toxicity. No dose-limiting toxicities were observed at the 5 mg/day (n = 3) or 10 mg/day (n = 6) dosage level in phase 1. Twenty-five patients received everolimus at 10 mg/day. Grade 3-4 adverse events included lymphopenia (n = 3), aspartate transaminase (n = 3), hyponatremia (n = 2), and 1 patient each with anemia, alanine transaminase, hyperglycemia, proteinuria, rash, and hypoxia. One patient (4%) had partial response (95% confidence interval [CI], 0.9%-19.6%). The median PFS and overall survival were 3.8 months (95% CI, 2.1-4.6) and 8.4 months (95% CI, 3.9-21.1), respectively. The estimated PFS rate at 24 weeks was 28.6% (95% CI, 7.9%-49.3%). CONCLUSION: Everolimus was well tolerated in patients with advanced HCC, and 10 mg/day was defined as the phase 2 dosage. Although the study did not proceed to the second stage of phase 2, preliminary antitumor activity was observed with everolimus in patients with advanced HCC, most of whom had prior systemic treatment.
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Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sirolimo/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Everolimo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sirolimo/uso terapêuticoAssuntos
Carcinossarcoma/diagnóstico , Neoplasias do Endométrio/diagnóstico , Endométrio/patologia , Fosfatidilinositol 3-Quinases/genética , Hemorragia Uterina/etiologia , Idoso , Biópsia , Carcinossarcoma/genética , Carcinossarcoma/terapia , Classe I de Fosfatidilinositol 3-Quinases , Terapia Combinada , Diagnóstico Diferencial , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Evolução Fatal , Feminino , Humanos , Histerectomia , MutaçãoRESUMO
OBJECTIVES: Gynecologic carcinosarcoma is an aggressive malignancy that requires more effective treatment approaches. However, therapeutic implications regarding the specific gynecologic site of origin and the admixture of carcinomatous and sarcomatous elements that define this tumor remain uncertain. Therefore, broad genotyping was performed to identify tissue-specific somatic mutational profiles that may help direct targeted therapies in this complex neoplasia. METHODS: Genotyping was conducted on primary gynecologic carcinosarcomas arising from various disease sites (uterus, ovary, fallopian tube, vagina) and within isolated histological subcomponents. Nucleic acids extracted from diagnostic tissue were used in a genotyping platform that simultaneously queried >120 common mutations across 14 cancer genes. Mutational status was correlated with clinical variables using logistic regression and Kaplan-Meier survival estimates. RESULTS: Cancer gene mutations were identified in 46% of the 52 patient cohort and include TP53 (23%), PIK3CA (19%), KRAS (15%), CTNNB1 (4%) and NRAS (2%). Mutation in a single gene was observed in 31% of patient samples, while synchronous mutations involving 2 and 3 genes were noted in 13% and 2% of samples, respectively. Comparative evaluation of the carcinomatous and sarcomatous elements within a tumor demonstrated a similar mutation signature. Mutations in PIK3CA, KRAS and NRAS were exclusive to tumors of uterine origin and age-adjusted Cox proportional hazards modeling associated advanced age, stage and TP53 mutations with decreased survival in the uterine subset. CONCLUSION: While carcinosarcomas across gynecologic disease sites are histologically similar, therapeutically relevant mutations in the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways predominated in carcinosarcomas arising in the uterus.
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Carcinossarcoma/genética , Genes ras , Neoplasias dos Genitais Femininos/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinossarcoma/metabolismo , Carcinossarcoma/patologia , Classe I de Fosfatidilinositol 3-Quinases , Estudos de Coortes , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Genótipo , Humanos , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , beta Catenina/genética , beta Catenina/metabolismo , Proteínas ras/metabolismoRESUMO
BACKGROUND: Recent data provide significant evidence to support the hypothesis that there are sub-populations of cells within solid tumors that have an increased tumor initiating potential relative to the total tumor population. CD133, a cell surface marker expressed on primitive cells of neural, hematopoietic, endothelial and epithelial lineages has been identified as a marker for tumor initiating cells in solid tumors of the brain, colon, pancreas, ovary and endometrium. Our objectives were to assess the relative level of CD133 expressing cells in primary human endometrial tumors, confirm their tumorigenic potential, and determine whether CD133 expression was epigenetically modified. METHODS: We assessed CD133 expression in primary human endometrial tumors by flow cytometry and analyzed the relative tumorigenicity of CD133+ and CD133- cells in an in vivo NOD/SCID mouse model. We assessed potential changes in CD133 expression over the course of serial transplantation by immunofluorescence and flow cytometry. We further examined CD133 promoter methylation and expression in normal endometrium and malignant tumors. RESULTS: As determined by flow cytometric analysis, the percentage of CD133+ cells in primary human endometrial cancer samples ranged from 5.7% to 27.4%. In addition, we confirmed the tumor initiating potential of CD133+ and CD133- cell fractions in NOD/SCID mice. Interestingly, the percentage of CD133+ cells in human endometrial tumor xenografts, as evidenced by immunofluorescence, increased with serial transplantation although this trend was not consistently detected by flow cytometry. We also determined that the relative levels of CD133 increased in endometrial cancer cell lines following treatment with 5-aza-2'-deoxycytidine suggesting a role for methylation in the regulation of CD133. To support this finding, we demonstrated that regions of the CD133 promoter were hypomethylated in malignant endometrial tissue relative to benign control endometrial tissue. Lastly, we determined that methylation of the CD133 promoter decreases over serial transplantation of an endometrial tumor xenograft. CONCLUSIONS: These findings support the hypotheses that CD133 expression in endometrial cancer may be epigenetically regulated and that cell fractions enriched for CD133+ cells may well contribute to endometrial cancer tumorigenicity, pathology and recurrence.
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Antígenos CD/genética , Transformação Celular Neoplásica/patologia , Neoplasias do Endométrio/patologia , Epigenômica , Glicoproteínas/genética , Células-Tronco Neoplásicas/patologia , Peptídeos/genética , Antígeno AC133 , Animais , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Decitabina , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/imunologiaRESUMO
Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.