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1.
Zhonghua Zhong Liu Za Zhi ; 42(5): 353-361, 2020 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-32482023

RESUMO

Objective: Breast cancer is a kind of malignant tumor which seriously endangers women's health. With the development of molecular biology technology and the further understanding of pathogenesis, the treatment of breast cancer has entered a new era of molecular targeted therapy, and has been making new progress. At present, molecular targeted drugs for the treatment of breast cancer keep emerging, mainly including endocrine therapy targeting estrogen and progesterone receptor (ER/PR), targeted drugs treatment for epidermal growth factor receptor-2 (HER-2); phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA1/2 mutations, cyclin-dependent kinases (CDK) 4/6 inhibitors, etc. Because some signal pathway abnormalities may occur in different molecular types of breast cancer, the same targeted drugs are cross-used in different types.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Terapia de Alvo Molecular , Neoplasias da Mama/patologia , Feminino , Humanos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptor ErbB-2/metabolismo , Receptores Estrogênicos , Serina-Treonina Quinases TOR/metabolismo
2.
Medicine (Baltimore) ; 99(24): e20396, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541460

RESUMO

RATIONALE: Patients with, or who develop, metastatic breast cancer have a 5-year relative survival of about 25%. Endocrine therapy clearly improves outcomes in patients with estrogen receptor-positive breast cancer. In the metastatic setting, the primary goal of treatment is to maintain long-term disease control with good quality of life. Rarely, exceptional responders achieve durable disease control, and potential cures cannot be ruled out. PATIENT CONCERNS: We report the case of a 39-year-old woman with primary breast cancer and associated synchronous bone metastases, who experienced a disease response of 12 years with hormonal therapy as maintenance after first line chemotherapy, with a good toxicity profile. DIAGNOSIS: The patient was diagnosed with estrogen receptor + human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer with synchronous bone metastases. INTERVENTIONS: This patient was treated with chemotherapy for 6 cycles as a first-line therapy following by endocrine treatment given as a maintenance therapy. OUTCOMES: Our patient experienced a progression-free survival >12 years with an exceptionally good quality of life. LESSONS: Our anecdotal experience highlights the existence of exceptional responders among patients with hormone receptor-positive metastatic breast cancer, who achieve clinical remission and durable disease control with endocrine therapy. Being able to identify these patients could help in the selection of the best treatment option among the many available.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Feminino , Humanos , Intervalo Livre de Progressão , Qualidade de Vida , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Resultado do Tratamento
3.
Medicine (Baltimore) ; 99(23): e20575, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502026

RESUMO

BACKGROUND: Recently, many studies have suggested that the aberrant expression of c-erbB-2 existed in oral cancer (OC) patients and had a correlation with poor clinical features across OC patients. Considering the inconsistent results among published articles, we performed the meta-analysis to assess the prognostic and clinical effect of c-erbB-2 expression on oral tumors. METHODS: Web of Science, Embase, and PubMed were retrieved to acquire relevant publications based on selection criteria, up to February 8, 2020. Pooled odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) were applied to evaluate the associations between c-erbB-2 expression and overall survival (OS), disease specific survival, disease-free survival as well as clinicopathology of OC. RESULTS: A total of 30 literatures with 1499 patients for survival of OC were enrolled in this meta-analysis. The results indicated that c-erbB-2 overexpression was significantly associated with poor OS (HR = 2.40, 95% CI = 1.53-2.55, P < .05), disease specific survival (HR = 2.60, 95% CI = 1.11-4.10, P < .05) and disease-free survival (HR = 2.22, 95% CI = 1.46-2.99, P < .05). Subgroup analysis based on race showed that the significant prognostic value of c-erbB-2 in OC was found both in Caucasians and Asians (OS of Caucasians, HR = 2.90, 95% CI = 1.50-4.31, P < .05; OS of Asians, HR = 1.90, 95% CI = 1.27-2.53, P < .05). Moreover, OC patients with enhanced c-erbB-2 expression were prone to male (OR = 1.97, 95% CI = 1.22-3.19, P < .05), advanced TNM stage (OR = 1.84, 95% CI = 1.17-2.88, P < .05), lymph node metastasis (OR = 2.23, 95% CI = 1.47-3.36, P < .05) and advanced grade (OR = 1.98, 95% CI = 1.30-3.01, P < .05), but not associated with distant metastasis (OR = 1.65, 95% CI = 0.98-3.04, P > .05). CONCLUSIONS: c-erbB-2 may be a potential indicator in the prediction of prognosis and clinicopathological features in OC patients.


