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1.
Cancer Immunol Immunother ; 73(7): 132, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38753055

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.


Assuntos
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Inibidores de Checkpoint Imunológico , Receptor ErbB-2 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/metabolismo , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Fase III como Assunto , Biomarcadores Tumorais/metabolismo
3.
Acta Oncol ; 63: 277-287, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38711384

RESUMO

BACKGROUND: Primary metastatic breast cancer (pMBC) accounts for 5-10% of annual breast cancers with a median survival of 3-4 years, varying among subtypes. In Denmark, the incidence of breast cancer increased until 2010, followed by a stabilisation. Several factors influencing pMBC incidence and survival, including screening prevalence, staging methods, and classification standards, remain pivotal but inadequately documented. MATERIAL AND METHOD: This retrospective observational study involving pMBC patients diagnosed between 2000 and 2020 encompassed all Danish oncology departments. Data from the Danish Breast Cancer Group database and the National Patient Register included diagnosis specifics, demographics, treatment, and follow-up. RESULTS: Between 2000 and 2020, 3,272 patients were diagnosed with pMBC, a rise from 355 patients in 2000-2004 to 1,323 patients in 2015-2020. The increase was particularly observed in patients aged 70 years or older. Changes in tumour subtypes were observed, notably with a rise in human epidermal growth factor receptor 2 (HER2)-positive cases but a steady distribution of estrogen receptor (ER) status. Diagnostic practices changed over the two decades, with 6% evaluated with PET/CT (positron emission tomography-computed tomography) or CT (computed tomography) with a bone evaluation in 2000-2004 and 65% in 2015-2020. Overall survival (OS) improved from 23 months in 2000-2004 to 33 months in 2015-2020. In patients with ER-positive and HER2-positive disease, the multivariable model showed improved survival by year of diagnosis, and further, patients with ER-negative/HER2-negative disease fared worse the first 2 years after diagnosis. INTERPRETATION: Our study delineates changes in the treatment and survival of pMBC over two decades. Stage migration, screening introduction, and changes in registration practice, however, prevent a valid assessment of a possible causal relationship.


Assuntos
Neoplasias da Mama , Detecção Precoce de Câncer , Estadiamento de Neoplasias , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/epidemiologia , Feminino , Dinamarca/epidemiologia , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Incidência , Adulto , Idoso de 80 Anos ou mais , Taxa de Sobrevida , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Metástase Neoplásica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análise
5.
Zhonghua Yi Xue Za Zhi ; 104(17): 1507-1513, 2024 May 07.
Artigo em Chinês | MEDLINE | ID: mdl-38706058

RESUMO

Objective: To evaluate the efficacy of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment in hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer. Methods: Patients with metastatic breast cancer diagnosed with HR positive/HER2 low expression at the Fifth Medical Center of PLA General Hospital from October 1, 2018 to September 30, 2023 were retrospectively included. All patients received sequential chemotherapy or sequential endocrine therapy combined with targeted drugs after progression on CDK4/6 inhibitor treatment.The median follow-up was 9 months, and the follow-up ended on October 31, 2023. The patients were divided into chemotherapy group (receiving sequential chemotherapy) and endocrine therapy group (receiving sequential endocrine therapy combined with targeted drugs), according to the treatment plan. Information on demographic data, clinical and pathological diagnosis, treatment regimen, and efficacy evaluation was collected. The basic conditions of patients who may affect the curative effect of different treatment schemes were preset as stratified subgroups, including age, progesterone receptor (PR) status, HER2 status, disease-free survival, number of previous endocrine therapy and chemotherapy, and visceral metastasis. The primary endpoint was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), clinical benefit rate(CBR) and PFS based on stratification factors. The survival curve was plotted by Kaplan-Meier method, the comparison of PFS between groups was performed by log-rank test, and the comparison of ORR and CBR between groups were performed by χ2 test. Results: A total of 188 patients were included, including 126 patients in the chemotherapy group [all females, aged 29-74 (51±10) years] and 62 patients in the endocrine therapy group [1 male and 61 female, aged 29-77 (51±12) years]. ORR of chemotherapy group was 23.0% (29/126), higher than that of endocrine treatment group [3.2% (2/62)] (P<0.001); The CBR of chemotherapy group and endocrine therapy group were 46.8% (59/126) and 33.9% (21/62), respectively, with no statistical significance (P=0.091). The median PFS of chemotherapy group and endocrine therapy group were 5.0 (95%CI: 4.3-5.7) and 4.0 (95%CI: 1.6-6.4) months, respectively, with no statistical significance (P=0.484). In the preset stratified subgroups, the median PFS of chemotherapy [6.0 (95%CI: 5.4-6.6) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 1.8-2.2) months] (P<0.001) in PR negative patients; In patients who had progressed on over 2 previous endocrine treatments, the median PFS of chemotherapy [5.0 (95%CI: 3.8-6.2) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 0.6-3.4) months] (P=0.045). Conclusions: After progression on treatment with CDK4/6 inhibitors for HR-positive/HER2-low expression metastatic breast cancer, both chemotherapy and endocrine therpy combined with targeted drugs are viable treatment options. However, for patients with PR negative or ≥2 lines of endocrine therapy previously, priority should be accorded to chemotherapy.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Receptor ErbB-2 , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo
6.
MAbs ; 16(1): 2324485, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38700511

