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1.
BMC Cancer ; 22(1): 508, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35524184

RESUMO

BACKGROUND: A high percentage of epithelial ovarian cancers (EOC) express the estrogen receptor (ER), which is an ideal target for endocrine therapy. Letrozole is a proven, potent aromatase inhibitor, extensively tested and used in the treatment of ER positive breast cancer. In addition, it seems a potent drug for patients with heavily pre-treated OC as demonstrated in several distinctive settings. However, it has never been evaluated prospectively in a maintenance setting for ovarian cancer after standard of care. The here proposed trial aims to define a population of EOC patients, who would benefit from the effectiveness of the generic agent letrozole, with little expected toxicity and thus beneficial impact on overall quality of life (QoL). METHODS: In this international multicenter randomized, placebo-controlled phase III trial at clinical centers in Switzerland, Germany and Austria, we plan to include 540 patients with primary, newly diagnosed FIGO Stage II to IV and histologically confirmed low- or high-grade serous or endometrioid epithelial ovarian/fallopian tube/peritoneal cancer. Patients are randomized in a 1:1 ratio into two groups: receiving blinded study treatment (letrozole or placebo tablets). When assuming a HR of 0.7, a median PFS of 18 months in the control arm and a median PFS of 25.7 months in the treatment arm, a two-sided alpha level of 5%, 3.5 years recruitment and 1.5 years observation time, we expect 330 events to have occurred within these 5 years in the total cohort yielding a power of 90%. Follow-up data for the whole cohort will be collected for up to 10 years and for the low-grade cancer for up to 12 years. DISCUSSION: The here proposed randomized phase III trial aims to identify patients with EOC in the maintenance setting, who benefit from the effectiveness of the letrozole, by proving its efficacy whilst maintaining a high standard of QoL due to the limited toxicity expected in comparison to the current alternative drugs on the market for this treatment phase. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov under the identifier NCT04111978 . Registered 02 October 2019.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Humanos , Letrozol/uso terapêutico , Estudos Multicêntricos como Assunto , Neoplasias Ovarianas/tratamento farmacológico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
World J Surg Oncol ; 20(1): 42, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35189907

RESUMO

BACKGROUND: Lateral excess tissue after mastectomy is a frequent problem, which should be included into preoperative planning. Women with lateral tissue abundance are frequently impaired cosmetically and functionally. We suggest a novel oncoplastic mastectomy technique to eliminate the above mentioned. METHODS: Surgical technique Two small horizontal lines are drawn, one line above and one line below the Nipple Areola Complex. These lines should represent the possible skin excision and allow tight skin closure. Consecutively, two ending points of the incision are planned, one close to the xyphoid area and the other one in the anterior axillary line. These points are then interconnected in an s-shaped manner to form a double s-shaped skin excision. RESULTS: The double S-shaped technique is an easy reproducible technique which not only allows good access to the lateral side of the mastectomy, but also and mainly the reduction of lateral fat and skin. CONCLUSION: The double S mastectomy allows for simultaneous removal of access in the axillary region, eliminating skin, and fat as needed and preventing the lateral dog ear.


Assuntos
Neoplasias da Mama , Mamoplastia , Neoplasias da Mama/cirurgia , Estética , Feminino , Humanos , Mamoplastia/métodos , Mastectomia/métodos , Mamilos/cirurgia
3.
Breast Care (Basel) ; 16(5): 452-460, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34720804

RESUMO

BACKGROUND: The aim of this study was to compare the risk of complications and recurrence between oncoplastic and conventional breast surgery. METHODS: This is a retrospective analysis of a consecutive series of 436 patients with stage I-III breast cancer who underwent surgery at the University Hospital of Basel between 2011 and 2018. RESULTS: The nipple/skin-sparing mastectomy (NSM/SSM) group showed significantly more delayed wound healing (32.7 vs. 5.8%, p < 0.001) and skin necrosis (13.9 vs. 1.9%, p = 0.020) compared to conventional mastectomy (CM), which corresponded to significantly higher odds of short-term complications (OR 2.34, 95% CI 1.02-5.35, p = 0.044). The incidence rate of long-term morbidity in oncoplastic breast-conserving surgery (OBCS) was significantly higher compared to conventional breast-conserving surgery (CBCS; 25.5 vs. 11.3 per 100 patient years [PY], p < 0.001), in particular concerning chronic pain (13.3 vs. 6.6, p = 0.011) and lymphedema (4.1 vs. 0.4, p = 0.003). Seroma as a long-term morbidity occurred more often in the CM group compared to the NSM/SSM group (5.8 vs. 0.5 per 100 PY, p = 0.004). Patients received adjuvant treatment earlier after CM compared to NSM/SSM (HR 1.83, 95% CI 1.05-3.19, p = 0.034). There were no significant differences in the incidence of positive margins nor in the odds of recurrence after OBCS versus CBCS and after NSM/SSM versus CM. CONCLUSIONS: Even though the present study confirmed expected differences in complications and morbidity, it suggested that oncoplastic surgery is oncologically safe. Patients undergoing NSM/SSM should be followed closely to allow early detection and treatment of frequently associated complications and ensure timely start of adjuvant therapy.

