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BACKGROUND: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response. CONCLUSIONS: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Paclitaxel , Humanos , Paclitaxel/uso terapéutico , Paclitaxel/farmacología , Paclitaxel/administración & dosificación , Femenino , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Masculino , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos , Taxoides/uso terapéutico , Taxoides/farmacología , Dosis Máxima Tolerada , Quinasa Syk/metabolismoRESUMEN
BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. PATIENTS AND METHODS: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities. RESULTS: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified. CONCLUSIONS: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.
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Neoplasias , Proteína-Arginina N-Metiltransferasas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteína-Arginina N-Metiltransferasas/genética , Anciano , Adulto , Mutación , Dosis Máxima Tolerada , Factores de Empalme de ARN , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples. PATIENTS AND METHODS: HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples. RESULTS: HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC. CONCLUSION: Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies.
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Neoplasias de la Mama , Neoplasias Primarias Secundarias , Humanos , Femenino , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Hibridación in Situ , Inmunohistoquímica , Genómica/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type.
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Neoplasias , Medicina de Precisión , Humanos , Frecuencia de los Genes , Mutación de Línea Germinal , Genes BRCA2 , Predisposición Genética a la EnfermedadRESUMEN
Bacterial urinary tract infection (UTI) is a common clinical concern in dogs. However, incidence of feline UTI is much lower than in dogs although an increasing prevalence has been registered. The main objective of the present study was to describe and characterize the prevalence of urinary tract pathogens in urine samples of dogs and cats with urinary clinical signs throughout different Spanish provinces. Secondary aims were to determine if there were differences in urine sample characterizations based on species (i.e., dog and cat) or season. Dogs were found to have a higher rate of positive urinary cultures than cats (39.3% and 24.7% of the cultures submitted, respectively). The bacterial genera most commonly isolated in dogs were Escherichia spp. (45.3%), Proteus spp. (13.2%), Staphylococcus spp. (11%), and Enterococcus spp. (8.6%). Whereas in the feline population, Escherichia spp. (42.7%), Enterococcus spp. (22.2%), and Staphyloccoccus spp. (15.2%) were the most frequently isolated bacteria. The highest rates of positive urine cultures were registered in Melilla (70%), Zamora (66.7%), Teruel (64.3%), and Guadalajara (60%). Moreover, the proportion of positive urine cultures was not homogeneously distributed across provinces. Finally, some seasonality was found among most isolated bacterias. Enterococcus spp. was significantly more prevalent in summer, whereas Escherichia spp. and Proteus spp. were more commonly isolated in spring and Pseudomonas spp. in autumn.
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Enfermedades de los Gatos , Enfermedades de los Perros , Infecciones Urinarias , Animales , Enfermedades de los Gatos/epidemiología , Gatos , Enfermedades de los Perros/epidemiología , Perros , Prevalencia , España/epidemiología , Infecciones Urinarias/epidemiología , Infecciones Urinarias/veterinariaRESUMEN
Glomerulonephropathy associated with Dirofilaria immitis (heartworm) is relatively frequent in infected dogs. Given the importance and the scarcity of studies focused on its prevalence and diagnosis, the objective was to determine the prevalence of proteinuria and functional indicators of glomerular filtration rate in dogs with heartworm disease and discuss its utility in the detection of renal impairment. Sera and urine from 47 infected dogs were analyzed in a reference laboratory. Urea, creatinine, plasma proteins and serum symmetric dimethylarginine (SDMA) were analyzed in sera, while the UPC ratio was performed in urine. Dogs were further evaluated for the presence/absence of microfilariae, pulmonary and systemic hypertension, and the parasite burden was assessed. The results showed that 19.1 % of dogs showed proteinuria (UPC > 0.5) and 17 % showed borderline proteinuria (UPC 0.2-0.5). Creatinine and SDMA were high (>1.8 mg/dl and ≥18 µg/dl, respectively) in 4.2 % of dogs. UPC ratio was significantly increased in dogs with high parasite burden and in dogs with microfilariemia (p < 0.05). Dogs with pulmonary hypertension showed higher increases in proteinuria as well, which was probably due to the chronicity of the infection. No significant differences were found in serum and urine values regarding systemic blood pressure. Despite the limitations of this study, proteinuria/borderline proteinuria was present in 36.2 % of dogs with heartworm disease, and this may be due to glomerular disease. Therefore, the detection of proteinuria, along with other renal biomarkers in the diagnostic protocols, could help identify kidney alterations or risk of renal damage in heartworm disease.
