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1.
Qual Life Res ; 31(2): 473-485, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34115280

RESUMEN

PURPOSE: This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. METHODS: Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0-10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. RESULTS: Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. CONCLUSION: Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Investigación Cualitativa , Calidad de Vida/psicología
2.
Invest New Drugs ; 39(2): 477-487, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33052556

RESUMEN

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazinas/uso terapéutico , Triazinas/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Relación Dosis-Respuesta a Droga , Receptores ErbB/genética , Femenino , Gefitinib/administración & dosificación , Gefitinib/efectos adversos , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-met/biosíntesis , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Triazinas/administración & dosificación , Triazinas/efectos adversos
3.
Clin Cancer Res ; 25(16): 4924-4932, 2019 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-30952639

RESUMEN

PURPOSE: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). PATIENTS AND METHODS: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. RESULTS: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. CONCLUSIONS: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.


Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazinas/uso terapéutico , Triazinas/uso terapéutico , Biomarcadores de Tumor , Monitoreo de Drogas , Femenino , Humanos , Masculino , Terapia Molecular Dirigida , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias/etiología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Resultado del Tratamiento , Triazinas/administración & dosificación , Triazinas/efectos adversos , Triazinas/farmacocinética
4.
Clin Cancer Res ; 24(15): 3510-3518, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29440181

RESUMEN

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2- advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. ©2018 AACRSee related commentary by Jordan, p. 3480.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Cinamatos/administración & dosificación , Indoles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Cinamatos/efectos adversos , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Indoles/efectos adversos , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/inducido químicamente , Náusea/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/genética , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos
5.
Clin Cancer Res ; 24(23): 5860-5872, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30082476

RESUMEN

PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , ADN Tumoral Circulante , Antagonistas de Estrógenos/farmacología , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Biopsia Líquida , Mutación , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico
6.
J Clin Oncol ; 35(26): 2993-3001, 2017 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-28644771

RESUMEN

Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirazinas/administración & dosificación , Triazinas/administración & dosificación , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Pirazinas/efectos adversos , Triazinas/efectos adversos , Adulto Joven
7.
Cell Metab ; 23(1): 77-93, 2016 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-26626460

RESUMEN

VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Leptina/farmacología , Quinazolinas/uso terapéutico , Transcriptoma , Animales , Antineoplásicos/farmacología , Índice de Masa Corporal , Línea Celular Tumoral , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Humanos , Estimación de Kaplan-Meier , Leptina/uso terapéutico , Melanoma Experimental/sangre , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Obesos , Modelos de Riesgos Proporcionales , Quinazolinas/farmacología , Estudios Retrospectivos , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Virchows Arch ; 464(2): 145-56, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24306956

RESUMEN

Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2 % of cases and associated with worse survival (P = 0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P = 0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P < 0.001). On multivariate analysis, only cMet retained significance (P = 0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P = 0.004) and pERK (P = 0.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials.


Asunto(s)
Adenocarcinoma/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Transducción de Señal/fisiología , Neoplasias Gástricas/mortalidad , Análisis de Matrices Tisulares
9.
Clin Colorectal Cancer ; 13(1): 46-53, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24355210

