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INTRODUCTION: This multicenter, phase II randomized, non-inferiority study reports from the first prospective two-armed randomized control trial that compared the efficacy, safety and quality-of-life of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based as adjuvant chemotherapy for stage I-II Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer. METHODS: Patients with stage I/II HER2-negative breast cancer received PLD (37.5mg/m2, Q3W, 5 cycles, LC arm) plus cyclophosphamide (600mg/m2) or epirubicin (90mg/m2, Q3W, 4 cycles, EC arm) plus cyclophosphamide (600mg/m2). Randomization was stratified by lymph node, ER and PR status. The primary endpoint was disease-free survival (DFS), and secondary endpoints were overall survival (OS), safety profiles, and quality of life (QoL). QoL was assessed using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. RESULTS: A total of 256 patients were assigned to LC (n=148) and EC (n=108). There was no difference in 5-year DFS and OS rate between two groups. LC-based adjuvant regimens had significantly less alopecia, less grade 3-4 hematologic adverse events (AEs). Significantly improved QoL was observed in the LC arm during and after treatment for symptoms including fatigue, nausea and vomiting, and systemic therapy side effects. CONCLUSION: Comparable efficacy and safety between adjuvant PLD and epirubicin for stage I-II HER2-negative breast cancer was observed. There was no difference in 5-year DFS and OS rate between the two treatment arms. However, less grade 3-4 AEs and a trend of favorable QoL symptom scales were observed in the LC arm, suggesting that PLD-containing regimen could become a new standard treatment for early stage HER2-negative breast cancer patients.
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Triple-negative breast cancer (TNBC) represents a challenging malignancy with limited treatment options and a poor prognosis. Adjuvant therapies, including chemotherapy and immune checkpoint inhibitors (ICI), are commonly employed following breast conservation surgery. However, these treatments can lead to various adverse effects, including cutaneous complications and connective tissue disorders. Here, we present the case of a 54-year-old woman with TNBC who developed morphea, a form of localized scleroderma, following adjuvant chemotherapy and pembrolizumab administration. This case highlights the rarity of drug-induced morphea and emphasizes the importance of recognizing and managing such adverse events in breast cancer patients. We discuss the clinical characteristics, diagnostic challenges, and treatment considerations associated with drug-induced scleroderma-like lesions, as well as the potential mechanisms underlying their development. Furthermore, we review the literature on the incidence, clinical features, and outcomes of scleroderma-like lesions induced by chemotherapy and ICIs. This case underscores the need for increased awareness of immune-related adverse events in patients receiving immunotherapy, as well as the importance of individualized treatment approaches to optimize patient care and outcomes.
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Anticorpos Monoclonais Humanizados , Humanos , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Esclerodermia Localizada/induzido quimicamente , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.
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Neoplasias da Mama , Autofagia Mediada por Chaperonas , RNA Helicases DEAD-box , Ribonuclease III , Feminino , Humanos , Autofagia/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Choque Térmico HSC70/genética , Proteínas de Choque Térmico HSC70/metabolismo , Lisossomos/metabolismo , Proteólise , Metástase Neoplásica , RNA Helicases DEAD-box/metabolismo , Ribonuclease III/metabolismoRESUMO
PURPOSE: We analyzed data from the National Health Insurance Research Database (NHIRD) in Taiwan, collected information regarding human papillomavirus (HPV) and breast cancer prevalence, and explored the association between HPV infection and the risk of breast carcinoma. METHODS: We included the NHIRD data of 30,936 insured patients aged 20 years an older without breast cancer prior to the index date (date of HPV diagnosis) and matched each patient with a reference subject according to age, comorbidities, and index year (1:1 ratio). We calculated the incidence rates of breast cancer in the cohorts, age groups, and comorbidity groups, as well as the relative risk of breast cancer stratified by age and comorbidity in the HPV and non-HPV groups. RESULTS: The patients with and without HPV had incidence rates of 12.5 and 9.81 per 10,000 person years, respectively. The risk of breast cancer for the 50-64 and ≥65 age groups was 1.67 and 1.36 times higher than that in patients younger than 49 years, respectively, and hypertension, chronic obstructive pulmonary disease, and diabetes mellitus were significant risk factors for breast cancer. The HPV group had a higher risk of developing breast cancer than the non-HPV group, regardless of age group and the presence or absence of comorbidities. Patients with HPV in the 50-64 age group were 1.39 times more likely to develop breast cancer than patients of the same age without HPV. CONCLUSION: Patients older than 49 were more likely to develop breast cancer, and patients with HPV had a higher likelihood of developing breast cancer, regardless of age and the presence or absence of comorbidities. HPV likely plays a causal role in breast cancer.