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Dirofilariasis/epidemiología , Enfermedades de los Perros/epidemiología , Tasa de Filtración Glomerular/veterinaria , Proteinuria/veterinaria , Insuficiencia Renal/veterinaria , Animales , Biomarcadores/sangre , Dirofilaria immitis/fisiología , Dirofilariasis/parasitología , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/parasitología , Perros , Femenino , Masculino , Prevalencia , Proteinuria/epidemiología , Proteinuria/parasitología , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/epidemiología , Insuficiencia Renal/parasitología , España/epidemiologíaRESUMEN
BACKGROUND: Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline pathogenic and likely pathogenic variants (LPV/PV). The American College of Medical Genetics (ACMG) recommends return of secondary results for a subset of 59 genes, but other genes with evidence of clinical utility are emerging. We previously reported that 4.3% of patients who underwent NGS of a targeted panel of 201 genes had LPV/PV based on the ACMG list. Here we report the frequency of additional germline cancer-related gene variants and discuss their clinical utility. PATIENTS AND METHODS: Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in a research laboratory on samples from 1000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed. RESULTS: Among 1000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR-(5), ATM-(4), BAP1-(1), CDH1-(1), CDKN2A-(1), CHEK1-(2), CHEK2-(10), EGFR-(1), ERCC3-(4), ERCC5-(1), HNF1B-(1), HRAS-(1), MITF-(4), MLL3-(1), NF1-(3), PKHD1-(4), PTCH1-(1), and SMARCA4-(1). Thus, a total 8.7% of patients had an LPV/PV with 2 patients having 2 concomitant germline LPV/PV. Five mutations in high-penetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4. CONCLUSIONS: Broader genomic testing is likely to identify additional secondary pathogenic germline alterations, some with potential clinical utility for return to patients and their relatives. The recommended genes for which germline results should be returned are continually changing, warranting continued study.
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Leptospira is a widespread zoonosis that has been linked to transmission between dogs and humans. The main purposes were to determine the seroprevalence of anti-Leptospira serum antibody and to identify the most common serovars in dogs in Spain. This is a cross-sectional study with 1,310 records of canine Leptospira testing data from Spain since 2015 to 2017. Inclusion criteria were individual cases with MAT test results for 8 serovars (Bratislava, Icterohaemorrhagiae, Australis, Pomona, Grippotyphosa, Autumnalis, Canicola and Saxkoebing) and to have the zip code data. Three hundred and thirty-eight samples (25.8%; 95%CI 23.6-28.4) were seropositive (≥1:100). According to geographic areas, North had the highest seroprevalence (38.0%; 95%CI 28.9-47.1) followed by South (29.4%; 95%CI 20.1-38.8), Center (28.6%; 95%CI 24.3-33.0), Mediterranean (22.3%; 95%CI 19.1-25.6) and Northwest (22.2%; 95%CI 7.9-36.4). Seropositivity (MAT ≥1:100) was most common to serovars Icterohaemorrhagiae (19.4%; 95%CI 17.2-21.5) and Bratislava (8.5%; 95%CI 7.0-10.0), followed by Grippotyphosa (7.2%; 95%CI 5.8-8.6), Australis (6.4%; 95%CI 5.0-7.7), Autumnalis (5.0%; 95%CI 3.8-6.2), Pomona (4.5%; 95%CI 3.3-5.6), Canicola (3.4%; 95%CI 2.4-4.4) and Saxkoebing (0.8%; 95%CI 0.3-1.3). An association was found between positivity (MAT ≥1:100) and males (P = 0.003) and dogs that were 6 years old or older were at higher risk of exposure (P = 0.001; OR 4.61; 95%CI 1.86-11.43). This study has shown that dogs in Spain are commonly exposed to Leptospira infection and points out the necessity to control the prevalence of this severe widespread zoonosis in dogs and humans.
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Background: Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods: This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results: A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an â¼80% inhibition of plasma Aß, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion: Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID: NCT01695005.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Benzazepinas/administración & dosificación , Neoplasias/tratamiento farmacológico , Receptores Notch/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Anciano , Secretasas de la Proteína Precursora del Amiloide/sangre , Antineoplásicos/efectos adversos , Benzazepinas/efectos adversos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Criterios de Evaluación de Respuesta en Tumores Sólidos , Adulto JovenRESUMEN
Background: Precision medicine is rapidly evolving within the field of oncology and has brought many new concepts and terminologies that are often poorly defined when first introduced, which may subsequently lead to miscommunication within the oncology community. The European Society for Medical Oncology (ESMO) recognises these challenges and is committed to support the adoption of precision medicine in oncology. To add clarity to the language used by oncologists and basic scientists within the context of precision medicine, the ESMO Translational Research and Personalised Medicine Working Group has developed a standardised glossary of relevant terms. Materials and methods: Relevant terms for inclusion in the glossary were identified via an ESMO member survey conducted in Autumn 2016, and by the ESMO Translational Research and Personalised Medicine Working Group members. Each term was defined by experts in the field, discussed and, if necessary, modified by the Working Group before reaching consensus approval. A literature search was carried out to determine which of the terms, 'precision medicine' and 'personalised medicine', is most appropriate to describe this field. Results: A total of 43 terms are included in the glossary, grouped into five main themes-(i) mechanisms of decision, (ii) characteristics of molecular alterations, (iii) tumour characteristics, (iv) clinical trials and statistics and (v) new research tools. The glossary classes 'precision medicine' or 'personalised medicine' as technically interchangeable but the term 'precision medicine' is favoured as it more accurately reflects the highly precise nature of new technologies that permit base pair resolution dissection of cancer genomes and is less likely to be misinterpreted. Conclusions: The ESMO Precision Medicine Glossary provides a resource to facilitate consistent communication in this field by clarifying and raising awareness of the language employed in cancer research and oncology practice. The glossary will be a dynamic entity, undergoing expansion and refinement over the coming years.