RESUMEN

INTRODUCTION: Bevacizumab improves outcome for patients with advanced colorectal cancer (CRC) when added to chemotherapy. The HORIZON I trial resulted in similar outcome with bevacizumab or cediranib, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor, as treatment of advanced CRC. The spectrum of lactate dehydrogenase (LDH) isoenzyme expression was examined in serum samples of HORIZON I participants to identify biomarkers predictive of efficacy of VEGF pathway inhibitors. MATERIALS AND METHODS: Total LDH levels, as well as LDH isoenzyme levels in frozen baseline serum samples, were retrospectively evaluated. Total LDH serum levels measured during the study, progression-free survival (PFS), and overall survival (OS) were available from the HORIZON I study data. RESULTS: Total LDH levels measured in the frozen serum samples correlated with those measured in fresh samples. The expected reciprocal correlation was found between hypoxic and oxic LDH isoenzymes. High total LDH correlated with shorter PFS, and high hypoxia-related LDH isoenzymes correlated with shorter PFS and OS. The difference in outcome of the cediranib-treated patients vs. those treated with bevacizumab was not substantially different in the various LDH isoform expression subgroups. In patients with a hypoxic LDH pattern of expression, there was a nonsignificant trend of better outcome in cediranib-treated patients. CONCLUSION: Evaluation of total LDH and its isoforms in frozen serum samples is feasible. High total LDH and high hypoxic LDH isoenzymes were associated with poor prognosis. Further studies are needed to evaluate the predictive value of LDH isoenzyme expression pattern for VEGF-pathway inhibition efficacy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/enzimología , L-Lactato Deshidrogenasa/sangre , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Neoplasias Colorrectales/mortalidad , Fluorouracilo , Humanos , Isoenzimas/sangre , Estimación de Kaplan-Meier , Leucovorina , Compuestos Organoplatinos , Pronóstico , Quinazolinas/administración & dosificación , Estudios Retrospectivos , Resultado del Tratamiento
10.
Eur J Cancer ; 49(10): 2424-32, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23510802

RESUMEN

PURPOSE: The prognostic potential of KRAS mutations in advanced colorectal cancer (CRC) patients and the impact of KRAS mutation status on the effectiveness of chemotherapy or vascular endothelial growth factor (VEGF) signalling inhibitor therapy remain unclear. KRAS mutation status was evaluated retrospectively as a potential prognostic/predictive marker of clinical outcomes using tumour samples from patients with metastatic CRC receiving cediranib or placebo plus FOLFOX/XELOX in a Phase III trial (HORIZON II; NCT00399035). METHODS: KRAS codon 12 and 13 mutation analyses were performed using a commercially available, allele-specific, amplification refractory mutation system (ARMS)-based polymerase chain reaction (PCR) assay. Retrospective analyses of progression-free survival (PFS) and overall survival (OS) according to KRAS mutation status were performed for patients randomised to cediranib 20mg or placebo. RESULTS: KRAS status was determined in 599/1076 patients (cediranib 20mg, n=285/502; cediranib 30 mg, n=110/216; placebo, n=204/358). Baseline characteristics were similar across KRAS mutant (n=258; 24.0%), wild-type (n=341; 31.7%) and status unknown (n=477; 44.3%) groups. There was a trend towards improved PFS and OS in the wild-type versus mutant subgroups independent of treatment (cediranib 20 mg and placebo: PFS hazard ratio (HR)=0.85 [median PFS: wild-type=8.5 months; mutant=8.3 months]; OS HR=0.71 [median OS: wild-type=20.9 months; mutant=16.9 months]). Treatment effects were similar between KRAS subgroups for cediranib 20mg versus placebo (PFS: wild-type HR=0.78, mutant HR=0.82; OS: wild-type HR=0.92, mutant HR=1.01). CONCLUSION: Data from this large randomised Phase III study show that KRAS codon 12/13 mutations have negative prognostic value in metastatic CRC patients receiving treatment with FOLFOX/XELOX, but KRAS mutation status is not predictive of treatment benefit with cediranib, using PFS or OS.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Ensayos Clínicos Fase III como Asunto , Codón/genética , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Quinazolinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Resultado del Tratamiento
11.
Clin Med Insights Pathol ; 5: 15-22, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22661904