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BACKGROUND: Breast cancer is an umbrella term referring to a group of biologically and molecularly heterogeneous diseases originating from the breast. Globally, incidences of breast cancer has been increasing dramatically over the past decades. Analyses of multiple clinical "big data" can aid us in clarifying the means of preventing the disease. In addition, predisposing risk factors will be the most important issues if we can confirm their relevance. This study aims to provide an overview of the predisposing factors that contribute to a higher possibility of developing breast cancer and emphasize the signs that we ought to pay more attention to. METHODS: This is a matched nested case-control study. The cohort focused on identifying the eligible risk factors in breast cancer development by data screening (2000-2013) from the Taiwan National Health Insurance Research Database (NHIRD) under approved protocol. A total of 486,069 females were enrolled from a nationwide sampled database, and 3281 females was elligible as breast cancer cohort, 478,574 females who had never diagnosed with breast cancer from 2000 to 2013 were eligible as non-breast cancer controls, and matched to breast cancer cases according to age using a 1:6 ratio. RESULTS: We analyzed 3281 breast cancer cases and 19,686 non-breast cancer controls after an age-matched procedure. The significant predisposing factors associated with breast cancer development including obesity, hyperlipidemia, thyroid cancer and liver cancer. As for patients under the age of 55, gastric cancer does seem to have an impact on the development of breast cancer; compared with their counterparts over the age of 55, endometrial cancer appears to exhibit an evocative effect. CONCLUSIONS: In this nationwide matched nested case-control study, we identified obesity, hyperlipidemia, previous cancers of the thyroid, stomach and liver as risk factors associated with breast cancer. However, the retrospective nature and limited case numbers of certain cancers still difficult to provide robust evidence. Further prospective studies are necessitated to corroborate this finding in order to nip the disease in the bud. TRIAL REGISTRATION: The studies involving human participants were reviewed and approved by the China Medical University Hospital [CMUH104-REC2-115(AR-4)].
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Neoplasias da Mama , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Obesidade/complicações , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Distant metastasis is the leading cause of death in patients with breast cancer. Despite considerable treatment advances, the clinical outcomes of patients with metastatic breast cancer remain poor. CSCs can self-renew, enhancing cancer progression and metastasis. Dicer, a microRNA (miRNA) processing-related enzyme, is required for miRNA maturation. Imbalanced Dicer expression may be pivotal in cancer progression. However, whether and how Dicer affects the stemness of metastatic breast cancer cells remains unclear. Here, we hypothesized that Dicer regulates the migration, invasion, and stemness of breast cancer cells. We established highly invasive cell lines (MCF-7/I-3 and MDA-MB-231/I-3) and observed that Dicer expression was conspicuously lower in the highly invasive cells than in the parental cells. The silencing of Dicer significantly enhanced the cell migratory/invasive abilities and CSCs properties of the breast cancer cells. Conversely, the overexpression of Dicer in the highly invasive cells reduced their migration, invasion, and CSCs properties. Our bioinformatics analyses demonstrated that low Dicer levels were correlated with increased breast cancer risk. Suppression of Dicer inhibited miR-200b expression, whereas miR-200b suppression recovered Dicer knockdown-induced migration, invasion, and cancer stem cells (CSCs) properties of the breast cancer cells. Thus, our findings reveal that Dicer is a crucial regulator of the migration, invasion, and CSCs properties of breast cancer cells and is significantly associated with poor survival in patients with breast cancer.
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Neoplasias da Mama , RNA Helicases DEAD-box , MicroRNAs , Ribonuclease III , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , RNA Helicases DEAD-box/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Ribonuclease III/genéticaRESUMO
The aim of this study was to confirm post-traumatic growth with respect to the psychological well-being of women with breast cancer compared to women without disease. Propensity score was used to match the two groups according to age, religious beliefs, education level, monthly income, and marital status. A psychological well-being scale with six factors was used, including positive relations with others (PR), autonomy (AU), environmental mastery (EM), personal growth (PG), purpose in life (PL), and self-acceptance (SA). A total 178 women with vs. 178 women without breast cancer were compared by matching with propensity scores, using factorial invariance tests to reduce measurement errors. The results showed that women with breast cancer had significantly higher psychological well-being for all the six factors (Δχ2 = 37.37, p < 0.001) and higher variability in terms of PR, AU, and PL than women without breast cancer (Δχ2 = 45.94, p < 0.001). Furthermore, women with breast cancer exhibited a significantly higher association between PG and PL and a significantly lower association between PG and EM than women without breast cancer (Δχ2 = 44.49, p < 0.001). This implies that psychological well-being could assess broader and more subtle post-traumatic growth in women with breast cancer and that growth was more associated with internal life value than with external environmental control.