RESUMO

Model-informed drug discovery advocates the use of mathematical modeling and simulation for improved efficacy in drug discovery. In the case of monoclonal antibodies (mAbs) against cell membrane antigens, this requires quantitative insight into the target tissue concentration levels. Protein mass spectrometry data are often available but the values are expressed in relative, rather than in molar concentration units that are easier to incorporate into pharmacokinetic models. Here, we present an empirical correlation that converts the parts per million (ppm) concentrations in the PaxDb database to their molar equivalents that are more suitable for pharmacokinetic modeling. We evaluate the insight afforded to target tissue distribution by analyzing the likely tumor-targeting accuracy of mAbs recognizing either epidermal growth factor receptor or its homolog HER2. Surprisingly, the predicted tissue concentrations of both these targets exceed the Kd values of their respective therapeutic mAbs. Physiologically based pharmacokinetic (PBPK) modeling indicates that in these conditions only about 0.05% of the dosed mAb is likely to reach the solid tumor target cells. The rest of the dose is eliminated in healthy tissues via both nonspecific and target-mediated processes. The presented approach allows evaluation of the interplay between the target expression level in different tissues that determines the overall pharmacokinetic properties of the drug and the fraction that reaches the cells of interest. This methodology can help to evaluate the efficacy and safety properties of novel drugs, especially if the off-target cell degradation has cytotoxic outcomes, as in the case of antibody-drug conjugates.


Assuntos
Anticorpos Monoclonais , Espectrometria de Massas , Humanos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/imunologia , Espectrometria de Massas/métodos , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores ErbB/imunologia , Receptores ErbB/antagonistas & inibidores , Distribuição Tecidual , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
7.
Nat Commun ; 15(1): 3684, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693181

RESUMO

The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.


Assuntos
Aptâmeros de Nucleotídeos , DNA Catalítico , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Humanos , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Linhagem Celular Tumoral , DNA Catalítico/metabolismo , DNA Catalítico/química , Animais , Receptor ErbB-2/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Reparo do DNA , Dano ao DNA , Glutationa/metabolismo , Glutationa/química , Ácidos Nucleicos/metabolismo , Ácidos Nucleicos/química
8.
Pol J Pathol ; 75(1): 8-18, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38741425