5.
Breast ; 60: 98-110, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34555676

RESUMO

AIM: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. METHODS: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. RESULTS: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. CONCLUSIONS: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.


Assuntos
Neoplasias da Mama , Axila/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Viabilidade , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Estadiamento de Neoplasias , Estudos Prospectivos , Biópsia de Linfonodo Sentinela
6.
BMJ Open ; 11(9): e045239, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475143

RESUMO

INTRODUCTION: The emphasis on aesthetic outcomes and quality of life (QoL) has motivated surgeons to develop skin-sparing or nipple-sparing mastectomy (SSM/ NSM) for breast cancer treatment or prevention. During the same operation, a so-called immediate breast reconstruction is performed. The breast can be reconstructed by positioning of a breast implant above (prepectoral) or below (subpectoral) the pectoralis major muscle or by using the patients' own tissue (autologous reconstruction). The optimal positioning of the implant prepectoral or subpectoral is currently not clear. Subpectoral implant-based breast reconstruction (IBBR) is still standard care in many countries, but prepectoral IBBR is increasingly performed. This heterogeneity in breast reconstruction practice is calling for randomised clinical trials (RCTs) to guide treatment decisions. METHODS AND ANALYSIS: International, pragmatic, multicentre, randomised, superiority trial. The primary objective of this trial is to test whether prepectoral IBBR provides better QoL with respect to long-term (24 months) physical well-being (chest) compared with subpectoral IBBR for patients undergoing SSM or NSM for prevention or treatment of breast cancer. Secondary objectives will compare prepectoral versus subpectoral IBBR in terms of safety, QoL and patient satisfaction, aesthetic outcomes and burden on patients. Total number of patients to be included: 372 (186 per arm). ETHICS AND DISSEMINATION: This study will be conducted in compliance with the Declaration of Helsinki. Ethical approval has been obtained for the lead investigator's site by the Ethics Committee 'Ethikkommission Nordwest- und Zentralschweiz' (2020-00256, 26 March 2020). The results of this study will be published in a peer-reviewed medical journal, independent of the results, following the Consolidated Standards of Reporting Trials standards for RCTs and good publication practice. Metadata describing the type, size and content of the datasets will be shared along with the study protocol and case report forms on public repositories adhering to the FAIR (Findability, Accessibility, Interoperability, and Reuse) principles. TRIAL REGISTRATION NUMBER: NCT04293146.


Assuntos
Implante Mamário , Implantes de Mama , Neoplasias da Mama , Mamoplastia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia , Mamilos/cirurgia
7.
Nature ; 594(7864): 566-571, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34079127

RESUMO

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1-3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis4 that is often associated with a poor prognosis5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.


Assuntos
Neoplasias da Mama/patologia , Células Estreladas do Fígado/citologia , Células Matadoras Naturais/citologia , Animais , Linhagem Celular Tumoral , Quimiocina CXCL12/metabolismo , Técnicas de Cocultura , Feminino , Humanos , Imunoterapia , Interferon gama , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Neoplasias Experimentais/patologia , Proteômica , Transcriptoma , Microambiente Tumoral
8.
Br J Cancer ; 125(1): 23-27, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33762721

RESUMO

Circulating tumour cell (CTC) clusters have been proposed to be major players in the metastatic spread of breast cancer, particularly during advanced disease stages. Yet, it is unclear whether or not they manifest in early breast cancer, as their occurrence in patients with metastasis-free primary disease has not been thoroughly evaluated. In this study, exploiting nanostructured titanium oxide-coated slides for shear-free CTC identification, we detect clustered CTCs in the curative setting of multiple patients with early breast cancer prior to surgical treatment, highlighting their presence already at early disease stages. These results spotlight an important aspect of metastasis biology and the possibility to intervene with anti-cluster therapeutics already during the early manifestation of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Titânio/química , Neoplasias da Mama/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Humanos , Nanoestruturas , Metástase Neoplásica , Estadiamento de Neoplasias
9.
Lancet Oncol ; 21(8): e375-e385, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32758475