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PURPOSE: A special association between breast cancer and second primary lung cancer in Taiwanese women has been discovered not only in clinical practice, but also in a large population-based study. We hereby investigate the association between breast cancer and second primary lung cancer in Taiwanese women. METHODS: This study was conducted from the National Health Insurance Research Database (NHIRD) from Taiwan National Health Insurance (NHI). Patients older than 18 years old and hospitalized with a first diagnosis of breast cancer during 2000 to 2012 were enrolled in the breast cancer group. Patients who were cancer free were frequency-matched with the breast cancer group by age (every five-year span) and index year. The ratio of breast cancer group to non-breast cancer group was 1:4. The event as the outcome in this study was lung cancer. The comorbidities viewed as important confounding factors included coronary artery disease, stroke, hypertension, diabetes, chronic obstructive pulmonary disease, hyperlipidemia, tuberculosis, chronic kidney disease, and chronic liver disease and cirrhosis. We estimated the hazard ratios (HRs), adjusted hazard ratios (aHRs), and 95% confidence intervals (CIs) for risk of lung cancer in the breast cancer group and non-breast cancer group using Cox proportional hazard models. Sensitivity analysis was also done using propensity score matching. All of the statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: There were 94,451 breast cancer patients in the breast cancer group and 377,804 patients in the non-breast cancer group in this study. After being stratified by age, urbanization level, and comorbidities, the patients with breast cancer had a significantly higher risk of lung cancer compared with the patients without breast cancer, particularly for those who aged between 20 and 49 years (aHR = 2.10, 95% CI = 1.71-2.58), 50 and 64 years (aHR = 1.35, 95% CI = 1.15-1.58), and those without any comorbidities (aHR = 1.92, 95% CI = 1.64-2.23). CONCLUSION: Patients with breast cancer had a significantly higher risk of developing second primary lung cancer compared with patients without breast cancer, particularly in younger groups and in those without any comorbidities. The special association may be attributed to some potential risk factors such as genetic susceptibility and long-term exposure to PM2.5, and is supposed to increase public awareness. Further studies are necessary given the fact that inherited genotypes, different subtypes of breast cancer and lung cancer, and other unrecognized etiologies may play vital roles in both cancers' development.
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BACKGROUND: Insomnia, depressive disorders, and to a more general view, mood disorders are raising people's concerns and causing disability of life. Herein, we try to seek the association of such illnesses with subsequent breast cancer. METHODS: This population-based, retrospective cohort study used data from the Taiwan National Health Insurance Research Database. This study included 232,108 women diagnosed with insomnia, depressive disorders, and mood disorders from January 1, 2000 to December 31, 2013. Physician diagnosed insomnia, depressive disorders, or mood disorders using outpatient and inpatient records before diagnosis of breast cancer. Cox proportional hazards regression analysis is adjusted for women with insomnia, depressive disorders, mood disorders, and other factors like insured amount, urbanization, and comorbidities such as having subsequent breast cancer. RESULTS: Sleep medication was associated with a significantly increased incidence rate of breast cancer (aHR = 1.23 (95% CI = 1.13, 1.35), p < 0.001). Insomnia was associated with significant increased hazard of breast cancer (aHR = 1.16 (95% CI = 1.07, 1.27), p < 0.001). Annual insured amount >20,000 (TWD), high urbanization area, and hyperlipidemia were associated with increased hazard of breast cancer (aHR = 1.13 (95% CI = 1.01, 1.27), p = 0.04; aHR = 1.41 (95% CI = 1.17, 1.71), p < 0.001; aHR = 1.14 995% CI = 1.02, 1.29), p = 0.02, respectively). There was a positive correlation between depressive disorders and increased incidence rate of breast cancer but not statistically significant (aHR = 1.11 (95% CI = 0.99, 1.25), p = 0.08). Mood disorders were not associated with increased hazard (aHR = 1.11 (95% CI = 0.91, 1.34), p = 0.31). CONCLUSION: In this study, women with insomnia had increased risk of breast cancer, particularly those in high urbanization or with high insured amounts. Sleep medication (benzodiazepine (BZD) or non-BZD) and hyperlipidemia were independently associated with a higher hazard ratio of breast cancer. Insomnia along with sleep medication did not yield more hazards than each alone. Mood disorders appeared to be not associated with subsequent breast cancer. However, depressive disorders, the subgroups of mood disorders, could possibly increase the incidence rate of breast cancer though not statistically significant.