Assuntos
Neoplasias Bucais/genética , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Regulação da Expressão Gênica , Humanos , Metástase Linfática/genética , Masculino , Neoplasias Bucais/mortalidade , Intervalo Livre de Progressão , Fatores Sexuais
5.
N Engl J Med ; 382(25): e98, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32558480
6.
Medicine (Baltimore) ; 99(19): e19957, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384443

RESUMO

Studies of PDPN in cancers have focused on the interactions with palates through the binding with CECL-2 which mainly express on palates and immune cells, while little is known on its interactions with immune cells.PDPN expression in cancers was analyzed through Oncomine, GEPIA, and TIMER database. Prognostic value (HR, P value from log-rank test) was evaluated through Kaplan-Meier plotter and OncoLnc database. The correlations between PDPN and the infiltrating levels of immune cells in different cancers, and diverse immune markers in gastric cancer were investigated through TIMER database.High PDPN expression predicted poor overall survival (OS) and post-progression survival (PPS) particularly in gastric cancer (OS P = .0089; PPS P = .00085), especially among patients with Her-2 (+) and lymph node metastasis. In addition, PDPN was positively correlated with infiltrating levels of immune cells, other than B cells in gastric cancer. However, PDPN showed more correlations with immune markers of M2 type TAM (CD163, VSIG4, MS4A4A) and T cell exhaustion (TIM-3, TOX, and GZMB).These findings all suggest that high PDPN predicts poor survival outcomes, especially for Her-2 (+) gastric cancer patients. Though inducing M2 type TAM and T cell exhaustion, high PDPN can predict high levels of various immune cells infiltration in STAD. Those correlations may bring new ideas to immunology treatment for gastric cancer patients who do not benefit from the existing immune checkpoint inhibitors.


Assuntos
Linfócitos do Interstício Tumoral/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Bases de Dados Factuais , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/genética , Masculino , Prognóstico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/mortalidade
7.
Anticancer Res ; 40(4): 2303-2309, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234930

RESUMO

BACKGROUND/AIM: To predict pCR during neoadjuvant chemotherapy is still difficult. The aim of this study was to evaluate the optimal tumor reduction rate and modalities for predicting pCR after two cycles of docetaxel. PATIENTS AND METHODS: We analyzed 52 patients with HER2-positive or triple-negative breast cancer. The tumor reduction rate was evaluated after two 3-week cycles of docetaxel (plus trastuzumab for HER2-positive cancer patients). Patients without progression completed two additional cycles of docetaxel and four cycles of an anthracycline-containing regimen. RESULTS: Twenty-eight patients achieved pCR. The optimal tumor reduction rates for predicting pCR were 23, 39, 32, and 40% for US, caliper, MMG, and MRI measurements, respectively. The AUC was highest for caliper measurements. The optimal modality for predicting pCR differed among subtypes. CONCLUSION: Although tumor reduction rate after two cycles of chemotherapy is highly predictive of pCR, the optimal cutoff value differed among the modalities and breast cancer subtype.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Mama/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Antraciclinas/administração & dosagem , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/metabolismo , Docetaxel/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Indução de Remissão , Trastuzumab/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Ultrassonografia
8.
Anticancer Res ; 40(4): 2133-2139, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234906