RESUMO

The aims of the Oncoplastic Breast Consortium initiative were to identify important knowledge gaps in the field of oncoplastic breast-conserving surgery and nipple-sparing or skin-sparing mastectomy with immediate breast reconstruction, and to recommend appropriate research strategies to address these gaps. A total of 212 surgeons and 26 patient advocates from 55 countries prioritised the 15 most important knowledge gaps from a list of 38 in two electronic Delphi rounds. An interdisciplinary panel of the Oncoplastic Breast Consortium consisting of 63 stakeholders from 20 countries obtained consensus during an in-person meeting to select seven of these 15 knowledge gaps as research priorities. Three key recommendations emerged from the meeting. First, the effect of oncoplastic breast-conserving surgery on quality of life and the optimal type and timing of reconstruction after nipple-sparing or skin-sparing mastectomy with planned radiotherapy should be addressed by prospective cohort studies at an international level. Second, the role of adjunctive mesh and the positioning of implants during implant-based breast reconstruction should ideally be investigated by randomised controlled trials of pragmatic design. Finally, the BREAST-Q questionnaire is a suitable tool to assess primary outcomes in these studies, but other metrics to measure patient-reported outcomes should be systematically evaluated and quality indicators of surgical morbidity should be further assessed.


Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia , Feminino , Humanos
10.
Int J Gynecol Cancer ; 30(12): 1997-2001, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32606097

RESUMO

BACKGROUND: Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment. PRIMARY OBJECTIVE: To test if the activity of non-platinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab. STUDY HYPOTHESIS: The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months. TRIAL DESIGN: Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PD-L1) status. MAJOR INCLUSION/EXCLUSION CRITERIA: Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatment-free interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria. PRIMARY ENDPOINT: Overall survival and progression-free survival are co-primary endpoints. SAMPLE SIZE: It is planned to randomize 664 patients. TRIAL REGISTRATION: NCT03353831.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Eur J Cancer Prev ; 29(1): 53-59, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30998527

RESUMO

One in five women will experience depression over her lifetime, and one out of eight will develop breast cancer. We evaluated the effect of depression on adherence to mammography in Switzerland, where opportunistic and organized screening programs coexist. We analyzed data from 3206 women aged 50-69 who participated in the Swiss Health Survey 2012. We compared mammographic rates among women with no to mild versus moderate to severe depressive symptoms. The effect of the type of screening on the odds of undertaking a mammography was calculated using multivariable logistic regression analysis. Women with moderate to severe major depressive symptoms were more likely to have had a mammography in the previous 2 years than their nondepressed or less-depressed counterparts (51 vs. 39.2%, respectively, P = 0.005). In the multivariable analysis, women with no to mild major depression living in cantons with an organized screening program had an adjusted odds ratio of 2.7 (95% confidence interval: 2.30-3.17, P < 0.001) of having had a mammography within the past 24 months compared with those living in the regions with an opportunistic screening. The adjusted odds ratio for women with moderate to severe major depression was 4.21 (95% confidence interval: 2.13-8.33, P < 0.001). In Switzerland. adherence to mammographic screening among women with moderate to severe major depression is higher than among women with no or minimal major depressive symptoms. This increased adherence is even more pronounced in regions with organized screening.


Assuntos
Neoplasias da Mama/prevenção & controle , Transtorno Depressivo Maior/epidemiologia , Detecção Precoce de Câncer/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Idoso , Neoplasias da Mama/diagnóstico , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Detecção Precoce de Câncer/psicologia , Detecção Precoce de Câncer/normas , Feminino , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Mamografia/psicologia , Mamografia/normas , Mamografia/estatística & dados numéricos , Programas de Rastreamento/organização & administração , Programas de Rastreamento/psicologia , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia , Questionário de Saúde do Paciente/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença , Suíça/epidemiologia
12.
Clin Cancer Res ; 26(1): 213-219, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31527166

RESUMO

PURPOSE: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome. EXPERIMENTAL DESIGN: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status. RESULTS: A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent de novo signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology. CONCLUSIONS: Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker.See related commentary by Handley and Sood, p. 9.


Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Biomarcadores , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Estadiamento de Neoplasias
13.
Front Med (Lausanne) ; 6: 200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572728

