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1.
Medicine (Baltimore) ; 98(44): e17614, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689768

RESUMO

INTRODUCTION: The efficacy of neoadjuvant buparlisib for breast cancer remains controversial. We conduct a systematic review and meta-analysis to explore the influence of neoadjuvant buparlisib versus placebo for breast cancer. METHODS: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2019 for randomized controlled trials (RCTs) assessing the efficacy and safety of neoadjuvant buparlisib versus placebo for breast cancer. This meta-analysis is performed using the random-effect model. RESULTS: Four RCTs are included in the meta-analysis. Overall, compared with control group for breast cancer, neoadjuvant buparlisib can substantially reduce progressive disease (risk ratios [RR] = 0.66; 95% confidence interval [CI] = 0.52-0.82; P = .0003) and improve stable disease (RR = 1.29; 95% CI = 1.02-1.64; P = .04), but has no notable influence on overall response rate (RR = 1.32; 95% CI = 0.84-2.06; P = .22), clinical benefit rate (RR = 1.06; 95% CI = 0.79-1.43; P = .69). Neoadjuvant buparlisib results in the increase in adverse grade 3/4 adverse events including increased alanine aminotransferase (ALT) (RR = 11.87; 95% CI = 5.65-24.90; P < .00001), increased aspartate aminotransferase (AST) (RR = 6.50; 95% CI = 4.14-10.21; P < .00001) and hyperglycaemia (RR = 36.65; 95% CI = 10.44-128.68; P < .00001), as well as serious adverse events (RR = 1.47; 95% CI = 1.23-1.76; P < .0001) compared to placebo. Deaths is found to be similar between two groups (RR = 0.88; 95% CI = 0.75-1.04; P = .13). CONCLUSIONS: Neoadjuvant buparlisib may provide some efficacy for breast cancer, but leads to the increase in serious adverse events.


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Morfolinas/uso terapêutico , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Neoplasias da Mama/patologia , Humanos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Terapia Neoadjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/biossíntese
2.
Medicine (Baltimore) ; 98(40): e17374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577740

RESUMO

RATIONALE: Prepubertal unilateral gynecomastia is extremely rare, whose etiology and management strategy are not familiar. We would like to present a case and a literature review of unilateral prepubertal gynecomastia. PATIENT CONCERNS: A 11-year old male patient with complaints of unilateral enlargement of breast tissue presented in our clinic, whose physical examination, biochemical, hormonal and oncologic findings were normal. DIAGNOSES: This patient was diagnosed as idiopathic unilateral prepubertal gynecomastia (IUPG) and self-abasement, social isolation and sensitive of interpersonal relationship. INTERVENTIONS: The patient received subcutaneous mastectomy. Histopathological examinations showed idiopathic gynecomastia of ductal epithelial hyperplasia and active interstitial fibrous hyperplasia, with no evidence of any pathological finding. Immunohistochemical examination showed estrogen receptor (ER)-α positive (70%), epidermal growth factor receptor (EGFR) positive, Her-2 positive (1+), Progesterone Receptor (PR) positive (80%). OUTCOMES: A remarkable improvement was observed both in the physical and mental conditions at the post-surgical 6-month follow-up visit, showing no evidence of recurrence. LESSONS: Further investigation is needed to clarify the pathogenesis of IUPG. All patients with IUPG should have a full endocrine and oncologic evaluation, and surgical excision may be the individually designed for each patient with the help of MRI of breast.


Assuntos
Ginecomastia/patologia , Puberdade , Criança , Receptores ErbB/biossíntese , Receptor alfa de Estrogênio/biossíntese , Ginecomastia/diagnóstico , Ginecomastia/cirurgia , Humanos , Masculino , Mastectomia/métodos , Receptor ErbB-2/biossíntese , Receptores de Progesterona/biossíntese
3.
Medicine (Baltimore) ; 98(36): e15719, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490359