RESUMEN

Testing for mutations in the KRAS oncogene for patients with metastatic colorectal cancer (mCRC) is generally performed using DNA from formalin-fixed paraffin-embedded tumor tissue; however, access to specimens can be limited and analysis challenging. This study assessed the identification of KRAS mutations in circulating free DNA (cfDNA) using a commercially available KRAS polymerase chain reaction (PCR) kit. Matched plasma, serum and tumor samples were available from 71 patients with mCRC who had received prior therapy but whose disease progressed following therapy. Yields of cfDNA from plasma and serum samples were comparable. Analyses were successful in 70/71 plasma-extracted samples (specificity: 97%, sensitivity: 31%) and 67/71 serum- extracted samples (specificity: 100%, sensitivity: 25%). This study demonstrates that KRAS mutations can be detected in cfDNA using a commercially available KRAS PCR kit, confirming cfDNA as a potential alternative source of tumor DNA in a diagnostic setting if access to archival tumor specimens is limited.

12.
Clin Cancer Res ; 15(12): 4138-46, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19509160

RESUMEN

PURPOSE: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts and to seek biomarkers predictive of activity. EXPERIMENTAL DESIGN: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using the K-Top Scoring Pairs (K-TSP) method. RESULTS: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors (100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair (LRRC19 and IGFBP2) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity in an independent test set that consists of eight xenograft cases. CONCLUSIONS: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair (LRRC19 and IGFBP2) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for pancreatic tumor sensitivity to AZD0530.


Asunto(s)
Antineoplásicos/farmacología , Benzodioxoles/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/antagonistas & inhibidores , Quinazolinas/farmacología , Animales , Femenino , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Quinasa 1 de Adhesión Focal/metabolismo , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/patología , Paxillin/antagonistas & inhibidores , Paxillin/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Arthritis Rheum ; 50(12): 3783-91, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15593225

RESUMEN

OBJECTIVE: To create greater understanding of the changes in synovial tissue parameters that occur in conjunction with clinical response by using an effective therapy, in order to facilitate the planning of future studies with therapeutic agents for rheumatoid arthritis (RA). METHODS: Twenty-one patients with active RA were randomized to receive either oral prednisolone (n = 10) or placebo (n = 11) for 2 weeks. In all patients, synovial tissue biopsy specimens were obtained by arthroscopy directly before treatment and after 14 days of treatment. Immunohistochemical analysis was performed to characterize the cell infiltrate and vascularity. Stained tissue sections were analyzed by digital imaging. Statistical analysis was performed using an analysis of covariance model. RESULTS: After treatment, the mean Disease Activity Score in 28 joints (DAS28) was 2.0 units lower (95% confidence interval [95% CI] 1.0-3.0) in patients who received prednisolone than in those who received placebo. In the prednisolone group, the mean (+/-SD) DAS28 decreased from 6.27 +/- 0.95 to 4.11 +/- 1.43 after therapy; minimal change was observed in the placebo group. For macrophages, the estimated effect of prednisolone was large. Patients receiving active treatment had fewer (mean 628 cells/mm(2) [95% CI 328-927]) macrophages after therapy compared with those receiving placebo. A reduction in the total number of CD68+ macrophages, from 1,038 +/- 283 cells/mm(2) before treatment to 533 +/- 248 cells/mm(2) after treatment, was observed in the prednisolone group. There were clear trends toward decreased infiltration by T cells, plasma cells, and fibroblast-like synoviocytes after active treatment. We observed a trend toward a reduction in alphavbeta3+ newly formed blood vessels and expression of vascular growth factors after prednisolone therapy. CONCLUSION: Prednisolone therapy in RA is associated with a marked reduction in macrophage infiltration in synovial tissue, suggesting that synovial macrophage numbers could be used as a biomarker for clinical efficacy.


Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Prednisolona/uso terapéutico , Membrana Sinovial/efectos de los fármacos , Sinovitis/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Artritis Reumatoide/complicaciones , Artritis Reumatoide/patología , Biomarcadores/metabolismo , Recuento de Células , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Articulaciones/efectos de los fármacos , Articulaciones/patología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Prednisolona/farmacología , Índice de Severidad de la Enfermedad , Membrana Sinovial/metabolismo , Sinovitis/etiología , Sinovitis/patología
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