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Mutant p53 (mutp53) commonly loses its DNA binding affinity to p53 response elements (p53REs) and fails to induce apoptosis fully. However, the p53 mutation does not predict chemoresistance in all subtypes of breast cancers, and the critical determinants remain to be identified. In this study, mutp53 was found to mediate chemotherapy-induced long intergenic noncoding RNA-p21 (lincRNA-p21) expression by targeting the G-quadruplex structure rather than the p53RE on its promoter to promote chemosensitivity. However, estrogen receptor alpha (ERα) suppressed mutp53-mediated lincRNA-p21 expression by hijacking mutp53 to upregulate damaged DNA binding protein 2 (DDB2) transcription for subsequent DNA repair and chemoresistance. Levels of lincRNA-p21 positively correlated with the clinical responses of breast cancer patients to neoadjuvant chemotherapy and had an inverse correlation with the ER status and DDB2 level. In contrast, the carboplatin-induced DDB2 expression was higher in ER-positive breast tumor tissues. These results demonstrated that ER status determines the oncogenic function of mutp53 in chemoresistance by switching its target gene preference from lincRNA-p21 to DDB2 and suggest that induction of lincRNA-p21 and targeting DDB2 would be effective strategies to increase the chemosensitivity of mutp53 breast cancer patients.
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ABSTRACT: Breast cancer has the highest incidence of cancer among women in Taiwan, and air pollutants have been documented to have multiple adverse effects on human health. There is no relevant data, there has been no research in Taiwan to discuss the relevance of air pollutants to breast cancer, and evidence is sparse and inconclusive.Air quality data used in this study was collected from the 78 air quality monitoring stations situated in 74 municipalities in Taiwan during 2000 to 2011. The daily measurements taken at each monitoring station represented the level of exposure for each participant residing in that zone. The air pollution concentration is partitioned based on the concentration level in Quartile. We calculate the annual average air pollutants concentration (CO, NO, NO2, PM2.5, THC, and CH4) and the long-term average exposure levels of these pollutants until diagnosis of breast cancer, ending the study period for each individual.Patients who were living in areas with the highest air pollutants concentration (Quartile 4) had the most people diagnosed with breast cancer (CO:1.47%, NO:1.41%, NO2:1.63%, PM2.5:0.91%, THC:1.53%, CH4:2.33%). The patients who were exposed to Quartile 1 level of CO, NO, and NO2 concentration were the oldest, and other patients who were exposed to Quartile 4 level of CO, NO, and NO2 concentration were living in the areas of highest urbanization. Participants exposed to Quartile 4 level concentrations of air pollutants were associated with highest hazards ratios for breast cancer incidences.Most participants who were exposed to the high concentration of air pollutants (CO, THC and CH4) had a significantly higher risk of breast cancer. If we can improve air pollution in the environment, we can reduce the incidence of breast cancer and save precious medical resources.