RESUMO

BACKGROUND: We evaluated the relationship between the age at first use of oral contraceptives (OC) and breast cancer (BC) risk. METHODS: We searched PubMed, Embase, and related reviews published through June 28, 2018, and used summary relative risk (RR) and 95% confidence intervals (CIs) to evaluate the cancer risks, and fixed-effects dose-response meta-analysis to assess potential linear and non-linear dose-response relationships. RESULTS: We included 10 studies, with 8585 BC cases among 686,305 participants. The pooled RR for BC was 1.24 (95% CI: 1.10-1.41), with moderate heterogeneities (I = 66.5%, P < .001). No significant publication bias was found (P = .584 for Begg test, P = .597 for Egger test). A linear dose-response relationship between the age at first OC use and BC risk was detected (P = .518 for non-linearity). Subgroup analyses were restricted to studies done by BC subtypes, region, sample size, follow-up time and study quality. Inconsistent consequences with no statistical significance were explored when limited to studies from Western countries, study quality <7, sample size <10,000, follow-up time <5 years, and BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expression status in tumor tissue. Sensitivity analyses indicated that our results were stable and reliable after removing each study in turn and omitting studies of adjusted unreported variables. CONCLUSION: A significant linear relationship between the age at first OC use and BC risk was confirmed. No further consistent differences are noted in multiple aspects of BC subtypes defined by progesterone or ER status.


Assuntos
Neoplasias da Mama/epidemiologia , Anticoncepcionais Orais/administração & dosagem , Fatores Etários , Relação Dose-Resposta a Droga , Feminino , Humanos , Receptor ErbB-2/biossíntese , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/biossíntese , Fatores de Risco
4.
Medicine (Baltimore) ; 98(36): e16937, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490377

RESUMO

Metadherin (MTDH), also known as astrocyte elevated gene-1 (AEG-1), is an oncoprotein closely related to the development of breast cancer. However, few studies have been done on the expression and clinical significance of MTDH in human epidermal growth factor receptor-2 (HER-2) positive breast cancer patients.This study aimed to investigate the expression of MTDH in locally advanced HER-2 positive breast cancer, and evaluate the clinical significance of MTDH in predicting the prognosis of patients with HER-2 positive advanced breast cancer who received the neoadjuvant chemotherapy plus trastuzumab.In 144 HER-2 positive breast cancer tissues, 79 cases showed high expression of MTDH and 65 cases showed low expression. The expression of MTDH in locally advanced HER-2 positive breast cancer tissues was correlated with TNM stage, lymph node metastasis, Miller-Payne (MP) grade, and pathologic complete response (pCR) status (P < .05), but was not correlated with patient age, estrogen receptor (ER) expression level, progesterone receptor (PR) expression level, and Ki-67 expression level (P > .05). Kaplan-Meier univariate analysis revealed a negative correlation between MTDH expression and the disease-free survival (DFS) and overall survival (OS) in the post-operative patients with locally advanced HER-2 positive breast cancer (log rank test: P < .001). By using the COX proportional hazard regression model, it was found that MTDH expression, TNM stage, lymph node metastasis, and Ki-67 expression were closely related to DFS in patients. The hazard ratio (HR) of high MTDH expression was 1.816 (95% CI: 1.165-2.829). In addition, MTDH expression, TNM stage, and lymph node metastasis were also closely related to the OS of patient. The HR of the high expression of MTDH was 2.512 (95% CI: 1.472-4.286). The expression of MTDH in tumor tissues of patients with HER2-positive locally advanced breast cancer was significantly elevated, which was related to the poor pathological features.High MTDH expression was closely correlated with poor prognosis of patients and was an important factor affecting tumor progression.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/biossíntese , Receptor ErbB-2/biossíntese , Trastuzumab/uso terapêutico , Adulto , Fatores Etários , Idoso , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/biossíntese
5.
Malays J Pathol ; 41(2): 133-138, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31427548

RESUMO

INTRODUCTION: Evaluation of HER2 status in breast cancer using immunohistochemistry (IHC) and in-situ-hybridisation (ISH) study is important to establish prognosis and to select patient for targeted therapy. OBJECTIVE: The study aims to determine the concordance between HER2 protein IHC score and its gene status by dual-colour dual-hapten in-situ-hybridization (DDISH) study. MATERIALS AND METHODS: Retrospective study was performed on 767 referred breast cancer cases over a period of five years. The HER2 IHC score (the initial and repeat test score) and the results of HER2 gene status by DDISH were retrieved from the histopathological reports. The agreement between initial IHC score with repeat test score was measured using Cohen Kappa. Chi square test analyzed the association between HER2 IHC score with its gene status by DDISH. RESULTS: The concordance of HER2 IHC score between the initial and repeat test were 52.7% and 89.4% for IHC score 2+ and 3+ respectively. There was moderate agreement of HER2 IHC score between the initial and repeat test score (Ï° = 0.526, p<0.001). A significant association noted between HER2 IHC score with its gene status by DDISH (p<0.001). Only 56 out of 207 cases (27.1%) with 2+ IHC score showed HER2 gene amplification while the majority of cases with 3+ IHC score were gene-amplified (446 out of 451, 98.9%). CONCLUSION: ISH study should be done in all IHC-equivocal cases (2+) to select patient for targeted therapy. Gene amplification must also be confirmed in IHC-positive cases (3+) to prevent from giving non-effective treatment with possible adverse effects to patient with non-amplified HER2 gene.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Receptor ErbB-2/análise , Adulto , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Reprodutibilidade dos Testes , Estudos Retrospectivos
6.
J Cancer Res Clin Oncol ; 145(7): 1845-1856, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31025094

