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1.
Clin Cancer Res ; 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992589

RESUMEN

PURPOSE: The relevance of the MET/Hepatocyte Growth Factor (HGF) pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease. PATIENTS & METHODS: PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib in women with endometrial cancer with progression after chemotherapy. Co-primary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort. RESULTS: A total of 102 patients were accrued. Amongst 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67% and median PFS, 4.8 mths. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56% and median PFS 4.0 mths. In a separate cohort of 32 patients with uncommon histology EC (including carcinosarcoma), response rate was 6% and 12-wk PFS was 47%. Six patients were on treatment for > 12months, including 2 for > 30 months. Common cabozantinib-related toxicities (> 30% patients) included hypertension, fatigue, diarrhea, nausea and hand-foot syndrome. Gastrointestinal fistula/perforation occurred in 4 of 70 (6%) patients with serous/endometrioid cancer and 5 of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic CTNNB1 mutation (4 PRs in 10 pts, median PFS 7.6 mths) and concurrent KRAS and PTEN/PIK3CA mutations (3 PRs in 12 patients, median PFS 5.9 mths). CONCLUSIONS: Cabozantinib has activity in serous and endometrioid histology EC. These results support further evaluation in genomically characterized patient cohorts.

2.
Int J Gynecol Cancer ; 2019 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-30659026

RESUMEN

OBJECTIVE: Mutations in TP53 are found in the majority of high grade serous ovarian cancers, leading to gain of function or loss of function of its protein product, p53, involved in oncogenesis. There have been conflicting reports as to the impact of the type of these on prognosis. We aim to further elucidate this relationship in our cohort of patients. METHODS: 229 patients with high grade serous ovarian cancer underwent tumor profiling through an institutional molecular screening program with targeted next generation sequencing. TP53 mutations were classified using methods previously described in the literature. Immunohistochemistry on formalin-fixed paraffin embedded tissue was used to assess for TP53 mutation. Using divisive hierarchal clustering, we generated patient clusters with similar clinicopathologic characteristics to investigate differences in outcomes. RESULTS: Six different classification schemes of TP53 mutations were studied. These did not show an association with first platinum-free interval or overall survival. Next generation sequencing reliably predicted mutation in 80% of cases, similar to the proportion detected by immunohistochemistry. Divisive hierarchical clustering generated four main clusters, with cluster 3 having a significantly worse prognosis (p<0.0001; log-rank test). This cluster had a higher concentration of gain of function mutations and these patients were less likely to have undergone optimal debulking surgery. CONCLUSIONS: Different classifications of TP53 mutations did not show an impact on outcomes in this study. Immunohistochemistry was a good predictor for TP53 mutation. Cluster analysis showed that a subgroup of patients with gain of function mutations (cluster 3) had a worse prognosis.

3.
Hematol Oncol Clin North Am ; 32(6): 1041-1055, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30390759

RESUMEN

Epithelial ovarian cancer remains the most lethal gynecologic cancers with a 5-year survival rate of less than 50%. Cytotoxic combinations are associated with incremental toxicity, leading to interest in evaluating cytotoxic/biologic combinations with improved therapeutic ratios. Angiogenesis is critical to the normal physiology of the gynecologic tract and a novel drug target. Current data suggests antiangiogenics should be considered a critical component of epithelial ovarian cancer treatment. Given the serious adverse event of gastrointestinal perforation/fistula in advanced disease, priority should be given to front-line treatment. Active investigation continues in the development of novel combinations with other biologics.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario , Neovascularización Patológica , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/irrigación sanguínea , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Femenino , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología
4.
Clin Cancer Res ; 24(24): 6168-6174, 2018 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-30108107

RESUMEN

PURPOSE: Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemoresistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multitarget kinase selective against Aurora A and VEGFR. PATIENTS AND METHODS: This multicenter phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression-free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by IHC and gene sequencing with a targeted custom capture next-generation sequencing panel. RESULTS: Forty patients were enrolled with a median age of 54, of which 38 patients were evaluable. ENMD-2076 was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%), and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA- vs. ARID1A+; 33% vs. 12%, P = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with PI3KCA wild-type versus PI3KCA-mutated group was 5 versus 3.7 months (P = 0.049). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), and TP53 (7%). The patient with the longest treatment duration (22 months) was PTEN wild-type, diploid PTEN with putative biallelic inactivation of ARID1A. CONCLUSIONS: Single-agent ENMD-2076 did not meet the preset bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker.