RESUMO

The use of chemotherapy in breast cancer management has significantly contributed to the decrease in its mortality. Currently, the prognosis is determined by molecular biomarkers, such as oestrogen receptors, and human epidermal growth factor receptor 2. However, the increasing use of advanced molecular technologies, including oncotype DX recurrence score (ODX-RS), has provided the ability to estimate the risk of recurrence. Research has demonstrated that the ODX-RS helps to predict recurrence risk and the potential benefit of chemotherapy in breast cancer. As a result, it can assist clinicians in making decisions regarding using the chemotherapy. The goal of work is to explore the correlation between the ODX-RS and Ki-67 proliferative index (Ki-67-PI). This study included 137 patients with oestrogen positive, human epidermal growth factor receptor 2-negative early breast cancer, and had non- or early axillary disease. Patients with low Ki-67-PI were as follows: low ODX-RS in 17%, intermediate ODX-RS in 80%, and high ODX-RS in 2%. In the high Ki-67-PI group: low ODX-RS in 12%, intermediate ODX-RS in 48%, and high ODX-RS in 40%. In conclusion, the results show no significant correlation between the ODX-RS and Ki-67-PI (r = 0.511, p-value < 0.9).


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Antígeno Ki-67 , Recidiva Local de Neoplasia , Receptor ErbB-2 , Receptores de Estrogênio , Humanos , Neoplasias da Mama/patologia , Feminino , Antígeno Ki-67/análise , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , Biomarcadores Tumorais/análise , Adulto , Recidiva Local de Neoplasia/patologia , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Idoso , Metástase Linfática/patologia , Proliferação de Células , Axila , Receptores de Progesterona/metabolismo , Receptores de Progesterona/análise , Idoso de 80 Anos ou mais
9.
Zhonghua Zhong Liu Za Zhi ; 46(5): 428-437, 2024 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-38742356

RESUMO

Objective: This study aims to explore the predictive value of T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC), and early-delayed phases enhanced magnetic resonance imaging (DCE-MRI) radiomics prediction model in determining human epidermal growth factor receptor 2 status in breast cancer. Methods: A retrospective study was conducted, involving 187 patients with confirmed breast cancer by postsurgical pathology at Zhenjiang First People's Hospital during January 2021 and May 2023. Immunohistochemistry or fluorescence in situ hybridization was used to determine the HER-2 status of these patients, with 48 cases classified as HER-2 positive and 139 cases as HER-2 negative. The training set was used to construct the prediction models and the validation set was used to verify the prediction models. Layers of T2WI, ADC, and early-delayed phase DCE-MRI images were used to delineate the volumeof interest and 960 radiomic features were extracted from each case using Pyradiomic. After screening and dimensionality reduction by intraclass correlation coefficient, Pearson correlation analysis, least absolute shrinkage, and selection operator, the radiomics labels were established. Logistic regression analysis was used to construct the T2WI radiomics model, ADC radiomics model, DCE-2 radiomics model, DCE-6 radiomics model, and the joint sequence radiomics model to predict the HER-2 expression status of breast cancer, respectively. Based on the clinical, pathological, and MRI image characteristics of patients, univariate and multivariate logistic regression analysis wasused to construct a clinicopathological MRI feature model. The radscore of every patient and the clinicopathological MRI features which were statistically significant after screening were used to construct a nomogram model. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of each model and the decision curve analysis wasused to evaluate the clinical usefulness. Results: The T2WI, ADC, DCE-2, DCE-6, and joint sequence radiomics models, the clinicopathological MRI feature model, and the nomogram model were successfully constructed to predict the expression status of HER-2 in breast cancer. ROC analysis showed that in the training set and validation set, the areas under the curve (AUC) of the T2WI radiomics model were 0.797 and 0.760, of the ADC radiomics model were 0.776 and 0.634, of the DCE-2 radiomics model were 0.804 and 0.759, of the DCE-6 radiomics model were 0.869 and 0.798, of the combined sequence radiomics model were 0.908 and 0.847, of the clinicopathological MRI feature model were 0.703 and 0.693, and of the nomogram model were 0.938 and 0.859, respectively. In the training set, the combined sequence radiomics model outperformed the clinicopathological features model (P<0.001). In the training and validation sets, the nomogram outperformed the clinicopathological features model (P<0.05). In addition, the diagnostic performance of the nomogram was better than that of the four single-modality radiomics models in the training cohort (P<0.05) and was better than that of DCE-2 and ADC models in the validation cohort (P<0.05). Decision curve analysis indicated that the value of individualized prediction models was higher than clinical and pathological prediction models in clinical practice. The calibration curve showed that the multimodal radiomics model had a high consistency with the actual results in predicting HER-2 expression. Conclusions: T2WI, ADC and early-delayed phase DCE-MRI imaging histology models for HER-2 expression status in breast cancer are expected to provide a non-invasive virtual pathological basis for decision-making on preoperative neoadjuvant regimens in breast cancer.