RESUMO

PURPOSE: The protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer. METHODS: Protein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot. RESULTS: Low PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation. CONCLUSION: We confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15-18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Comunicação Celular , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Células MCF-7 , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 2/biossíntese , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Receptor ErbB-2/biossíntese , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
7.
Med Sci Monit ; 25: 3005-3013, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31015393

RESUMO

BACKGROUND The purpose of the present study was to evaluate the effect of leptin and leptin receptor (LEPR) expression on the efficacy of neoadjuvant chemotherapy in breast cancer. MATERIAL AND METHODS There were 325 breast cancer patients with complete data enrolled in this study. Patients were categorized into 3 groups: pathological complete response group, non-pathological complete response group, and progressive disease group. Immunohistochemistry was performed to determine leptin and its receptor LEPR expression levels that were compared among the 3 groups. RESULTS Compared with the non-pathological complete response group, patients in the pathological complete response group had increased leptin and LEPR expression, although the difference was not statistically significant (P=0.194, P=0.110). In addition, the expression of leptin and LEPR in the pathological complete response group was also higher than that in the progressive disease group, and the difference of LEPR expression was statistically significant (P=0.008) while the leptin expression was not (P=0.065). There were more HER2+ breast cancer patients in the pathological complete response group categorized into strong positive, and positive expression of leptin and LEPR compared with the progressive disease group (P<0.05). There were significant differences of leptin and LEPR expression among breast cancer patients under different molecular subtypes HER2+, HR+, and triple negative, in which the triple negative patients had the highest expression of leptin and LEPR. In addition, patients in the progressive disease group had high and low expression of leptin and LEPR: 13.25% versus 11.32% and 13.1% versus 10.42% respectively. CONCLUSIONS Overexpression of leptin and LEPR improved the therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer, especially for those with HER2+ subtype. Overexpression of leptin and LEPR was distinct among the different molecular subtypes of breast cancer, suggesting a certain predictive value for breast cancer prognosis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Leptina/biossíntese , Receptores para Leptina/biossíntese , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Imuno-Histoquímica , Leptina/genética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptores para Leptina/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
Medicine (Baltimore) ; 98(13): e14987, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921210

RESUMO

RATIONALE: Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells that cause hemolytic anemia. Some anticancer drugs are reported to trigger oxidative stress; however, events of hemolysis are rarely discussed in patients with G6PD deficiency required oncologic treatments. PATIENT CONCERNS: Here we reported a young woman with G6PD deficiency safely undergoing breast cancer treatment. DIAGNOSIS: A 29-year-old patient was diagnosed with advanced cancer of the right breast with tumors positive for hormone receptor and human epidermal growth factor receptor 2. INTERVENTIONS: The patient received chemotherapy with doxorubicin, cyclophosphamide, and docetaxel. During the administration of docetaxel, trastuzumab was concurrently administered and was continued after the completion of docetaxel. The patient underwent adjuvant radiotherapy; meanwhile, tamoxifen was administered as adjuvant endocrine treatment. OUTCOMES: The treatment process was smooth. There was no evidence of hemolytic anemia. Except for hot flushes, the patient lives without remarkable side effects from ongoing or previous treatments. LESSONS: Some patients have both G6PD deficiency and malignancy in a geographic area with relatively high incidence of the enzymatic disorder and certain types of cancer. We suggest that our report can contribute to the concern regarding the safety of patients with G6PD deficiency undergoing cancer treatment.


