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1.
J Oncol Pract ; 15(12): e1066-e1075, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31550202

RESUMEN

PURPOSE: Malignant bowel obstruction (MBO) is a common and distressing complication in women with advanced gynecologic cancer. A pilot, interprofessional MBO program was launched in 2016 at a large Canadian tertiary cancer center to integrate these patients' complex care needs across multiple disciplines and support women with MBO. METHOD: Retrospective analysis to evaluate the outcomes of women with advanced gynecologic cancer who were admitted to hospital because of MBO, before (2014 to 2016: baseline group) and after (2016 to 2018) implementation of the MBO program. RESULTS: Of the 169 women evaluated, 106 and 63 were in the baseline group and MBO program group, respectively. Most had ovarian cancer (n = 124; 73%) and had small-bowel obstruction (n = 131; 78%). There was a significantly shorter cumulative hospital length of stay (LOSsum) within the first 60 days of MBO diagnosis in the MBO program group compared with the baseline group (13 v 22 days, respectively; adjusted P = .006). The median overall survival for women treated in the MBO program was also significantly longer compared with the baseline group (243 v 99 days, respectively; adjusted P = .002). Using the interprofessional MBO care platform, a greater proportion of patients received palliative chemotherapy (83% v 56%) and less surgery (11% v 21%) in the MBO program group than in the baseline group, respectively. A subgroup of women (n = 11) received total parenteral nutrition for longer than 6 months. CONCLUSION: Implementation of a comprehensive, interprofessional MBO program significantly affects patient care and may improve outcomes. Unique to this MBO program is an integrated outpatient model of care and education that empowers patients to recognize MBO symptoms for early intervention.

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.
Genome Med ; 10(1): 81, 2018 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-30382883

RESUMEN

BACKGROUND: Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percentage of women experience exceptional long-term survival (long term (LT), 10+ years), while others develop primary resistance to therapy and succumb to disease in less than 2 years (short term (ST)). To improve clinical management of HGSOC, there is a need to better characterize clinical and molecular profiles to identify factors that underpin these disparate survival responses. METHODS: To identify clinical and tumor molecular biomarkers associated with exceptional clinical response or resistance, we conducted an integrated clinical, exome, and transcriptome analysis of 41 primary tumors from LT (n = 20) and ST (n = 21) HGSOC patients. RESULTS: Younger age at diagnosis, no residual disease post debulking surgery and low CA125 levels following surgery and chemotherapy were clinical characteristics of LT. Tumors from LT survivors had increased somatic mutation burden (median 1.62 vs. 1.22 non-synonymous mutations/Mbp), frequent BRCA1/2 biallelic inactivation through mutation and loss of heterozygosity, and enrichment of activated CD4+, CD8+ T cells, and effector memory CD4+ T cells. Characteristics of ST survival included focal copy number gain of CCNE1, lack of BRCA mutation signature, low homologous recombination deficiency scores, and the presence of ESR1-CCDC170 gene fusion. CONCLUSIONS: Our findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.


Asunto(s)
Supervivientes de Cáncer , Genoma Humano , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína BRCA1/genética , Proteína BRCA2/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación/genética , Clasificación del Tumor , Proteínas de Fusión Oncogénica/genética , Factores de Tiempo , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética
4.
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
5.
Int J Gynecol Cancer ; 27(8): 1619-1627, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28692635

RESUMEN

OBJECTIVES: The Response Evaluation Criteria in Solid Tumors (RECIST) International Working Group developed criteria for tumor response and progression to standardize radiological assessment in patients receiving chemotherapy in phase 2 trials. However, it is unclear whether the defined percentage change in tumor size and volume reflects true clinical benefit for the patient. The RECIST criteria were designed to improve objectivity in trials, but not to replace clinical decision making. The aim of this study was to understand clinicians' opinions about RECIST in current oncology practice. METHODS: Using Web-based questionnaires, we investigated attitudes to the use of RECIST at a large comprehensive cancer center and in an international group of gynecologic cancer specialists through the Gynecologic Cancer InterGroup. The results reported here relate to the survey focusing on gynecologic cancer. RESULTS: Sixty medical professionals from 13 countries responded to the survey. The majority of respondents worked at a tertiary or specialist cancer center (51; 86%). Overall, 66% of respondents felt RECIST increased trial objectivity and was a good measure of response. The majority of respondents (81%) reported that they infrequently challenged RECIST evaluation. Overall, 60% felt more than 10% of patients came off trial for clinical rather than radiological progression. In the context of a new small lesion, only 35% felt that should always be considered disease progression. The importance of both clinician and radiologist input was highlighted with nontarget progression. Nontarget progression and target progression were recognized as equally important for clinical decision making (72%). CONCLUSIONS: RECIST is a key criterion for endpoint assessment in clinical trials with its value recognized by clinicians. However, this survey also highlights the practical limitations of RECIST. Disconnect can be seen between the radiological result and the clinical picture-learning from these patients is critical. Continued efforts to improve metrics assessing patient benefit in trials remains a priority.