Asunto(s)
Adenocarcinoma de Células Claras/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/mortalidad , Administración Oral , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biomarcadores de Tumor , Femenino , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Retratamiento , Resultado del Tratamiento
5.
J Genet Couns ; 27(4): 988-995, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29441441

RESUMEN

Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.


Asunto(s)
Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético , Mutación , Neoplasias Pancreáticas/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad
6.
Clin Colorectal Cancer ; 17(1): 73-79, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29128266

RESUMEN

BACKGROUND: Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well-described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center. PATIENTS AND METHODS: Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, ≥ 500× coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN was determined by immunohistochemistry. RESULTS: From March 2012 to April 2014, 245 patients were enrolled. At least one mutation was found in 54% (97/178) and 91% (61/67) of patients using MassArray or MiSeq platforms, respectively (P < .01). Of all patients, KRAS G12/13 mutation was identified in 39%, and non-G12/13 KRAS, BRAF, or NRAS mutations were present in 9%, 6%, and 4%, respectively. Other common mutations included TP53 (68.7%), APC (41.8%), and PIK3CA (13.5%). Co-mutation with KRAS, NRAS, or BRAF was found in 75% of patients with PIK3CA mutation. Of 106 patients with known PTEN immunohistochemistry status, 16% were negative. A higher average number of mutations were observed in right versus left colorectal cancer (P < .01), with 13 of 14 BRAF mutations located in right colon cancer. CONCLUSION: Mutations are common in advanced colorectal cancer. Right colon cancers harbor more genetic aberrations than left colon or rectal cancers. These aberrations may contribute to differential outcomes to anti-epidermal growth factor receptor therapy among patients with right colon, left colon, or rectal cancers.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/mortalidad , Análisis Mutacional de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación
7.
JAMA Oncol ; 4(7): e173776, 2018 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-29145543

RESUMEN

Importance: Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response. Objective: To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer. Design, Setting, and Participants: A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy. A run-in safety cohort using ipilimumab, 3 mg/kg, every 21 days for 4 cycles in 6 patients was followed by a phase II cohort of ipilimumab, 10 mg/kg, every 21 days for 4 cycles and then 4 cycles of maintenance therapy every 12 weeks for patients demonstrating radiologic response or stabilization. Immune correlative studies were performed on peripheral blood before and after therapy on archival tissue and fresh tumor obtained prior to registration and 7 days after cycle 2. The study was conducted from December 3, 2012, to September 15, 2014. The data were analyzed from April 2016 to June 2016 and in July 2017. Main Outcomes and Measures: The primary end points were safety and objective response rate. Immune analyses were performed on blood and tumor tissue. Results: A total of 42 women (median age, 49 years; range, 23-78 years) were enrolled (29 [69%] squamous cell cervical cancer and 13 [31%] adenocarcinoma; 37 [93%] of 40 patients with tissue available for analysis had HPV-positive confirmation; there was no archival tissue for 2 women). Grade 3 toxic effects included diarrhea in 4 patients, 3 of whom had colitis. Of 34 patients evaluated for best response (Response Evaluation Criteria in Solid Tumors, version 1.1), 1 patient had partial response and 10 had stable disease. The median progression-free survival and overall survival were 2.5 months (95% CI, 2.1-3.2 months) and 8.5 months (95% CI, 3.6-not reached; 1 patient was still alive), respectively. Intratumoral pretreatment CD3, CD4, CD8, FoxP3, indoleamine 2,3-dioxygenase, and programmed cell death ligand 1 (PD-L1) expression was not predictive of benefit and did not significantly change with treatment. Multicolor flow cytometry on peripheral lymphocytes revealed a treatment-dependent increase of inducible T-cell costimulator, human leukocyte antigen-antigen D related, and PD-1 during initial treatment, which returned to baseline during maintenance. Conclusions and Relevance: Ipilimumab was tolerable in this population but did not show significant single-agent activity. Immune changes were induced by anti-CTLA-4 therapy but did not correlate with clinical activity. Changes in these markers may guide further treatment strategies.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Ipilimumab/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Inmunológicos/farmacología , Femenino , Humanos , Ipilimumab/farmacología , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Neoplasias del Cuello Uterino/patología , Adulto Joven
8.
EJNMMI Res ; 7(1): 101, 2017 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-29273939