RESUMO

Background: Triple-negative breast cancer (TNBC) represents about 10-20% of all invasive breast cancers and is associated with a poor prognosis. The nectin cell adhesion protein 4 (Nectin-4) is a junction protein involved in the formation and maintenance of cell junctions. Nectin-4 has previously shown to be expressed in about 60% of TNBC as well as in TNBC metastases, but to be absent in normal breast tissue, which makes it a potential specific target for TNBC therapy. Previous studies have shown an association of Nectin-4 protein expression with worse prognosis in TNBC in a small patient cohort. The aim of our study was to explore the role of Nectin-4 in TNBC and confirm its impact on survival in a larger TNBC patient cohort. Material and Methods: We performed immunohistochemical staining for Nectin-4 on a tissue microarray encompassing 148 TNBC cases with detailed clinical annotation and outcomes data. Results: A high expression of Nectin-4 was present in 86 (58%) of the 148 TNBC cases. In multivariate survival analysis, high expression of Nectin-4 was associated with a significantly better overall survival when compared with low expression of Nectin-4 (p < 0.001). Nectin-4-high expression was also significantly associated with a lower tumor stage (p = 0.025) and pN0 lymph node stage (p = 0.034). Conclusion: Our results confirm that expression of Nectin-4 serves as a potential prognostic marker in TNBC and is associated with a significantly better overall survival. In addition, Nectin-4 represents a potential target in TNBC, and its role in molecular defined breast cancer subtype should be investigated in larger patient cohorts.

14.
Int J Gynecol Cancer ; 29(7): 1141-1147, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31420414

RESUMO

INTRODUCTION: The PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes. PATIENTS AND METHODS: Eligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression. RESULTS: At database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms. DISCUSSION: Consistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes. ClinicalTrials.gov: ClinicalTrials.gov: NCT01684878.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , RNA Mensageiro/biossíntese , Receptor ErbB-3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Paclitaxel/administração & dosagem , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , RNA Mensageiro/genética , Receptor ErbB-3/biossíntese , Topotecan/administração & dosagem
15.
Eur J Cancer ; 117: 99-106, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31279306

RESUMO

BACKGROUND: Platinum-resistant ovarian cancer (PROC) is associated with a variable prognosis and unpredictable survival times. We have developed and validated a prognostic nomogram with the objective of improving the prediction of overall survival (OS) in patients treated with chemotherapy. METHODS: The nomogram was developed using data from a training cohort of patients from two trials, including the chemotherapy-only arm in AURELIA and all randomised patients in CARTAXHY. Multivariable proportional hazards models were generated based on pretreatment characteristics to develop a nomogram that classifies patients based on OS. We subsequently assessed the performance of the nomogram in terms of discrimination and calibration in independent validation patient cohorts: PENELOPE and the bevacizumab-chemotherapy arm of AURELIA. RESULTS: The nomogram included six significant OS predictors, in order of importance: performance status, ascites, size of the largest tumour, CA-125, platinum-free interval and primary platinum resistance (C-statistic 0.69). In the training cohort, the median OS in the good, intermediate and poor prognosis groups was 25.3, 15.2 and 7.4 months, respectively. In the PENELOPE validation cohort (C-statistic 0.59), the median OS in the good, intermediate and poor prognosis groups was 18.5, 10.3 and 5.8 months, respectively. In the AURELIA bevacizumab-chemotherapy validation cohort (C-statistic 0.67), the median OS in good, intermediate and poor prognosis groups was 26.7, 13.8 and 10.0 months, respectively. CONCLUSIONS: This nomogram with six pretreatment characteristics allows prediction of OS in PROC and could be used for stratification of patients in clinical trials as well as for counselling patients about prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nomogramas , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida , Topotecan/administração & dosagem
16.
Clin Cancer Res ; 25(17): 5342-5350, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936122

RESUMO

PURPOSE: Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments. EXPERIMENTAL DESIGN: Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) ± gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP ± topotecan; n = 192); and ICON7 (validation set: CP ± bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses. RESULTS: The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM ≥ upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. <35 months). CONCLUSIONS: Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment-related variations in a GCIG meta-analysis is warranted.See related commentary by Maitland et al., p. 5182.


Assuntos
Antígeno Ca-125/sangue , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/sangue , Carboplatina/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Estudos Longitudinais , Modelos Estatísticos , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taxa de Sobrevida
17.
Nature ; 566(7745): 553-557, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728496

RESUMO

A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies1. However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized2,3. Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer4-6, and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs)7,8. The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC-WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell-cell junction and cytokine-receptor pairs that define CTC-neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Ciclo Celular , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes/patologia , Neutrófilos/patologia , Animais , Neoplasias da Mama/terapia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Junções Intercelulares , Camundongos , Mutação/genética , Metástase Neoplásica/genética , Células Neoplásicas Circulantes/metabolismo , Neutrófilos/metabolismo , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
19.
Cell ; 176(1-2): 98-112.e14, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30633912

RESUMO

The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.


Assuntos
Neoplasias da Mama/genética , Metástase Neoplásica/genética , Células Neoplásicas Circulantes/patologia , Animais , Neoplasias da Mama/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Proteína Homeobox Nanog/metabolismo , Metástase Neoplásica/fisiopatologia , Células Neoplásicas Circulantes/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Complexo Correpressor Histona Desacetilase e Sin3
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