Asunto(s)
Ensayos Clínicos Fase II como Asunto/métodos , Neoplasias de los Genitales Femeninos/diagnóstico por imagen , Neoplasias de los Genitales Femeninos/terapia , Criterios de Evaluación de Respuesta en Tumores Sólidos , Actitud del Personal de Salud , Toma de Decisiones Clínicas , Femenino , Humanos , Internet , Encuestas y Cuestionarios
6.
Expert Opin Biol Ther ; 17(8): 927-943, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28641048

RESUMEN

INTRODUCTION: Ovarian cancer (OC) is the second most common and the most lethal of the gynecological malignancies. Currently, there exists no effective screening tool for OC. MicroRNAs (miRNAs) are endogenous 18-23 nucleotide non-coding RNAs that refine gene expression. MiRNAs have been found to be aberrantly expressed in OC tumor tissue as well as detectable in biological fluids such as the blood, urine, and ascites and have been proposed as biomarkers and therapeutic targets for OC. Areas covered: This review summarizes the current knowledge regarding the application of miRNAs as diagnostic, prognostic, and predictive biomarkers in OC. It describes the various tissues allowing for the analysis of miRNAs such as tumor tissue, blood, ascites and urine. It also highlights the potential of miRNAs as a therapy in other cancers and how these therapies may be applied to ovarian cancer. Expert opinion: The study of miRNAs is an innovative and promising field for the diagnosis and treatment of ovarian cancer. Methodological issues surrounding their detection and application therapeutically remain, such as the study of various OC histotypes within the same cohort, the choice of 'normal tissue' for comparison and the difficulties surrounding the choice of a normalization miRNA.


Asunto(s)
Biomarcadores de Tumor/análisis , MicroARNs/análisis , Neoplasias Ováricas/diagnóstico , Medicina de Precisión , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/orina , Ensayos Clínicos como Asunto , Bases de Datos Factuales , Femenino , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/uso terapéutico , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Pronóstico
7.
Clin Cancer Res ; 23(15): 4086-4094, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28223274

RESUMEN

Purpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib.Experimental Design: A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as <3 months. Molecular analyses included germline BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort.Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (>42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation.Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. Clin Cancer Res; 23(15); 4086-94. ©2017 AACR.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación
8.
J Clin Oncol ; 35(11): 1240-1249, 2017 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-28221868

RESUMEN

Purpose Durable and long-term responses to the poly (ADP-ribose) polymerase inhibitor olaparib are observed in patients without BRCA1/2 mutations. However, beyond BRCA1/2 mutations, there are no approved biomarkers for olaparib in high-grade serous ovarian cancer (HGSOC). To determine mechanisms of durable response and resistance to olaparib therapy, we performed an analysis of HGSOC tumors from three patients without germline BRCA1/2 mutations who experienced exceptional responses to olaparib. Patients and Methods We performed integrated exome, low-pass genome, and RNA sequence analysis of tumors at diagnosis and upon relapse from patients with platinum-sensitive HGSOC recurrence who were treated > 5 years with olaparib therapy as a single agent. Results We observed somatic disruption of BRCA1/2 in all three patients at diagnosis, followed by subsequent BRCA recovery upon progression by copy number gain and/or upregulation of the remaining functional allele in two patients. The third patient with ongoing response (> 7 years) had a tumor at diagnosis with biallelic somatic deletion and loss-of-function mutation, thereby lacking a functional allele for recovery of BRCA1 activity and indicating a potential cure. Conclusion Olaparib has durable benefit for patients with ovarian cancer beyond germline BRCA1/2 carriers. These data suggest that biallelic loss of BRCA1/2 in cancer cells may be a potential marker of long-term response to poly (ADP-ribose) polymerase inhibition and that restoration of homologous repair function may be a mechanism of disease resistance.


Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Anciano , Alelos , Análisis Mutacional de ADN , Exoma , Femenino , Dosificación de Gen , Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Reparación del ADN por Recombinación , Análisis de Secuencia de ARN , Resultado del Tratamiento , Regulación hacia Arriba
9.
Front Oncol ; 6: 119, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27242959

RESUMEN

Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities, where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much-needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer and those at risk of developing cancer but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many of which are now being found to have BRCA1/2 involvement.

10.
Curr Oncol Rep ; 18(4): 23, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26922329

RESUMEN

Endometrial cancer is the most common gynecological malignancy in Europe and North America. Metastatic and recurrent disease is generally incurable with poor prognosis. Recent advances in molecular profiling of endometrial cancer have elucidated four distinct molecular subtypes with different biology and prognosis which should facilitate the development of treatments tailored to disease-specific subgroups. To date, some molecular-targeted agents have shown interesting clinical activity in the recurrent setting, but no targeted therapies are approved for endometrial cancer. Novel pan-PI3K, AKT, and dual PI3K-mTOR inhibitors are being investigated with early signs of activity, but there are concerns about tolerability and toxicity in this often elderly patient population with comorbidities. The development of anti-angiogenic therapies, PARP inhibitors, and immunotherapies, alone or in combinations, appear to be promising strategies. This paper will describe the current evidence supporting the efficacy of molecular-targeted agents already tested in the treatment of metastatic and recurrent EC, and provide some insights on emerging data related to novel-targeted therapies.


Asunto(s)
Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/inmunología , Inmunoterapia , Terapia Molecular Dirigida , Terapia Combinada , Neoplasias Endometriales/patología , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética
11.
Expert Opin Pharmacother ; 17(8): 1063-76, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26918413

RESUMEN

INTRODUCTION: Epithelial ovarian cancer is the most lethal gynecologic malignancy. Recent advances in understanding the biology and its molecular and histological diversity have led to mechanism based therapeutic strategies such as poly-ADP-ribose polymerase inhibitors (PARP) targeting homologous recombination deficient tumor cells and anti-angiogenic therapies. Clinical trial designs in ovarian cancer have to evolve to incorporate assessment of the genomic complexity and identify predictive biomarkers to improve precision of treatment and outcome. AREAS COVERED: This review summarizes present-day strategies used in the management of ovarian cancer and novel promising therapeutic approaches in development. The article is based on English peer-reviewed articles located on MEDLINE and related abstracts presented at major international meetings. EXPERT OPINION: Two types of molecular targeted therapies, anti-angiogenics and PARP inhibitors, have been shown to be active in randomized clinical trials and approved by regulatory agencies. Management of ovarian cancer is poised to change with the continued advancement of precision medicine that is founded upon improved understanding of disease biology; separation into histologically and molecularly defined subgroups; and the incorporation of this new knowledge into early phase drug development and novel clinical trial design.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Femenino , Humanos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico
12.
Cancer ; 121(18): 3203-11, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26096019

RESUMEN

The diagnosis, investigation, and management of ovarian cancer are in a state of flux-balancing ever rapid advances in our understanding of its biology with 3 decades of clinical trials. Clinical trials that started with empirically driven selections have evolved in an evidence-informed manner to gradually improve outcome. Has this improved understanding of the biology and associated calls to action led to appropriate changes in therapy? In this review, the authors discuss incorporating emerging data on biology, combinations, dose, and scheduling of new and existing agents with patient preferences in the management of women with ovarian cancer.