RESUMO

BACKGROUND/AIM: Metaplastic breast carcinoma (MBC) is a rare malignancy, which is often triple-negative for the hormone receptors and human epidermal growth factor receptor 2, and thus, does not benefit from targeted therapy. In this study, we examined the expression of methylation and demethylation enzymes by immunostaining MBC and the adjacent normal tissues or triple-negative ductal carcinoma (TNDC), and identified alterations that may be used as therapeutic targets. MATERIALS AND METHODS: We retrospectively studied surgical specimens from 15 patients who underwent surgery for MBC at Kanagawa Cancer Center between 2005 and 2016, and similarly from 14 patients with TNDC. The frequencies of high methylation/demethylation enzyme expression were compared among them. RESULTS: The frequencies of high enhancer of zeste homolog 2 (EZH2) and multiple myeloma SET domain (MMSET) expression were significantly higher in both MBC and TNDC than in normal tissue. CONCLUSION: EZH2 and MMSET may be useful therapeutic targets in MBC.


Assuntos
Neoplasias da Mama/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histona-Lisina N-Metiltransferase/genética , Metaplasia/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metaplasia/diagnóstico , Metaplasia/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética
10.
Anticancer Res ; 40(4): 1921-1930, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234881

RESUMO

BACKGROUND/AIM: Targeting of the human epidermal growth factor receptor 2 (HER2) is suggested to be beneficial for esophageal squamous cell carcinoma (ESCC) patients with HER2 amplification. In this study, we evaluated the effects of combination chemotherapy with HER2-targeted drug trastuzumab in ESCC cells and examined the underlying mechanism contributing to these effects. MATERIALS AND METHODS: HER2 expression was verified, and the efficacy of chemotherapy with and without trastuzumab was investigated in vitro and in vivo. RESULTS: The combination of trastuzumab and a combined-modality therapy stimulated the PI3K/Akt pathway in ESCC cells overexpressing HER2. Trastuzumab treatment resulted in the intranuclear accumulation of FOXO3A in ESCC xenografts overexpressing HER2. The combination of trastuzumab and a combined-modality therapy enhanced antitumor effects in HER2-overexpressing ESCC xenografts. CONCLUSION: FOXO3A plays an important role in mediating the effects of trastuzumab, and combination chemotherapy may be a promising treatment for patients with HER2-overexpressing ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Proteína Forkhead Box O3/genética , Receptor ErbB-2/genética , Trastuzumab/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética
11.
Biol Res ; 53(1): 13, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293552

RESUMO

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.


Assuntos
Antígenos Glicosídicos Associados a Tumores/genética , Neoplasias da Vesícula Biliar/genética , Índios Sul-Americanos/genética , Animais , Antineoplásicos/farmacologia , Líquido Ascítico/metabolismo , Carcinogênese/genética , Testes de Carcinogenicidade , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Chile , Cisplatino/farmacologia , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Impressões Digitais de DNA , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Células Epiteliais/metabolismo , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica , Genes erbB-2/genética , Humanos , Queratina-19/genética , Queratina-7/genética , Masculino , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Análise de Sequência de RNA , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética
12.
Life Sci ; 252: 117646, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272178

RESUMO

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells causing resistance to immunotherapies in cancer tumors. In the current study, various immunogenic and therapeutic features of the combination therapies with non-liposomal Doxorubicin (Dox) and the E75 immunogenic peptide (Pep), derived from the human epidermal receptor-2 (HER-2), are investigated in parallel with their liposomal formulations (Lip-Dox (Doxil®) and Lip-Pep). Therefore, triple injection doses of Lip-Pep were preceded with Dox and Lip-Dox injections in TUBO/breast tumor-bearing BALB/c mice. Chemotherapy with either Dox or Lip-Dox reduced the frequency of MDSCs, the level of reactive oxygen species (ROS), and MDSCs-associated genes of Arg1, iNOS, S100A8, S100A9. Whereas Lip-Pep + Dox and Lip-Pep + Lip-Dox treatments synergistically potentiated the immunized splenocytes to produce INF-γ and enhanced the frequency of the anti-tumor CD8+ and CD4+ T cells as opposed to both chemotherapy and immunotherapy regimens. Chemo-immunotherapy increased the number of tumor-infiltrating lymphocytes (TILs) and reduced the level of CD25+ FoxP3+ T regulatory cells. Taken together, chemo-immunotherapy was the optimum treatment for the limitation of tumor progression as they targeted more cancer-related immune players.


Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Doxorrubicina/análogos & derivados , Receptor ErbB-2/imunologia , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/imunologia , Terapia Combinada , Progressão da Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Feminino , Imunoterapia/métodos , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia
13.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(2): 254-260, 2020 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-32306007

RESUMO

OBJECTIVE: Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world. METHODS: We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated. RESULTS: Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3. CONCLUSION: Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.


Assuntos
Acrilamidas/uso terapêutico , Aminoquinolinas/uso terapêutico , Neoplasias da Mama , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , China , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2 , Estudos Retrospectivos , Trastuzumab , Resultado do Tratamento
14.
PLoS One ; 15(4): e0227256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315295

RESUMO

There is growing interest in leveraging real-world data to complement knowledge gained from randomized clinical trials and inform the design of prospective randomized studies in oncology. The present study compared clinical outcomes in women with metastatic breast cancer who received letrozole as first-line monotherapy in oncology practices across the United States versus patients in the letrozole-alone cohort of the PALOMA-2 phase 3 trial. The real-world cohort (N = 107) was derived from de-identified patient data from the Flatiron Health electronic health record database. The clinical trial cohort (N = 222) comprised postmenopausal women in the letrozole-alone arm of PALOMA-2. Patients in the real-world cohort received letrozole monotherapy per labeling and clinical judgment; patients in PALOMA-2 received letrozole 2.5 mg/d, continuous. Real-world survival and response rates were based on evidence of disease burden curated from clinician notes, radiologic reports, and pathology reports available in the electronic health record. Progression-free survival and objective response rate in PALOMA-2 were based on Response Evaluation Criteria in Solid Tumors v1.1. Concordance of survival and response rates were retrospectively assessed using inverse probability of treatment weighting-adjusted Cox regression analysis. Inverse probability of treatment weighting-adjusted Cox regression results showed similar median progression-free survival in the real-world and PALOMA-2 cohorts (18.4 and 16.6 months, respectively): the hazard ratio using real-world data as reference was 1.04 (95% CI, 0.69-1.56). No significant difference was observed in response rates: 41.8% in the real-world cohort vs 39.4% in the PALOMA-2 cohort (odds ratio using real-world data as reference: 0.91 [95% CI, 0.57-1.44]). These findings indicate that data abstracted from electronic health records with proper quality controls can yield meaningful information on clinical outcomes. These data increase confidence in the use of real-world assessments of progression and response as efficacy endpoints. Trial registration NCT01740427; Funding: Pfizer.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Letrozol/uso terapêutico , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Estados Unidos/epidemiologia
15.
Cancer Sci ; 111(6): 2123-2131, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248641

RESUMO

HER2-targeting antibodies (trastuzumab, pertuzumab) and a HER2-directed antibody-drug conjugate (trastuzumab emtansine: T-DM1) are used for the treatment of HER2-overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small-molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T-DM1 for evaluating the effect of TAS0728 on HER2 antibody-resistant populations. Treatment with trastuzumab and pertuzumab or with T-DM1 initially induced tumor regression in NCI-N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T-DM1, HER2-HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti-tumor effect associated with HER2-HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient-derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T-DM1, TAS0728 exerted a potent anti-tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T-DM1 are still dependent on oncogenic HER2-HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti-HER2 therapies.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Ado-Trastuzumab Emtansina/farmacologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Cancer Res Clin Oncol ; 146(7): 1693-1700, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32333142