Assuntos
Neoplasias da Mama/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Feminino , Humanos , Receptor ErbB-2/biossíntese
9.
Pathol Res Pract ; 215(5): 977-982, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30738694

RESUMO

INTRODUCTION: Syndecan-1 is heparan sulfate proteoglycans (HSPGs) that is used as coreceptors for signaling of growth factors. The comprehensive effect of syndecan-1 is to augment receptor stimulation at little ligand concentrations. THE GOAL OF THIS RESEARCH: is to study syndecan-1 expression in breast carcinoma and its value in predicting the prognosis in comparison to other clinicopathological parameters. MATERIAL &METHODS: immunohistochemistry study for syndecan-1 is done on 103 cases of invasive breast carcinoma. Its expression is assessed and correlated to other clinicopathological parameters and prognosis. RESULTS: overexpression was significantly related to high histologic grade (p = 0.001), large tumor size (p = 0.043), HER2-positive status (p = 0.001), and ER&PR-negative status (p = 0.001). It was also have a negative impact on the overall survival (p=0.012) and disease free survival (p = 0.009). Syndecan-1 expression showed weak positive correlation with Her 2 expression (Correlation Coefficient (co): 0.332, p = 0.001). CONCLUSION: syndecan-1 is a good predictor of poor overall survival and recurrence/ metastasis free survival. It is associated with aggressive phenotype as HER2 enriched and Triple negative rather than luminal subtypes of breast carcinoma. So it can be added to the hormonal receptors and HER 2 assay in the routine management of invasive breast cancer after confirmation on a more larger study.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Carcinoma/patologia , Sindecana-1/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Carcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/análise , Receptor ErbB-2/biossíntese , Receptores Estrogênicos/análise , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/análise , Receptores de Progesterona/biossíntese , Estudos Retrospectivos , Sindecana-1/análise
10.
J Med Syst ; 43(4): 83, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30810823

RESUMO

This study aimed to deeply analyze the application of DWI and DCE-MRI imaging in breast cancer, the correlation between the imaging characteristics of DWI and DCE-MRI and the molecular subtypes and prognostic factors of breast cancer was studied. Firstly, DWI and DCE-MRI scans of all patients before interventional therapy were performed, and relevant information of the subjects was introduced in turn. Secondly, molecular subtypes were determined according to immunohistochemical results and gene amplification. Siemens 3.0 T post-processing workstation was used for image post-processing. The time signal curve (TIC), early enhancement rate (EER) and ADC values were measured, morphological characteristics were recorded, and the correlation between each image feature and molecular subtypes, prognostic factors (tumor size, pathological grade, lymph node metastasis, ER, PR, HER2, Ki67) was analyzed. The results showed that parameters such as ADC value, EER, lobulation sign, burr sign, enhancement way and TIC type were correlated with prognostic factors and molecular subtypes. And Bayesian model discriminant analysis showed that the above imaging parameters couldn't well predict the expression of immunohistochemical factors and molecular subtypes. However, the above characteristics had a good effect on the prediction of pathological grade, with a false diagnosis rate of 9.69%.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Detecção Precoce de Câncer/métodos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Adulto , Teorema de Bayes , Neoplasias da Mama/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Reações Falso-Positivas , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Receptor ErbB-2/biossíntese , Carga Tumoral
11.
Medicine (Baltimore) ; 98(5): e14261, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30702584

RESUMO

PURPOSE: The addition of anti-HER2 therapies to neoadjuvant treatment significantly enhances pathological complete response (PCR) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Selecting patients unlikely to benefit from neoadjuvant anti-HER2 therapies is increasingly important. In this study, we proposed to assess the role of the phosphatase and tensin homolog (PTEN) as a biomarker in predicting PCR to neoadjuvant anti-HER2 therapies by conducting meta-analysis. METHODS: Our team searched Embase, Medline, and the Cochrane Library by the end of September 16, 2018, for trials on patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapies. The associations between PTEN expression and PCR rate were then assessed. Odds ratio (ORs) and hazard ratio (HRs) with 95% confidence intervals (CIs) with 2-sided P values were calculated. The Newcastle-Ottawa scale (NOS) was used to estimate the quality of the involved trials. RESULTS: A total of 820 patients from 8 trials were included in this meta-analysis. Overall, the PTEN normal tumors was related to a significant increase in PCR rate (OR 0.55; 95% CI = 0.31-0.96; P = .04; I = 54%). In different anti-HER2 agents analysis, the PTEN normal tumors was related to a significant increase in PCR rate in patients treated with trastuzumab alone (OR 0.40; 95% CI = 0.24-0.67; P = .0005; I = 15%). Besides, no significant association between PTEN status and PCR rate was detected in patients treated with lapatinib alone (OR 1.90; 95% CI = 0.78-4.60; P = .16; I = 0%) or trastuzumab plus lapatinib (OR 1.27; 95% CI = 0.27-5.97; P = .76; I = 73%). CONCLUSION: Based on current evidence, PTEN status could be n suitable biomarker in predicting PCR rate to neoadjuvant anti-HER2 therapies, especially in trastuzumab-treated patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , PTEN Fosfo-Hidrolase/sangue , Receptor ErbB-2/biossíntese , Biomarcadores Tumorais , Neoplasias da Mama/terapia , Feminino , Humanos , PTEN Fosfo-Hidrolase/biossíntese , Trastuzumab/uso terapêutico
12.
Pathol Res Pract ; 215(5): 910-917, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772061