Assuntos
Neoplasias da Mama , Imageamento por Ressonância Magnética , Receptor ErbB-2 , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Receptor ErbB-2/metabolismo , Imageamento por Ressonância Magnética/métodos , Curva ROC , Radiômica
10.
Sci Rep ; 14(1): 10632, 2024 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724585

RESUMO

While some clinics have adopted abbreviated neoadjuvant treatment for HER2-positive breast cancer, there remains a shortage of comprehensive clinical data to support this practice. This is a retrospective, multicenter study. A total of 142 patients were included in the study who are HER2-positive breast cancer, aged ≤ 65 years, with left ventricular ejection fraction ≥ 50%, received neoadjuvant chemotherapy and underwent surgery at 10 different oncology centers in Türkiye between October 2016 and December 2022. The treatment arms were divided into 4-6 cycles of docetaxel/trastuzumab/pertuzumab for arm A, 4 cycles of adriamycin/cyclophosphamide followed by 4 cycles of taxane/TP for arm B. There were 50 patients (35.2%) in arm A and 92 patients (64.8%) in arm B. The median follow-up of all of the patients was 19.9 months (95% CI 17.5-22.3). The 3-year DFS rates for treatment arms A and B were 90.0% and 83.8%, respectively, and the survival outcomes between the groups were similar (p = 0.34). Furthermore, the pathologic complete response rates were similar in both treatment arms, at 50.0% and 51.1%, respectively (p = 0.90). This study supports shortened neoadjuvant treatment of HER2-positive breast cancer, a common practice in some clinics.


Assuntos
Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Terapia Neoadjuvante , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Feminino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Antraciclinas/uso terapêutico , Antraciclinas/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Trastuzumab/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Taxoides/uso terapêutico , Taxoides/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Resultado do Tratamento , Idoso , Anticorpos Monoclonais Humanizados
11.
Lancet Oncol ; 25(5): 614-625, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38697155

RESUMO

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.


Assuntos
Neoplasias da Mama , Camptotecina , Camptotecina/análogos & derivados , Imunoconjugados , Medidas de Resultados Relatados pelo Paciente , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Trastuzumab/uso terapêutico , Trastuzumab/administração & dosagem , Feminino , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Camptotecina/uso terapêutico , Camptotecina/administração & dosagem , Idoso , Adulto , Capecitabina/uso terapêutico , Capecitabina/administração & dosagem , Qualidade de Vida , Intervalo Livre de Progressão , Lapatinib/uso terapêutico , Lapatinib/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
12.
ACS Chem Biol ; 19(5): 1035-1039, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38717306

RESUMO

Red-shifted bioluminescence is highly desirable for diagnostic and imaging applications. Herein, we report a semisynthetic NanoLuc (sNLuc) based on complementation of a split NLuc (LgBiT) with a synthetic peptide (SmBiT) functionalized with a fluorophore for BRET emission. We observed exceptional BRET ratios with diverse fluorophores, notably in the red (I674/I450 > 14), with a brightness that is sufficient for naked eye detection in blood or through tissues. To exemplify its utility, LgBiT was fused to a miniprotein that binds HER2 (affibody, ZHER2), and the selective detection of HER2+ SK-BR-3 cells over HER2- HeLa cells was demonstrated.