RESUMO

PURPOSE: Osteosarcoma is the most common bone tumor, mainly affecting adolescents and young adults, and metastatic disease has poor outcomes with a dismal overall survival. Currently, chemotherapy is the standard of care with limited results, finding that new therapies could improve these outcomes. Preclinical and clinical studies have suggested a possible important role of ErbB pathway aberrations in osteosarcoma etiology. The present study shows the effect of afatinib, an irreversible ErbB family blocker in osteosarcoma cell lines. METHODS: Within a panel of human osteosarcoma cell lines, we addressed cell viability assay using afatinib at increasing concentrations. Motility was measured in wound-healing assays and invasion capacity was assessed in Transwell chamber assays. Finally, to monitor ErbB pathway modulation by afatinib and related compounds, we used Western blot analyses. RESULTS: Cell viability inhibition, as well as a reduction of motility and migration of osteosarcoma cell line were observed after treatment with afatinib. Likewise, in the HOS cell line, afatinib decreased phosphorylation of key components in the ErbB signaling pathway. CONCLUSIONS: Afatinib shows relevant antitumor effect in several osteosarcoma cell lines, as it causes a significant impact on cell viability, motility, and migration with a significant decrease in the activation of ErbB pathway activity.


Assuntos
Afatinib/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biomed Khim ; 66(1): 89-94, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32116231

RESUMO

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.


Assuntos
Neoplasias da Mama/metabolismo , Receptores Androgênicos/metabolismo , Receptores da Prolactina/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Feminino , Humanos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona
18.
Crit Rev Oncol Hematol ; 149: 102927, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32172224

RESUMO

Anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab are effective for all stages of HER2-positive breast cancer (BC). However, intrinsic or acquired resistance to these drugs may occur in a significant number of patients (pts) and, except for HER2 status, no validated predictive factors of response/resistance have been identified to date. This lack is in part due to the not yet fully elucidated mechanism of action of mAbs in vivo. Increasing evidence suggests a significant contribution of both innate and adaptive immunity to the antitumor effects of mAbs. The aim of this review was to describe the role of innate and adaptive immunity in the efficacy of anti-HER2 mAbs and to report known and novel strategies to be used for optimizing immune effects of anti-HER2 therapies for HER2-positive BC.


Assuntos
Imunidade Adaptativa , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Anticorpos Monoclonais/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Humanos , Receptor ErbB-2/química
19.
Medicine (Baltimore) ; 99(13): e19618, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32221087

RESUMO

BACKGROUND: Recently, many endocrine therapies have become available for hormone receptor-positive, human epidermal growth factor receptor 2-negative, pretreated, advanced breast cancer. Direct comparisons of these novel treatments to assess their added value, however, are lacking METHODS:: Our aim was to synthesize available evidence to compare all current endocrine treatments for hormone receptor-positive / human epidermal growth factor receptor 2-negative advanced breast cancer. We performed a systematic review to identify available randomized controlled trial evidence. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials. Two trials presented at international oncology congresses (American Society of Clinical Oncology [ASCO]) were added to include the most recent evidence. A frequent network meta-analysis was used, and the surface under cumulative ranking area (SUCRA) was calculated to determine the best treatment RESULTS:: In total, 32 trials and 12,726 patients were identified, including 27 arms. Compared with fulvestrant 500 mg alone, novel target inhibitors combined with fulvestrant or exemestane had significantly prolonged progression-free survival with hazard ratios ranging from 0.62 to 0.82. Fulvestrant 500 mg plus palbociclib 125 mg and exemestane 25 mg plus entinostat 5 mg similarly extended progression-free survival (hazard ratio: 0.64 and 0.62 with SUCRA values of 91% and 92%, respectively). The exemestane 25 mg plus everolimus 10 mg combination had the best clinical benefit rate (risk ratio: 1.84, SUCRA: 91%) and overall response rate (risk ratio: 6.05, SUCRA: 97%) CONCLUSIONS:: On the basis of this analysis, the 2 combinations of exemestane plus everolimus and fulvestrant plus palbociclib were the best treatment options.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pós-Menopausa , Receptor ErbB-2/biossíntese , Androstadienos/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Everolimo/uso terapêutico , Feminino , Fulvestranto/uso terapêutico , Humanos , Gradação de Tumores , Metanálise em Rede , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Cancer Treat Rev ; 86: 101996, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32135383

RESUMO

Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies. Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations. Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Receptor ErbB-2/genética , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Amplificação de Genes , Humanos , Imunoconjugados/imunologia , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/biossíntese , Receptor ErbB-2/imunologia
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