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Oncología Médica , Medicina de Precisión , Diccionarios Médicos como Asunto , Humanos , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapiaRESUMEN
The paradigm of early drug development in cancer is shifting from 'histology-oriented' to 'molecularly oriented' clinical trials. This change can be attributed to the vast amount of tumour biology knowledge generated by large international research initiatives such as The Cancer Genome Atlas (TCGA) and the use of next generation sequencing (NGS) techniques developed in recent years. However, targeting infrequent molecular alterations entails a series of special challenges. The optimal molecular profiling method, the lack of standardised biological thresholds, inter- and intra-tumor heterogeneity, availability of enough tumour material, correct clinical trials design, attrition rate, logistics or costs are only some of the issues that need to be taken into consideration in clinical research in small genomically stratified patient populations. This article examines the most relevant challenges inherent to clinical research in these populations. Moreover, perspectives from the Academia point of view are reviewed as well as initiatives to be taken in forthcoming years.
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Investigación Biomédica/tendencias , Genómica/métodos , Biología Molecular , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Ensayos Clínicos como Asunto , Dermatoglifia del ADN , Predisposición Genética a la Enfermedad/genética , Humanos , Medicina de Precisión/métodosRESUMEN
Gastric cancer is the third leading cause of death from cancer worldwide. Systemic chemotherapy remains the mainstay therapeutic option for this poor prognosis cancer. Trastuzumab, the epidermal growth factor receptor 2 (ERBB2 or HER2)-antibody, is the only biological agent approved for the molecularly selected population of HER2-positive gastric cancer patients. Over the last decade, several groups have been working for deepening into the molecular characterization of gastric cancer, shedding some light into the heterogeneity of this tumour. The published data have broadened the landscape towards a future molecular classification into several subtypes of gastric cancer, enabling a better selection of the optimal therapeutic strategy. The fibroblast growth factor receptor (FGFR) pathway plays a key role in gastric cancer pathogenesis, with 1.2%-9% of gastric cancer patients harbouring FGFR2 amplifications. Several selective FGFR inhibitors have been developed in the last years, with promising efficacy signals. However, there is still scarce evidence of the most reliant molecular determinants of response to these targeted agents. Homogeneous high-level clonal FGFR2-amplification, high FGFR2 mRNA or protein levels, specific FGFR2 C3 isoform expression, FGF ligand co-overexpression or detection of FGFR2 copy number in plasma circulating tumour DNA, are considered some of the potential predictive biomarkers to the FGFR inhibition. The successful development of highly specific FGFR inhibitors will rely on our capacity of establishing new personalized strategies, based on a deeper knowledge of the key alterations that drive oncogenesis in gastric cancer. Further efforts seem mandatory in order to implement accurate predictive biomarkers in the next stages of the FGFR inhibitors development.
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Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Neoplasias Gástricas/metabolismoRESUMEN
Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity. Further work needs to be undertaken to establish the clinical utility of liquid biopsies and the added clinical value of expanding from individual gene tests into large gene panels. Experts agreed that standardized bioinformatics methods for biological interpretation of genomic data are needed and that precision medicine trials should be stratified based on the level of evidence available for the genomic alterations identified.
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Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteómica , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias/patología , Medicina de PrecisiónRESUMEN
Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer.
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Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Medicina de Precisión/métodos , Antineoplásicos/economía , Antineoplásicos/provisión & distribución , Canadá , Ensayos Clínicos como Asunto/economía , Ensayos Clínicos como Asunto/legislación & jurisprudencia , Francia , Perfilación de la Expresión Génica , Genómica , Humanos , Israel , Neoplasias/metabolismo , Estudios Prospectivos , España , Estados UnidosRESUMEN
BACKGROUND: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). METHODS: Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. CONCLUSIONS: Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly.
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Antineoplásicos/administración & dosificación , Proteínas de Choque Térmico Pequeñas/administración & dosificación , Neoplasias/tratamiento farmacológico , Piridonas/administración & dosificación , Pirimidinas/administración & dosificación , Administración Oral , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico Pequeñas/efectos adversos , Proteínas de Choque Térmico Pequeñas/farmacocinética , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Resultado del TratamientoRESUMEN
The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.
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Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Anticuerpos Monoclonales/uso terapéutico , Factor 3 de Crecimiento de Fibroblastos/genética , Amplificación de Genes , Humanos , Hiperfosfatemia/terapia , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
BACKGROUND: Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe. METHODS: In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations. RESULTS: Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%. CONCLUSION: Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.