RESUMEN

BACKGROUND: The clinical impact of hypoxia in solid tumours is indisputable and yet questions about the sensitivity of hypoxia-PET imaging have impeded its uptake into routine clinical practice. Notably, the binding rate of hypoxia-sensitive PET tracers is slow, comparable to the rate of diffusive equilibration in some tissue types, including mucinous and necrotic tissue. This means that tracer uptake on the scale of a PET imaging voxel-large enough to include such tissue and hypoxic cells-can be as much determined by tissue transport properties as it is by hypoxia. Dynamic PET imaging of 20 patients with pancreatic ductal adenocarcinoma was used to assess the impact of transport on surrogate metrics of hypoxia: the tumour-to-blood ratio [TBR(t)] at time t post-tracer injection and the trapping rate k 3 inferred from a two-tissue compartment model. Transport quantities obtained from this model included the vascular influx and efflux rate coefficients, k 1 and k 2, and the distribution volume v d ≡k 1/(k 2+k 3). RESULTS: Correlations between voxel- and whole tumour-scale k 3 and TBR values were weak to modest: the population average of the Pearson correlation coefficients (r) between voxel-scale k 3 and TBR (1 h) [TBR(2 h)] values was 0.10 [0.01] in the 20 patients, while the correlation between tumour-scale k 3 and TBR(2 h) values was 0.58. Using Patlak's formula to correct uptake for the distribution volume, correlations became strong (r=0.80[0.52] and r=0.93, respectively). The distribution volume was substantially below unity for a large fraction of tumours studied, with v d ranging from 0.68 to 1 (population average, 0.85). Surprisingly, k 3 values were strongly correlated with v d in all patients. A model was proposed to explain this in which k 3 is a combination of the hypoxia-sensitive tracer binding rate k b and the rate k eq of equilibration in slow-equilibrating regions occupying a volume fraction 1-v d of the imaged tissue. This model was used to calculate the proposed hypoxia surrogate marker k b. CONCLUSIONS: Hypoxia-sensitive PET tracers are slow to reach diffusive equilibrium in a substantial fraction of pancreatic tumours, confounding quantification of hypoxia using both static (TBR) and dynamic (k 3) PET imaging. TBR is reduced by distribution volume effects and k 3 is enhanced by slow equilibration. We proposed a novel model to quantify tissue transport properties and hypoxia-sensitive tracer binding in order to improve the sensitivity of hypoxia-PET imaging.

9.
Br J Cancer ; 115(6): 649-54, 2016 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-27467054

RESUMEN

BACKGROUND: FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre. METHODS: This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. RESULTS: One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002). CONCLUSIONS: Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/análisis , Antígeno CA-19-9/análisis , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Carcinoma Ductal Pancreático/secundario , Carcinoma Ductal Pancreático/cirugía , Cisplatino/administración & dosificación , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Sustitución de Medicamentos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Irinotecán , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Ontario , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Calidad de Vida , Sepsis/etiología , Resultado del Tratamiento
10.
J Nucl Med ; 57(3): 361-6, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26769863

RESUMEN

UNLABELLED: Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. METHODS: We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer (18)F-fluoroazomycin arabinoside (or (18)F-1-α-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [(18)F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. RESULTS: Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. CONCLUSION: Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents.


