RESUMEN
BACKGROUND: Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed. METHODS: Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point. RESULTS: A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P < 0.001) and PFS, by univariate (P < 0.001) and multivariate analysis (P < 0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18 months) while the median PFS for TMBlow was 2 months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point. CONCLUSIONS: TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Mutación , Neoplasias Peritoneales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/genética , Metástasis Linfática , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Nivolumab/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/genética , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Metastatic penile squamous cell carcinoma is an aggressive malignancy with limited treatment options. We compared the potential therapy impacting genomic alterations between metastatic penile squamous cell carcinoma and nonpenile metastatic cutaneous squamous cell carcinoma. MATERIALS AND METHODS: DNA was extracted from 40 µ of formalin fixed, paraffin embedded samples from 78 cases of metastatic penile squamous cell carcinoma and 338 of metastatic cutaneous squamous cell carcinoma. Comprehensive genomic profiling was performed using a hybrid capture, adaptor ligation based, next generation sequencing assay to a mean coverage depth of greater than 500×. The tumor mutational burden was determined on 1.1 Mbp of sequenced DNA and microsatellite instability was determined on 114 loci. RESULTS: Potential targeted therapy opportunities in metastatic penile squamous cell carcinoma cases included alterations in the MTOR pathway ( NF1 genomic alterations in 7% and PTEN genomic alterations in 4%) and in the DNA repair pathway ( BRCA2 and ATM genomic alterations in 7% each) and tyrosine kinase ( EGFR genomic alterations in 6%, and FGFR3 and ERBB2 genomic alterations in 4% each). The tumor mutational burden was significantly higher in predominantly ultraviolet light exposed metastatic squamous cell carcinoma than in metastatic penile squamous cell carcinoma, making metastatic squamous cell carcinoma potentially more responsive to immunotherapies than metastatic penile squamous cell carcinoma. Microsatellite high status was extremely rare for metastatic penile and metastatic cutaneous squamous cell carcinoma. CD274 ( PD-L1) amplification was also rare in both tumor types. CONCLUSIONS: Metastatic penile squamous cell carcinoma is a unique subtype of squamous cell carcinoma with distinctive genomic features which contrast with those identified in metastatic cutaneous squamous cell carcinoma of nonpenile ultraviolet light exposed skin. Although not rich in predictors of the response to immunotherapy (the tumor mutational burden and microsatellite instability are low), more than a quarter of metastatic penile squamous cell carcinoma cases may potentially benefit from existing and available therapies targeting MTOR, DNA repair and tyrosine kinase pathways.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Neoplasias del Pene/genética , Neoplasias del Pene/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/secundario , Anciano , Carcinoma de Células Escamosas/terapia , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Perfil Genético , Genómica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Cutáneas/terapiaRESUMEN
BACKGROUND: Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative. PATIENTS AND METHODS: Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer. RESULTS: At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%). CONCLUSIONS: GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , ADN Tumoral Circulante/genética , Toma de Decisiones Clínicas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Genómica/métodos , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genéticaAsunto(s)
Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapiaRESUMEN
The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.
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Mieloma Múltiple/genética , Proteínas de Unión a Retinoblastoma/genética , Ubiquitina-Proteína Ligasas/genética , Humanos , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia , Pronóstico , Proteína de Retinoblastoma/genéticaRESUMEN
Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.
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Xenoinjertos/patología , Leucemia/genética , Enfermedad Aguda , Adolescente , Adulto , Animales , Células Sanguíneas/trasplante , Trasplante de Médula Ósea , Bovinos , Niño , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Leucemia/patología , Ratones , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations (GAs) that will inform therapeutic choices for patients with advanced disease. PATIENTS AND METHODS: Hybrid-capture-based next-generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. GAs were identified using an established algorithm and correlated with HPV status. RESULTS: Sixty-one samples (87%) were HPV-positive. A mean of 3.5 GAs per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (P < 0.0001). CONCLUSIONS: This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.