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Poluição do Ar/efeitos adversos , Neoplasias da Mama/epidemiologia , Adulto , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Neoplasias da Mama/diagnóstico , Monitoramento Ambiental , Feminino , Humanos , Pessoa de Meia-Idade , Material Particulado , Estudos Retrospectivos , Taiwan , Adulto JovemRESUMO
OBJECTIVES: The results of studies investigating the relationship between breast cancer and hypothyroidism vary greatly from study to study. In this study, we analyzed a large and reliable, population-based database to gain a better understanding of the correlation. METHODS: This retrospective cohort study analyzed patients with hypothyroidism between January 1, 2000 and December 31, 2012 (hypothyroidism cohort) from the Longitudinal Health Insurance Database 2000 in Taiwan. For each woman with hypothyroidism, 1 woman without a history of breast cancer was randomly selected from the Longitudinal Health Insurance Database 2000 and frequency matched (1:4) with women without hypothyroidism by age and index year of hypothyroidism. The study outcome was the diagnosis of breast cancer during a 12-year follow-up period. RESULTS: In this study, 6665 women with hypothyroidism and 26 660 women without hypothyroidism were identified. The hypothyroidism cohort had a significantly higher risk of breast cancer than the nonhypothyroidism cohort (adjusted hazard ratio [aHR] 1.69 [95% CI, 1.15-2.49]; P = .01), especially in the group aged 40 to 64 years (aHR 2.07 [95% CI, 1.32-3.23]; P = .01). Women in the hypothyroidism cohort taking levothyroxine for a duration Ë588 days showed a significantly decreased risk of breast cancer (aHR 0.37 [95% CI, 0.19-0.71]; P = .003). CONCLUSION: Women with hypothyroidism are at a higher risk of breast cancer than those without hypothyroidism. Levothyroxine may reduce the risk of breast cancer in a woman with hypothyroidism.
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Neoplasias da Mama , Hipotireoidismo , Adulto , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Feminino , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/epidemiologia , Incidência , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
BACKGROUND/AIM: Breast cancer is a common type of cancer in women, and metastasis frequently leads to therapy failure. Using next-generation sequencing (NGS), we aspired to identify the optimal differentially expressed genes (DEGs) for use as prognostic biomarkers for breast cancer. MATERIALS AND METHODS: NGS was used to determine transcriptome profiles in breast cancer tissues and their corresponding adjacent normal tissues from three patients with breast cancer. RESULTS: Herein, 15 DEGs (fold change >4 and <0.25) involved in extracellular matrix (ECM)-receptor interaction signaling were identified through NGS. Among them, our data indicated that high HMMR expression levels were correlated with a poor pathological stage (p<0.001) and large tumor size (p<0.001), whereas high COL6A6 and Reelin (RELN) expression levels were significantly correlated with an early pathological stage (COL6A6: p=0.003 and RELN: p<0.001). Multivariate analysis revealed that high HMMR and SDC1 expression levels were significantly correlated with poor overall survival (OS; HMMR: adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI]=1.10-3.41, p=0.023; SDC1: [aHR] 2.47, 95%CI=1.28-4.77, p=0.007) for breast cancer. Combined, the effects of HMMR and SDC1 showed a significant correlation with poor OS for patients with breast cancer (high expression for both HMMR and SDC1: [aHR] 3.29, 95%CI=1.52-7.12, p=0.003). CONCLUSION: These findings suggest that HMMR and SDC1 involved in the ECM-receptor interaction signaling pathway could act as effective independent prognostic biomarkers for breast ductal carcinoma.
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Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Receptores de Superfície Celular/genética , Transdução de Sinais/genética , Adulto , Biomarcadores Tumorais/genética , Mama/patologia , Neoplasias da Mama/patologia , Moléculas de Adesão Celular Neuronais/genética , Colágeno Tipo VI/genética , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Receptores de Hialuronatos/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Prognóstico , Proteína Reelina , Serina Endopeptidases/genética , Sindecana-1/genética , Transcriptoma/genéticaRESUMO
BACKGROUND: High Snail expression is known as a poor prognostic factor in breast cancer. However, its prognostic impact for breast cancer with different molecular subtypes is still controversial. METHODS: Snail expression was examined by immunohistochemistry in tissue microarray slides of 85 corresponding tumor-adjacent normal (CTAN) and 247 breast invasive ductal carcinoma (IDC) tissues. Multivariable Cox regression analysis was used to assess the impact of Snail expression on survival rate by different molecular subtypes of breast IDC patients. RESULTS: The level of Snail expression in IDC tumor tissues was significantly higher than that in CTAN tissues. Moreover, high Snail expression had direct impacts on poor disease specific survival (DSS) and disease-free survival (DFS) in breast IDC patients with human epidermal growth factor receptor 2 (HER2)-positive and human epidermal growth factor receptor (EGFR)-positive statuses as well as the HER2 intrinsic subtype. Additionally, breast IDC patients with a combination of three prognostic factors, including high Snail expression and HER2-positive and EGFR-positive statuses, had much poor DSS and DFS with a statistically significant linear trend. CONCLUSION: High Snail expression could predict a poor prognosis for breast IDC patients with HER2/EGFR-positive subtypes.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Receptores ErbB/metabolismo , Receptor ErbB-2/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de SobrevidaRESUMO