Asunto(s)
Medicina Basada en la Evidencia , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Humanos
13.
Expert Opin Drug Saf ; 14(8): 1305-16, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26051946

RESUMEN

INTRODUCTION: Olaparib (Lynparza®) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor that has become the first 'personalized' therapy available for patients with BRCA mutation-positive ovarian cancer (OC). A capsule formulation of the drug has recently received approval for use in this population for platinum-sensitive recurrent disease for maintenance therapy following platinum-based chemotherapy in Europe and as third- or fourth-line platinum-sensitive therapy in the USA. AREAS COVERED: This article reviews the development of olaparib in OC with a focus on safety evaluation. Data are based on published literature and reports available from the olaparib development program database. EXPERT OPINION: Oral olaparib 400 mg twice daily has acceptable tolerability when administered as maintenance monochemotherapy in women with relapsed OC. The common toxicities - nausea/vomiting, fatigue and anemia - are mild or moderate in severity and appear consistent across subgroups (BRCA carriers/wild-type). Though the risk is low, long-term monitoring of patients is warranted to determine the potential risk for hematological complications such as anemia, myelodysplastic syndrome or acute myeloid leukemia.


Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Monitoreo de Drogas/métodos , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Medicina de Precisión
15.
Cancer ; 121(18): 3360-1, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26079099
16.
Lancet Oncol ; 16(1): e32-42, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25638553

RESUMEN

Cancer treatment should allow patients to live better or longer lives, and ideally, both. Trial endpoints should show clinically meaningful improvements in patient survival or quality of life. Alternative endpoints such as progression-free survival, disease-free survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is controversial. In this Review we discuss the measurement, assessment, and benefits and limitations of trial endpoints in use for cancer treatment. Many stakeholders are affected, including regulatory agencies, industry partners, clinicians, and most importantly, patients. In an accompanying Review, reflections from individual stakeholders are incorporated into a discussion of what the future holds for clinical trial endpoints and design.


Asunto(s)
Ensayos Clínicos como Asunto/tendencias , Determinación de Punto Final/tendencias , Neoplasias/terapia , Proyectos de Investigación/tendencias , Ensayos Clínicos como Asunto/historia , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Determinación de Punto Final/historia , Predicción , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Neoplasias/mortalidad , Neoplasias/patología , Calidad de Vida , Factores de Tiempo , Resultado del Tratamiento
17.
Lancet Oncol ; 16(1): e43-52, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25638556

RESUMEN

Cancer is not one disease. Outcomes and endpoints in trials should incorporate the therapeutic modality and cancer type because these factors affect clinician and patient expectations. In this Review, we discuss how to: define the importance of endpoints; make endpoints understandable to patients; improve the use of patient-reported outcomes; advance endpoints to parallel changes in trial design and therapeutic interventions; and integrate these improvements into trials and practice. Endpoints need to reflect benefit to patients, and show that changes in tumour size either in absolute terms (response and progression) or relative to control (progression) are clinically relevant. Improvements in trial design should be accompanied by improvements in available endpoints. Stakeholders need to come together to determine the best approach for research that ensures accountability and optimises the use of available resources.


Asunto(s)
Ensayos Clínicos como Asunto/métodos , Determinación de Punto Final , Neoplasias/terapia , Proyectos de Investigación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Neoplasias/mortalidad , Neoplasias/patología , Calidad de Vida , Factores de Tiempo , Resultado del Tratamiento
18.
Cancer ; 120(4): 603-10, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24166148

RESUMEN

BACKGROUND: Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. METHODS: Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. RESULTS: Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14). CONCLUSIONS: No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents.


Asunto(s)
Neoplasias Endometriales/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
19.
Plant Cell Physiol ; 48(4): 655-61, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17327256

RESUMEN

Rhomboid proteases are present in bacteria, insects, yeasts, parasites, mammals and plants. These proteases are part of the regulated intramembrane proteolysis mechanism for controlling processes such as development, stress response, lipid metabolism and mitochondrial membrane remodeling. Specific rhomboid protease substrates linked to these processes have been identified from insects to mammals, but not for plants. Identification of a link is a key step for elucidating the role of each rhomboid protease. Here, using a yeast mitochondria-based approach, we report evidence of a potential link between a plastid translocon component and organellar rhomboid proteases. This identification expands the types of processes involving regulated intramembrane proteolysis potentially to include at least one aspect of plastid protein transport.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Chaperonas Moleculares/metabolismo , Péptido Hidrolasas/metabolismo , Plastidios/metabolismo , Saccharomyces cerevisiae/metabolismo , Arabidopsis/metabolismo , Ricinus/metabolismo
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