Assuntos
Medições Luminescentes , Humanos , Células HeLa , Medições Luminescentes/métodos , Luciferases/genética , Luciferases/metabolismo , Receptor ErbB-2/metabolismo , Linhagem Celular Tumoral , Corantes Fluorescentes/química
13.
PeerJ ; 12: e17377, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38766488

RESUMO

Objective: To explore the relationship between receptor heterogeneity and clinicopathological characteristics in 166 patients with invasive breast cancer during metastasis. Methods: We conducted a retrospective analysis of 166 patients diagnosed with metastatic breast cancer through biopsy, who were admitted to our hospital from January 2018 to December 2022. Statistical analysis was employed to assess the heterogeneity of receptors in both primary and metastatic lesions, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), Ki67, as well as their association with clinicopathological features such as tumor size, lymph node metastasis, treatment regimen, and disease-free survival. Results: The discordant expression rates of ER, PR, HER2, Ki-67 and Luminal classification between primary and metastatic lesions were 21.7%, 41.6%, 8.9%, 34.4% and 36.8%, respectively. There is a significant difference in disease-free survival between patients with consistent and inconsistent receptor status of primary and metastatic lesions, which is statistically significant. The median DFS for primary HER2(-) to metastatic HER2(+) was 84 months, which was relatively high. The Cox multivariate regression analysis revealed that the expression differences of ER, PR, HER2, and Ki67 were not influenced by endocrine therapy and chemotherapy. However, a statistically significant difference in HER2 expression was observed with targeted therapy. Tumor size was correlated with ER and Ki67 receptor status (P = 0.019, 0.016). Tumor size was not correlated with PR, and HER2 (P = 0.679, 0.440). Lymph node metastasis was not associated with changes in ER, PR, HER2, and Ki67. The discordant rates of ER, PR, HER2, and Ki-67 in patients with local recurrence were 22%, 23.7%, 5.1%, and 28.8% respectively, whereas those in patients with distant metastasis were 21.5%, 36.4%, 10.3%, and 31.8% respectively. Conclusions: The expression levels of ER, PR, HER2, and Ki-67 in primary and metastatic breast cancer exhibit heterogeneity, which is closely associated with the prognosis and treatment outcomes of patients.


Assuntos
Neoplasias da Mama , Antígeno Ki-67 , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Estudos Retrospectivos , Antígeno Ki-67/metabolismo , Receptores de Progesterona/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Pessoa de Meia-Idade , Adulto , Idoso , Metástase Linfática/patologia , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Prognóstico , Metástase Neoplásica , Relevância Clínica
14.
Sci Rep ; 14(1): 11432, 2024 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-38763942

RESUMO

HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations.


Assuntos
Neoplasias Colorretais , Amplificação de Genes , Instabilidade de Microssatélites , Mutação , Receptor ErbB-2 , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas ras/genética
15.
ACS Appl Mater Interfaces ; 16(20): 25710-25726, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38739808

RESUMO

The present study investigated the concurrent delivery of antineoplastic drug, doxorubicin, and HER2 siRNA through a targeted theranostic metallic gold nanoparticle designed using polysaccharide, PSP001. The as-synthesized HsiRNA@PGD NPs were characterized in terms of structural, functional, physicochemical, and biological properties. HsiRNA@PGD NPs exposed adequate hydrodynamic size, considerable ζ potential, and excellent drug/siRNA loading and encapsulation efficiency. Meticulous exploration of the biocompatible dual-targeted nanoconjugate exhibited an appealing biocompatibility and pH-sensitive cargo release kinetics, indicating its safety for use in clinics. HsiRNA@PGD NPs deciphered competent cancer cell internalization, enhanced cytotoxicity mediated via the induction of apoptosis, and excellent downregulation of the overexpressing target HER2 gene. Further in vivo explorations in the SKBR3 xenograft breast tumor model revealed the appealing tumor reduction properties, selective accumulation in the tumor site followed by significant suppression of the HER2 gene which contributed to the exclusive abrogation of breast tumor mass by the HsiRNA@PGD NPs. Compared to free drugs or the monotherapy constructs, the dual delivery approach produced a synergistic suppression of breast tumors both in vitro and in vivo. Hence the drawings from these findings implicate that the as-synthesized HsiRNA@PGD NPs could offer a promising platform for chemo-RNAi combinational breast cancer therapy.


Assuntos
Neoplasias da Mama , Doxorrubicina , Inativação Gênica , RNA Interferente Pequeno , Receptor ErbB-2 , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Animais , Camundongos , Inativação Gênica/efeitos dos fármacos , Nanopartículas Metálicas/química , Ouro/química , Linhagem Celular Tumoral , Camundongos Nus , Camundongos Endogâmicos BALB C , Apoptose/efeitos dos fármacos
16.
Cancer Med ; 13(10): e7249, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38770648

RESUMO

BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC. METHODS: From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. RESULTS: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). CONCLUSION: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.


Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Neoplasias da Mama , Piperazinas , Intervalo Livre de Progressão , Piridinas , Receptor ErbB-2 , Receptores de Estrogênio , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Receptor ErbB-2/metabolismo , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , China , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Adulto , Estudos Retrospectivos , Progressão da Doença , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem
17.
Arch Virol ; 169(5): 114, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700535

RESUMO

OBJECTIVE: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS: A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS: Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION: EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.


Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/virologia , Neoplasias Gástricas/patologia , Masculino , Feminino , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/mortalidade , Pessoa de Meia-Idade , Herpesvirus Humano 4/genética , Prognóstico , Estudos Retrospectivos , Idoso , Adulto , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Antígeno Ki-67/metabolismo , RNA Viral/genética , Gastrectomia
18.
Clin Transl Med ; 14(5): e1687, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38738791

RESUMO

OBJECTIVE: It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. METHODS: Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. RESULTS: From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. CONCLUSIONS: This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Trastuzumab/uso terapêutico , Trastuzumab/farmacologia , Estudos Prospectivos , Idoso , Receptor ErbB-2/metabolismo , Paclitaxel Ligado a Albumina/uso terapêutico , Paclitaxel Ligado a Albumina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Acrilamidas/uso terapêutico , Terapia Neoadjuvante/métodos , Proto-Oncogene Mas , Ácidos Sulfínicos/uso terapêutico , Ácidos Sulfínicos/farmacologia , Aminoquinolinas/uso terapêutico , Aminoquinolinas/farmacologia , Resultado do Tratamento
19.
Front Immunol ; 15: 1355130, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742103

RESUMO

Pre-operative radiation therapy is not currently integrated into the treatment protocols for breast cancer. However, transforming immunological "cold" breast cancers by neoadjuvant irradiation into their "hot" variants is supposed to elicit an endogenous tumor immune defense and, thus, enhance immunotherapy efficiency. We investigated cellular and immunological effects of sub-lethal, neoadjuvant irradiation of ER pos., HER2 pos., and triple-negative breast cancer subtypes in-vitro and in-vivo in humanized tumor mice (HTM). This mouse model is characterized by a human-like immune system and therefore facilitates detailed analysis of the mechanisms and efficiency of neoadjuvant, irradiation-induced "in-situ vaccination", especially in the context of concurrently applied checkpoint therapy. Similar to clinical appearances, we observed a gradually increased immunogenicity from the luminal over the HER2-pos. to the triple negative subtype in HTM indicated by an increasing immune cell infiltration into the tumor tissue. Anti-PD-L1 therapy divided the HER2-pos. and triple negative HTM groups into responder and non-responder, while the luminal HTMs were basically irresponsive. Irradiation alone was effective in the HER2-pos. and luminal subtype-specific HTM and was supportive for overcoming irresponsiveness to single anti-PD-L1 treatment. The treatment success correlated with a significantly increased T cell proportion and PD-1 expression in the spleen. In all subtype-specific HTM combination therapy proved most effective in diminishing tumor growth, enhancing the immune response, and converted non-responder into responder during anti-PD-L1 therapy. In HTM, neoadjuvant irradiation reinforced anti-PD-L1 checkpoint treatment of breast cancer in a subtype -specific manner. According to the "bench to bedside" principle, this study offers a vital foundation for clinical translating the use of neoadjuvant irradiation in the context of checkpoint therapy.


Assuntos
Antígeno B7-H1 , Inibidores de Checkpoint Imunológico , Terapia Neoadjuvante , Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas , Animais , Feminino , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/terapia , Terapia Neoadjuvante/métodos , Camundongos , Humanos , Receptor ErbB-2/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Linhagem Celular Tumoral , Receptores de Estrogênio/metabolismo , Modelos Animais de Doenças , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias da Mama/imunologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/terapia
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