BACKGROUND: In this multi-center study, we report the patient selection criteria for and preliminary oncologic outcomes associated with intraoperative radiotherapy (IORT) delivered by the Xoft Axxent® eBx® system for early-stage breast cancer in Taiwan. METHODS: Patients with early breast cancer in Taiwan received breast conserving surgery and received IORT with Xoft Axxent® eBx® System during 2013-2015 was search from database of Taiwan IORT study cooperative group (T-IORTSCG). Patients' clinicopathologic characteristics and early post-operative results were collected and reported. RESULTS: During the study period, 26 hospitals in Taiwan performed a total of 261 Xoft IORT procedures for breast cancer. The mean age of them was 52.9 ± 9.8 years (37-72), and tumor size was 1.5 ± 0.8 cm (0.1-4.2 cm) for invasive cancer and 1.2 ± 0.8 cm (range, 0.2-3.0 cm) for ductal carcinoma in situ (DCIS) lesions. Lymph node metastasis was found in 6 (2.3%) patients. The patients received IORT in Taiwan differed markedly from those used in the ELIOT and TARGIT-A studies. Specifically, patients selected for IORT in Taiwan tended to be younger, their tumors tended to be larger and the prevalence of lymph node metastasis tended to be lower. Among these 261 patients, 8 (3.1%) patients required whole breast radiotherapy. During a mean follow up of 15.6 months, locoregional recurrence was observed in 2 (0.8%) patients. CONCLUSION: In real world experience, patients received IORT differed quite significantly with criteria formulated by trials. The preliminary results of IORT in Taiwan showed it is well acceptable by patients and clinicians.
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Neoplasias da Mama/radioterapia , Cuidados Intraoperatórios/métodos , Seleção de Pacientes , Radioterapia/efeitos adversos , Adulto , Neoplasias da Mama/patologia , Diagnóstico Precoce , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , TaiwanRESUMO
Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin-dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK-mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor-induced Akt activation.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Retroalimentação Fisiológica , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Fosfotreonina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Sequência de Aminoácidos , Linhagem Celular Tumoral , Clatrina/metabolismo , Regulação para Baixo , Endocitose/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Ligação Proteica , Multimerização Proteica/efeitos dos fármacos , Receptor ErbB-2/químicaRESUMO
Since BRCA mutations are only responsible for 10-20% of cases of breast cancer in patients with early-onset or a family history and since next-generation sequencing technology allows the simultaneous sequencing of a large number of target genes, testing for multiple cancer-predisposing genes is now being considered, but its significance in clinical practice remains unclear. We then developed a sequencing panel containing 68 genes that had cancer risk association for patients with early-onset or familial breast cancer. A total of 133 patients were enrolled and 30 (22.6%) were found to carry germline deleterious mutations, 9 in BRCA1, 11 in BRCA2, 2 in RAD50, 2 in TP53 and one each in ATM, BRIP1, FANCI, MSH2, MUTYH, and RAD51C. Triple-negative breast cancer (TNBC) was associated with the highest mutation rate (45.5%, p = 0.025). Seven of the 9 BRCA1 mutations and the single FANCI mutation were in the TNBC group; 9 of the 11 BRCA2, 1 of the 2 RAD50 as well as BRIP1, MSH2, MUTYH, and RAD51C mutations were in the hormone receptor (HR)(+)Her2(-) group, and the other RAD50, ATM, and TP53 mutations were in the HR(+)Her2(+) group. Mutation carriers were considered as high-risk to develop malignancy and advised to receive cancer screening. Screening protocols of non-BRCA genes were based on their biologic functions; for example, patients carrying RAD51C mutation received a screening protocol similar to that for BRCA, since BRCA and RAD51C are both involved in homologous recombination. In conclusion, we consider that multiple gene sequencing in cancer risk assessment is clinically valuable.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Medição de Risco , Adulto , Idade de Início , Idoso , Neoplasias da Mama/classificação , Feminino , Genes Supressores de Tumor , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3'UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.
Assuntos
Movimento Celular/efeitos dos fármacos , Interleucina-6/metabolismo , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Quinazolinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/farmacologia , Western Blotting , Proliferação de Células/efeitos dos fármacos , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Interleucina-6/genética , Lapatinib , Proteína Quinase 1 Ativada por Mitógeno/genética , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-raf/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais CultivadasRESUMO
DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.