RESUMO

Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Receptor ErbB-2/biossíntese , Neoplasias Retais/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/análise , Neoplasias Retais/mortalidade , Neoplasias Retais/terapia , Estudos Retrospectivos
13.
Perm J ; 23: 18-088, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30624197

RESUMO

BACKGROUND: American Society of Clinical Oncology and College of American Pathologists guidelines recommend repeated evaluation of human epidermal growth factor receptor 2 (HER2) status on surgical specimens from patients with a diagnosis by core-needle biopsy of Grade 3, HER2-negative invasive tumors of the breast. However, there are limited data to support reflexive testing. OBJECTIVE: To evaluate the utility of HER2 retesting of histologic Grade 3, HER2-negative invasive breast carcinomas. METHODS: We evaluated 78 patients from Kaiser Permanente East Bay in whom Grade 3, HER2-negative invasive breast carcinoma was diagnosed between 2015 and 2017 by core biopsy, to compare HER2 status on core biopsy vs excisional biopsy specimen. The HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, or both. All patients were retested for HER2 status on surgical specimen according to the aforementioned guidelines. Recipients of neoadjuvant chemotherapy were excluded. RESULTS: One of the 78 patients demonstrated negative-to-positive status discordance between core biopsy and surgical specimens and was treated with trastuzumab. One patient was HER2 negative by core biopsy and was HER2 equivocal by immunohistochemical and fluorescent in situ hybridization evaluation of the surgical specimen. Seventy-six patients demonstrated concordant HER2 status between core biopsy and surgical specimens. CONCLUSION: The rate of clinically significant HER2 status discordance between core biopsy and surgical specimens in patients with Grade 3 breast carcinoma is low. However, given the dramatically improved survival conferred by trastuzumab therapy, our findings support reflex HER2 testing of surgical specimens for patients with core biopsy-diagnosed HER2-negative breast carcinoma.


Assuntos
Neoplasias da Mama/patologia , Receptor ErbB-2/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Grupos de Populações Continentais , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Valor Preditivo dos Testes , Trastuzumab/uso terapêutico
14.
Gynecol Oncol ; 153(1): 158-164, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30630630

RESUMO

OBJECTIVE: Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu. METHODS: We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting. RESULTS: We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AKT proteins after afatinib exposure when compared to controls ARK2. CONCLUSIONS: Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.


Assuntos
Afatinib/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Fosfatidilinositol 3-Quinases/genética , Adulto , Idoso , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/biossíntese , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias dos Genitais Femininos/enzimologia , Neoplasias dos Genitais Femininos/genética , Humanos , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinases/biossíntese , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Obes Surg ; 29(4): 1092-1098, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659466

RESUMO

BACKGROUND: Bariatric surgery is associated with a reduced risk of developing certain malignancies, particularly in women. However, the impact of bariatric surgery on tumor characteristics, cancer treatment, and oncologic outcomes is unknown. METHOD: In a retrospective cohort study, 42 subjects diagnosed with breast cancer after bariatric surgery (1989-2014) were matched to 84 subjects with breast cancer (1984-2012) who did not undergo bariatric surgery, based on age, body mass index (BMI), and menopausal status at the time of breast cancer diagnosis, as well as the date of cancer diagnosis. Medical records were reviewed for cancer and bariatric endpoints. Statistical analysis was performed using mixed effects regression models, generalized estimating equation, conditional logistic regression, and Fisher's exact tests. RESULTS: Women who developed breast cancer after bariatric surgery presented at an earlier stage compared to non-operated, obese controls. In the bariatric surgery group, there were fewer tumors with human epidermal growth factor receptor 2 overexpression (HER2+) (OR 0.16 (0.03-0.76); p = 0.02), with no significant differences seen in estrogen and progesterone receptor positivity. No HER2+ cancers were found in patients who underwent Roux-en-Y gastric bypass (OR 0.00 (0.00-0.43); p = 0.002). On multivariate analysis, bariatric surgery status remained associated with reduced HER2+ breast cancers (OR 0.18 (0.03-0.99); p < 0.05). At a mean follow-up of 5 years, bariatric surgery was associated with trends toward reduced cancer-specific and all-cause mortality. CONCLUSIONS: Bariatric surgery is associated with reduced HER2+ breast cancers, suggesting that bariatric surgery can influence breast cancer characteristics and, potentially, tumor biology.