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Neoplasias del Ano/genética , Carcinoma de Células Escamosas/genética , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Genómica , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Ano/patología , Neoplasias del Ano/virología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Exones/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Papillomaviridae/patogenicidad , Factores de Transcripción/genéticaAsunto(s)
Biomarcadores de Tumor/genética , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/genética , Mieloma Múltiple/genética , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Ciclina D2/genética , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Cadenas beta de Integrinas/genética , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores CCR1/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies. PATIENTS AND METHODS: DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison. RESULTS: Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles. CONCLUSION: The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Perfilación de la Expresión Génica/métodos , Neoplasias de Cabeza y Cuello/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Variaciones en el Número de Copia de ADN , ADN Viral/genética , Bases de Datos Genéticas , Femenino , Fijadores , Formaldehído , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/química , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Pruebas de ADN del Papillomavirus Humano , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Mutación , Papillomaviridae/genética , Adhesión en Parafina , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello , Fijación del TejidoAsunto(s)
Síndrome Hipereosinofílico/genética , Proteínas de Fusión Oncogénica/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Tanquirasas/genética , Benzamidas/administración & dosificación , Eosinofilia/tratamiento farmacológico , Eosinofilia/genética , Eosinofilia/patología , Femenino , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndrome Hipereosinofílico/tratamiento farmacológico , Síndrome Hipereosinofílico/patología , Mesilato de Imatinib , Leucemia , Persona de Mediana Edad , Trastornos Mieloproliferativos , Proteínas de Fusión Oncogénica/aislamiento & purificación , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificaciónRESUMEN
AIMS: Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice. METHODS: DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs). RESULTS: At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial. CONCLUSIONS: Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/genética , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Terapia Molecular Dirigida , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Biopsia , Diseño de Fármacos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Medicina de Precisión , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Adulto JovenAsunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mutación Missense , Proteínas de Neoplasias/genética , Mutación Puntual , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Terapia Recuperativa , Sulfonamidas/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/administración & dosificación , Bortezomib , Carcinoma de Células Escamosas , Terapia Combinada , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Resultado Fatal , Trasplante de Células Madre Hematopoyéticas , Humanos , Lenalidomida , Masculino , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/terapia , Persona de Mediana Edad , Mieloma Múltiple/etiología , Mieloma Múltiple/genética , Neoplasias Primarias Secundarias , Osteólisis/etiología , Osteólisis/patología , Osteólisis/radioterapia , Cuidados Paliativos , Plasmacitoma/tratamiento farmacológico , Plasmacitoma/patología , Plasmacitoma/terapia , Pirazinas/administración & dosificación , Inducción de Remisión , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Trasplante Autólogo , Resultado del Tratamiento , VemurafenibRESUMEN
AIMS: Small cell lung cancer (SCLC) carries a poor prognosis, and the systemic therapies currently used as treatments are only modestly effective, as demonstrated by a low 5-year survival at only â¼5%. In this retrospective collected from March 2013 to study, we performed comprehensive genomic profiling of 98 small cell undifferentiated lung cancer (SCLC) samples to identify potential targets of therapy not currently searched for in routine clinical practice. METHODS: DNA from 98 SCLC was sequenced to high, uniform coverage (Illumina HiSeq 2500) and analysed for all classes of genomic alterations. RESULTS: A total of 386 alterations were identified for an average of 3.9 alterations per tumour (range 110). Fifty-two (53%) of cases harboured at least 1 actionable alteration with the potential to personalise therapy including base substitutions, amplifications or homozygous deletions in RICTOR (10%), KIT (7%), PIK3CA (6%), EGFR (5%), PTEN (5%), KRAS (5%), MCL1 (4%), FGFR1 (4%), BRCA2, (4%), TSC1 (3%), NF1 (3%), EPHA3 (3%) and CCND1. The most common non-actionable genomic alterations were alterations in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%). CONCLUSIONS: Greater than 50% of the SCLC cases harboured at least one actionable alteration. Given the limited treatment options and poor prognosis of patients with SCLC, comprehensive genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.
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Biomarcadores de Tumor/genética , Diferenciación Celular/genética , Perfilación de la Expresión Génica , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Selección de Paciente , Fenotipo , Medicina de Precisión , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/terapiaRESUMEN
We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.
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Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Fusión de Oncogenes , Receptor trkA/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Antígenos de Diferenciación de Linfocitos B/genética , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidoresRESUMEN
OBJECTIVE: Targeted next generation sequencing (NGS) was evaluated for its ability to identify unanticipated targetable genomic alterations (GA) for patients with relapsed ovarian epithelial carcinoma (OC). METHODS: DNA sequencing was performed for 3320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries using DNA isolated from FFPE sections from 48 histologically verified relapsed OC specimens. The original primary tumor was sequenced in 26 (54%) of the cases and recurrent/metastatic tumor site biopsies were sequenced in 22 (46%) of the cases. Actionability was defined as: GA that predict sensitivity or resistance to approved or standard therapies or are inclusion or exclusion criteria for specific experimental therapies in NCI registered clinical trials. RESULTS: There were 38 (80%) serous, 5 (10%) endometrioid, 3 (6%) clear cell, 1 mucinous (2%) and 1 (2%) undifferentiated carcinomas. 141 GA were identified with an average of 2.9 GA (range 0-8) per tumor, of which 67 were actionable for an average of 1.4 actionable GA per patient (range 0-5). 33/48 (69%) of OC patient samples harbored at least one actionable GA. Most common GA were TP53 (79%); MYC (25%); BRCA1/2 (23%); KRAS (16.6%) and NF1 (14.5%). One tumor featured an ERBB2 point mutation. One of 3 (33%) of clear cell tumors featured cMET amplification validated by both FISH and IHC. CONCLUSIONS: NGS assessment of therapy resistant OC identifies an unexpectedly high frequency of GA that could influence targeted therapy selection for the disease.