Asunto(s)
Hipoxia/diagnóstico por imagen , Nitroimidazoles/farmacocinética , Neoplasias Pancreáticas/diagnóstico por imagen , Radiofármacos/farmacocinética , Anciano , Anciano de 80 o más Años , Algoritmos , Femenino , Humanos , Hipoxia/etiología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Metástasis de la Neoplasia/diagnóstico por imagen , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/complicaciones , Tomografía de Emisión de Positrones , Flujo Sanguíneo Regional
11.
BJU Int ; 110(6): 840-5, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22313860

RESUMEN

UNLABELLED: What's known on the subject? and What does the study add? To date, there has been limited impetus to examine the use of cytarabine in prostate cancer. We presented preliminary laboratory data to suggest its utility in the castration refractory prostate cancer (CRPC) population which, combined with a previous case report, suggested it may have hitherto unrecognized utility in this setting. Embedded in this study was peripheral blood sampling for TMPRSS2-ERG and SPINK1, two genes that are believed to define prostate cancer genotypes, to assess their utility as biomarkers This study suggests that at the delivered doses, cytarabine has limited efficacy and significant myelotoxicity suggesting, it does not have a role in the treatment of docetaxel-refractory CRPC. The presence of serum TMPRSS2-ERG and SPINK1 mRNA biomarkers recovered from blood suggest that their analysis is worthy of further study. OBJECTIVES: To run a phase II clinical trial of cytarabine in men with docetaxel-refractory, castration-resistant prostate cancer (CRPC), based on evidence that cytarabine might be effective in men with abnormalities of ERG oncogenes. To measure mRNA levels of prostate cancer-related genes in blood as biomarkers. PATIENTS AND METHODS: Ten of a planned maximum of 30 men received i.v. cytarabine at doses of 0.25-1g/m(2) at 21-day intervals. The primary endpoint was prostate-specific antigen (PSA) response. Archival tumour samples were assessed by fluorescence in-situ hybridization for TMPRSS2:ERG translocation, and by immunohistochemistry for serine peptidase inhibitor Kazal type 1 (SPINK1). Blood was processed for mRNA quantification of TMPRSS2:ERG (exon1:exon4), SPINK1 and PSA. RESULTS: A PSA response was not observed in any patient. The trial was stopped at the end of stage 1 of a modified Flemming design. The median number of cycles administered was 3. Grade 3-4 haematological toxicity was common. Five patients were subsequently excluded from the study for toxicity, and five for disease progression. Analysis of whole blood mRNA for T1:E4 translocation in TMPRSS2:ERG was consistent with that in the tumour in 8/9 evaluable cases (one was concordantly positive, seven were concordantly negative), SPINK1 results were concordant in 9/10 cases (two were concordantly positive, seven were concordantly negative [P = 0.047 for the predictive value]). There was no correlation between PSA or SPINK protein and their respective mRNA copy levels in blood. CONCLUSIONS: Cytarabine at the doses used is ineffective for men with CRPC. Blood mRNA levels of prostate cancer genes may represent a novel aspect of monitoring prostate cancer and have implications for the understanding of tumour-derived mRNA.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Proteínas Portadoras/genética , Citarabina/uso terapéutico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , ARN Mensajero/sangre , Serina Endopeptidasas/genética , Transactivadores/genética , Anciano , Antineoplásicos/uso terapéutico , Biomarcadores/sangre , Castración , Docetaxel , Resistencia a Antineoplásicos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/genética , Taxoides/uso terapéutico , Regulador Transcripcional ERG , Inhibidor de Tripsina Pancreática de Kazal
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