Assuntos
Cirurgia Bariátrica , Neoplasias da Mama/prevenção & controle , Obesidade/cirurgia , Receptor ErbB-2/biossíntese , Adulto , Idoso , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Derivação Gástrica , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Retrospectivos
16.
PLoS One ; 14(1): e0211047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682091

RESUMO

BACKGROUND/PURPOSE: Aptamers are oligonucleotide or peptide molecules that bind to a target molecule with high affinity and specificity. The present study aimed to evaluate the target specificity and applicability for in vivo molecular imaging of an aptamer labeled with a radioisotope. METHODS: The human epidermal growth factor receptor 2 (HER2/ErbB2) aptamer was radiolabeled with 18F-fluoride. HER2-positive tumor cell uptake of the aptamer was evaluated in comparison to negative controls by flow cytometry and confocal microscopy. Using 18F-labeled HER2-specific aptamer positron emission tomography (PET), in vivo molecular images of BT474 tumor-bearing mice were taken at 60, 90 and 120 minutes after injection. RESULTS: In flow cytometric analysis, HER2 aptamer showed strong binding to HER2-positive BT474 cells, while binding to HER2-negative MDA-MB231 cells was quite low. Likewise, in confocal microscopic images, the aptamer was bound to HER2-positive breast cancer cells, with minimal binding to HER2-negative cells. In vivo PET molecular imaging of BT474 tumor-bearing mice revealed significant higher uptake of the 18F-labeled HER2 specific aptamer into the tumor compared to the that of HER2-negative cell tumor(p = 0.033). HER2 aptamer was able to preferentially bind to HER2-positive breast cancer cells both in vitro and in vivo, by recognizing HER2 structure on the surface of these cells. CONCLUSION: The 18F-labeled aptamer enabled appropriate visualization of HER2 expression by human breast cancer cells. The results suggest that a radiolabeled HER2 aptamer could potentially be applied in the development of treatment strategies or in targeted therapy against HER2-positive breast cancer cells.


Assuntos
Aptâmeros de Nucleotídeos , Neoplasias da Mama , Radioisótopos de Flúor , Regulação Neoplásica da Expressão Gênica , Marcação por Isótopo , Tomografia por Emissão de Pósitrons , Receptor ErbB-2/biossíntese , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacocinética , Aptâmeros de Nucleotídeos/farmacologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Radioisótopos de Flúor/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
17.
Int J Cancer ; 145(3): 748-762, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30694565

RESUMO

An understanding of the mechanisms underlying acquired resistance to cetuximab is urgently needed to improve cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Here, we present a clinical observation that MET pathway activation constitutes the mechanism of acquired resistance to cetuximab in a patient with HNSCC. Specifically, RNA sequencing and mass spectrometry analysis of cetuximab-sensitive (CetuxSen ) and cetuximab-resistant (CetuxRes ) tumors indicated MET amplification and overexpression in the CetuxRes tumor compared to the CetuxSen lesion. Stimulation of MET in HNSCC cell lines was sufficient to reactivate the MAPK pathway and to confer resistance to cetuximab in vitro and in vivo. In addition to the direct role of MET in reactivation of the MAPK pathway, MET stimulation abrogates the well-known cetuximab-induced compensatory feedback loop of HER2/HER3 expression. Mechanistically, we showed that the overexpression of HER2 and HER3 following cetuximab treatment is mediated by the ETS homologous transcription factor (EHF), and is suppressed by MET/MAPK pathway activation. Collectively, our findings indicate that evaluation of MET and HER2/HER3 in response to cetuximab in HNSCC patients can provide the rationale of successive line of treatment.