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Carcinoma/genética , Resistencia a Antineoplásicos/genética , Neoplasias Ováricas/genética , Análisis de Secuencia de ADN , Adulto , Anciano , Carcinoma/tratamiento farmacológico , Dermatoglifia del ADN , Exones/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Genes de Neurofibromatosis 1 , Genes myc , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Ováricas/tratamiento farmacológico , Medicina de Precisión , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteína p53 Supresora de Tumor/genética , Adulto Joven , Proteínas ras/genéticaRESUMEN
BACKGROUND: The management of a childhood chronic illness can be challenging because it can involve frequent and complex treatment tasks that must be carried out on a daily basis. Parental monitoring of the treatment regimen and child disclosure of health-related information may impact effective illness management but are not well understood. METHODS: The present study utilized qualitative methods to examine parental monitoring-related behaviours, youth disclosure of health-related information, and both perceptions about, and reactions to, these behaviours in a sample of youth diagnosed with a chronic illness (e.g. asthma, diabetes and cystic fibrosis) and parents of youth with one of these illnesses. RESULTS: Parents solicited information from youth verbally, observed symptoms, reminded youth about treatments and tracked indicators of treatment adherence (e.g. dose counters; glucose meters). Youth reactions varied from acceptance to irritation. Youth behaviours included withholding information and freely disclosing spontaneously and in response to requests. CONCLUSIONS: Findings derived from this qualitative methodology demonstrate convergence with findings from quantitative studies on this topic, add to the literature related to parental monitoring of chronic illness management and suggest several avenues for future research.
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Enfermedad Crónica/psicología , Conocimientos, Actitudes y Práctica en Salud , Padres/psicología , Autocuidado/psicología , Adolescente , Adulto , Niño , Enfermedad Crónica/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Relaciones Padres-Hijo , Investigación Cualitativa , Adulto JovenRESUMEN
OBJECTIVE: The aim of the present study was to investigate the prevalence of sleep disturbances in children with migraine headaches and to describe individual differences in sleep behaviors based on headache features (eg, frequency, duration, intensity). BACKGROUND: A relationship between migraine headaches and sleep disturbances has been suggested in both children and adults, but there is a lack of research examining the relationship between specific headache features and the range of sleep behaviors in children. METHODS: One hundred eighteen children, aged 2 to 12 years (mean, 9.1; standard deviation, 2.3) were evaluated for headaches at two pediatric neurology departments. Parents completed the Children's Sleep Habits Questionnaire and a standardized questionnaire regarding headache characteristics. RESULTS: Parents reported a high rate of sleep disturbances in children, including sleeping too little (42%), bruxism (29%), child co-sleeping with parents (25%), and snoring (23%). Children with migraine headaches experienced more sleep disturbances compared to published healthy control norms. After controlling for child demographics, we found that the frequency and duration of migraine headaches predicted specific sleep disturbances, including sleep anxiety, parasomnias, and bedtime resistance. CONCLUSIONS: Children with migraine headaches have a high prevalence of sleep disturbances. The direction of the relationship between headaches and sleep is unknown. Regardless, interventions targeting sleep habits may improve headache symptoms, and effective treatment of headaches in children may positively impact sleep.
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Trastornos Migrañosos/fisiopatología , Trastornos del Sueño-Vigilia/complicaciones , Niño , Preescolar , Femenino , Humanos , Masculino , Trastornos Migrañosos/complicaciones , Ohio/epidemiología , Prevalencia , Sueño , Trastornos del Sueño-Vigilia/epidemiologíaRESUMEN
The 10-deazaaminopterins are a new class of rationally designed antifolates demonstrating greater antitumor effects than methotrexate in murine tumor models and human tumor xenografts. Their design was aimed at improving membrane transport and polyglutamylation in tumor cells, resulting in increased intracellular accumulation and enhanced cytotoxicity. Compared with other 4-aminofolate analogues, 10-propargyl-10-deazaaminopterin (PDX) is the most efficient permeant for the RFC-1-mediated internalization and substrate for folylpolyglutamate synthetase. PDX demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate or edatrexate. We undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Initially, PDX was administered weekly for 3 weeks in a 4-week cycle. Mucositis requiring dose reduction and/or delay in the first cycle occurred in four of six patients treated at the initial dose level (30 mg/m2), making this the maximal tolerated dose for PDX given on this schedule. The treatment schedule was then modified to every 2 weeks. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles (median, 2 cycles/patient). Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. The recommended Phase II dose is 150 mg/m2 biweekly. At that dose level, the mean area under the curve was 20.6 micromol x h, and the mean terminal half-life was 8 h. Two patients with stage IV NSCLC had major objective responses, and five patients had stable disease for 7 (two patients), 9 (one patient), 10 (one patient), and 13 months (one patient). PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC. A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.
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Aminopterina/efectos adversos , Aminopterina/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Antagonistas del Ácido Fólico/efectos adversos , Antagonistas del Ácido Fólico/farmacocinética , Neoplasias Pulmonares/metabolismo , Aminopterina/análogos & derivados , Aminopterina/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Antagonistas del Ácido Fólico/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
Earlier studies from this laboratory have shown that the uricosuric agent probenecid (PBCD) will inhibit the extrusion of folate analogues from tumor cells mediated by a plasma membrane ATPase resembling the canicular multispecific organic anion transporter/multidrug resistance-related protein (MRP) family of ATP binding cassette transporters. This inhibition of this outwardly directed membrane ATPase has been shown to have a favorable impact upon the cellular pharmacokinetics, cytotoxicity, and efficacy of methotrexate in vivo. In an extension of these earlier studies, which had focused only on murine ascites tumors, we now report that parental co-administration of PBCD will also enhance net intracellular accumulation in vitro and intracellular persistence in vivo of a new folate analogue, 10-propargyl-10-deazaaminopterin (PDX) in tumor cells. This resulted in marked enhancement of the efficacy of PDX against murine and human lung neoplasms and human prostate and mammary neoplasms growing as solid tumors in mice. As possible ATPases targeted by PBCD, all of these tumors expressed MRP-1, -4, and -7 genes, with expression of MRP-4 being greatest in each case. Four other MRP genes were expressed to a variable extent in some tumors but not others. The therapeutic enhancement of PDX by PBCD was manifested as tumor regression, where PDX alone was only growth inhibitory (A549 NSCL tumor), or as a substantial increase (3-4-fold) in overall regression and/or number of complete regressions (Lewis and LX-1 lung, PC-3 and TSU-PR1 prostate, and MX-1 mammary tumors) compared to PDX alone. Also, only in the case of PDX with PBCD, a significant number of mice transplanted with LX-1 or MX-1 tumors that experienced complete regression did not have regrowth of their tumor. In view of these results, clinical trials of this therapeutic modality appear to be warranted, especially in the case of new more efficacious folate analogues that are also permeants for this canicular multispecific organic anion transporter/MRP-like plasma membrane ATPase.
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Adenosina Trifosfatasas/antagonistas & inhibidores , Aminopterina/análogos & derivados , Aminopterina/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores Enzimáticos/farmacología , Antagonistas del Ácido Fólico/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Probenecid/farmacología , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/genética , Aminopterina/administración & dosificación , Aminopterina/farmacocinética , Animales , Proteínas de Transporte de Anión , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Membrana Celular/enzimología , Sinergismo Farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Antagonistas del Ácido Fólico/administración & dosificación , Antagonistas del Ácido Fólico/farmacocinética , Humanos , Ratones , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/metabolismo , Probenecid/administración & dosificación , Probenecid/farmacocinética , Células Tumorales Cultivadas/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) has high and reproducible single-agent activity in non-small cell lung cancer, inducing responses in nearly one third of patients treated first-line. As a second-line treatment, docetaxel is the only agent so far shown in randomized trials to prolong survival when compared with either vinorelbine or ifosfamide or best supportive care. When docetaxel is given on a weekly rather than once every 3 week schedule, the risk of neutropenia is reduced while activity appears to be maintained. The weekly schedule may prove to be a more favorable one for combination chemotherapy regimens. To date, docetaxel has been studied with other agents frequently using a once every 3 weeks schedule. Combinations of docetaxel with cisplatin, carboplatin, gemcitabine, or vinorelbine are generally well-tolerated. With all four combinations, the pooled response rates in phase II studies are approximately 40%. A phase II study of 51 patients treated with the combination of 100 mg/m2 docetaxel and 900 mg/m2 gemcitabine reported a 13-month median survival. In a randomized phase II trial comparing docetaxel/gemcitabine with docetaxel/cisplatin, the two regimens had comparable efficacy and toxicity. Response rates of up to 50% have been reported using docetaxel in conjunction with vinorelbine.