Assuntos
Cetuximab/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Cetuximab/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Expressão Gênica , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Distribuição Aleatória , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/biossíntese , Receptor ErbB-3/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Sulfonas/farmacologia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Cancer Res Clin Oncol ; 145(4): 821-828, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30603906

RESUMO

PURPOSE: Hormone receptors (HR) status in HER2 + breast cancer (BC) is a recognized stratification factor with relevant clinical implication. According to HR expression, HER2 + BC show different clinical characteristics, treatment sensitivity and prognosis. The interaction between HR and HER2 pathways remains incompletely understood. METHODS: Thirty-four HER2 + BC were included: 18 tumors with HER2+/HR + and 16 with HER2+/HR-. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer Pathway panel performed on FFPE BC biopsies. RESULTS: Gene expression analysis identified 127 genes with significantly different expression between the two cohorts. 83% of these genes were overexpressed in HER2+/HR- cohort. Globally, 23% of them belonged to PI3K pathway (41 genes), 15% to Trascriptional regulation (26 genes) and 12% to MAPK (22 genes). Regarding pathway expression, PI3K, MAPK and NOTCH were significantly differently expressed between the two groups (p = 0.003, p = 0.0018 and p = 0.02, respectively), all of them were overexpressed in HER2+/HR- tumors. CONCLUSIONS: According to HR status, HER2 + tumors express different pathways profiles: the overexpression of PI3K, MAPK and NOTCH pathways in HER2+/HR- group could justify different survival outcomes and treatment sensitivity. The identification of tumor driver pathways may be a useful instrument for individualized pathway-directed therapies. Further clinical implications are warranted.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/biossíntese , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/biossíntese , Biópsia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Inclusão em Parafina , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Estudos Retrospectivos
19.
Gastric Cancer ; 22(2): 335-343, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29951752

RESUMO

BACKGROUND: Receptor tyrosine kinases (RTKs) play critical roles in gastric cancer (GC) progression and are potential targets for novel molecular-targeted agents or photo-immunotherapies. During patient selection, targeted biopsy is the first step. However, heterogeneous expression of RTKs based on the macroscopic appearance in GC has not been extensively addressed. Accordingly, in this study, we evaluated differences in RTK expression associated with macroscopic appearance in GC. METHODS: In total, 375 consecutive patients who had undergone gastrectomy at the National Cancer Center Hospital East and who had histologically proven adenocarcinoma, available archived tumor sample, and no history of chemotherapy were enrolled in this study. For these cases, tissue microarray (TMA) samples were examined using immunohistochemistry (IHC). Based on the results of IHC, cases were selected for detailed examination. We re-evaluated IHC scores in more than three tumor blocks per case and comparatively evaluated differences in IHC expression in RTKs between the mucosal portion (MuP) and invasive portion (InP). RESULTS: Human epidermal growth factor receptor 2 (HER2)-, epidermal growth factor receptor (EGFR)-, and mesenchymal epithelial transition factor (c-MET)-positive rates were 6, 9, and 20%, respectively. Twenty-two cases were then analyzed to assess differences in IHC expression levels in the same lesion. Concordance rates of positive staining of HER2, EGFR, and MET between MuP and whole tumor were 100, 40, and 56% and those with InP were 46, 100, and 56%. CONCLUSIONS: To avoid underestimating expression status, biopsies must be taken from MuP for HER2, InP for EGFR, and both proportions for c-MET.


Assuntos
Adenocarcinoma/patologia , Proteínas Proto-Oncogênicas c-met/biossíntese , Receptor ErbB-2/biossíntese , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Receptores ErbB/análise , Receptores ErbB/biossíntese , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met/análise , Receptor ErbB-2/análise
20.
Gastric Cancer ; 22(2): 355-362, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30088161

RESUMO

BACKGROUND: Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma; however, there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial. METHODS: Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity. RESULTS: We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62 years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4 months, the 6-month PFS was 73% (95% CI 51-86%). The objective response rate was 65%, the median PFS was 13 months (95% CI 6.4-20.7) and the median OS was 24.9 months (95% CI 14.4-42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia. CONCLUSION: The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number NCT00515411.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/administração & dosagem , Adenocarcinoma/mortalidade , Adulto , Idoso , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Junção Esofagogástrica/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Receptor ErbB-2/biossíntese , Neoplasias Gástricas/mortalidade , Trastuzumab/efeitos adversos
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