RESUMO
BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).
Assuntos
Antineoplásicos Imunológicos , Neoplasias da Mama , Receptor ErbB-2 , Trastuzumab , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Camptotecina/análogos & derivados , Progressão da Doença , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/uso terapêutico , Imuno-Histoquímica , Receptor ErbB-2/análise , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêuticoRESUMO
PURPOSE: In our previous study, Developmental endothelial locus-1 (Del-1) was a promising predictive marker for breast cancer. However, the downstream targets of Del-1 remain unknown. Here, we sought to discover a druggable target downstream of Del-1 and investigate the mechanism by which it regulates the course of breast cancer. METHODS: To investigate Del-1 downregulation effect on breast cancer, we performed transcriptome analysis using RNA sequencing of Del-1 knockdowned MDA-MB-231 cell line Plus, to investigate the expression of Del-1 and Maternal embryonic leucine zipper kinase (MELK), mRNA levels in eight different triple-Negative Breast Cancer (TNBC) cell lines were analyzed. High-throughput sequencing was performed on total RNA isolated. OTS167 was used for MELK inhibition. The effects of MELK on cell proliferation and invasion were determined using the MTT and Matrigel transwell assays. Furthermore, we examined MELK expression in breast cancer tissue. RESULTS: Del-1 and MELK mRNA expression levels were significantly higher in the TNBC cell lines, MDA-MB-468, HCC-1806, and MBA-MB-231. Knocking down Del-1 with siRNA in HCC-1806 and MBA-MB-231 cells significantly decreased MELK expression and thus suggested a possible relationship between Del-1 and MELK. In MDA-MB-468 cells, a basal-like 1 TNBC cell line, OTS167 significantly inhibited breast cancer cell proliferation and promoted cell apoptosis. To further investigate the relationship between Del-1 and MELK, dual inhibition of both Del-1 and MELK was performed, which significantly reduced the viability of MDA-MB-468 and MBA-MB-231 cells. CONCLUSION: We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.
Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Linhagem Celular Tumoral , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Movimento Celular , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Perfilação da Expressão Gênica , ApoptoseRESUMO
BACKGROUND: Breast cancer (BC) is a complex disease with profound genomic aberrations. However, the underlying molecular disparity influenced by age and ethnicity remains elusive. METHODS: In this study, we aimed to investigate the molecular properties of 843 primary and metastatic BC patients enrolled in the K-MASTER program. By categorizing patients into two distinct age subgroups, we explored their unique molecular properties. Additionally, we leveraged large-scale genomic data from the TCGA and MSK-IMPACT studies to examine the ethnic-driven molecular and clinical disparities. RESULTS: We observed a high prevalence of PI3KCA mutations in K-MASTER HER2 + tumors, particularly in older patients. Moreover, we identified increased mutation rates in DNA damage response molecules, including ARID1A, MSH6, and MLH1. The K-MASTER patients were mainly comprised of triple-negative breast cancer (TNBC) and HER2-positive tumors, while the TCGA and MSK-IMPACT cohorts exhibited a predominance of hormone receptor-positive (HR +) subtype tumors. Importantly, GATA3 mutations were less frequently observed in East Asian patients, which correlated with poor clinical outcomes. In addition to characterizing the molecular disparities, we developed a gradient-boosting multivariable model to identify a new molecular signature that could predict the therapeutic response to platinum-based chemotherapy. CONCLUSIONS: Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.
Assuntos
Neoplasias da Mama , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Fatores Etários , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , População do Leste Asiático/genética , Fator de Transcrição GATA3/genética , Receptor ErbB-2/genéticaRESUMO
We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head and neck cancer (HNC). Part 1 was a 3 + 3 dose-escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose-expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 every week). No dose-limiting toxicities (DLTs) were observed. Maximum serum target engagement was reached with trough levels of doses ≥3 mg/kg IV weekly. Common adverse drug reactions were diarrhea, stomatitis, dermatitis acneiform and decreased appetite. One durable complete response of more than 17 months was observed, and the overall response and disease control rates were 36.4% (4/11) and 81.1% (9/11), respectively, in the combination therapy group. In conclusion, DLT was not observed in barecetamab at 1 to 20 mg/kg. The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects.
Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Humanos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cetuximab/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etiologia , Dose Máxima TolerávelRESUMO
BACKGROUND: Targeted axillary sampling (TAS) is a new surgical concept for the assessment of axillary lymph node status in breast cancer that is hypothesized to be more effective at minimizing postoperative morbidities than axillary lymph node dissection (ALND), provided the metastatic axillary lymph node can be accurately detected without missing data; however, the oncologic outcomes over long-term follow-up have not been sufficiently investigated. This was a retrospective analysis to evaluate the 10-year oncologic outcomes in T1-3N1 breast cancer after TAS. METHODS: Between 2008 and 2013, 230 female patients with cT1-3N1 breast cancer underwent breast and axillary surgery (ALND, n = 171; TAS, n = 59) at our institute. After TAS was applied, additional axillary radiotherapy was performed. Various postoperative complications, including postoperative seroma, lymphedema, and 10-year oncological outcomes, were evaluated and compared between the ALND and TAS groups. RESULTS: Although overall survival during the 10-year follow-up period was better in the TAS group, there was no statistically significant difference in oncologic outcomes, including locoregional recurrence, distant metastasis, and overall survival (p = 0.395, 0.818, and 0.555, respectively). Furthermore, the incidence of lymphedema on the ipsilateral arm was significantly higher in the ALND group (p < 0.001). CONCLUSIONS: The 10-year oncological outcomes of TAS were not inferior to those of conventional ALND in T1-3N1 breast cancers; however, the incidence of lymphedema was significantly higher in the ALND group.
Assuntos
Neoplasias da Mama , Linfedema , Feminino , Humanos , Neoplasias da Mama/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Excisão de Linfonodo/efeitos adversos , Linfonodos/cirurgia , Linfonodos/patologia , Linfedema/etiologia , Complicações Pós-Operatórias/epidemiologia , Axila/patologia , Biópsia de Linfonodo Sentinela/efeitos adversosRESUMO
PURPOSE: The incidence of depression and anxiety is higher in patients with breast cancer than in the general population. We evaluated the degree of depression and anxiety and investigated the changes in patients with breast cancer during the treatment period and short-term follow-up period. METHODS: Overall, 137 patients with breast cancer were evaluated using the Patient Health Questionnaire 9-item depression scale (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7). The scales were developed as a web-based electronic patient-reported outcome measure, and serial results were assessed before the operation, after the operation, in the post-treatment period, and in the 6-month follow-up period after surgery. RESULTS: The degree of depression and anxiety increased during treatment and decreased at 6-month follow-up, even if there were no statistical differences among the four periods (PHQ-9: p = 0.128; GAD-7: p = 0.786). However, daily fatigue (PHQ-9 Q4) and insomnia (PHQ-9 Q3) were the most serious problems encountered during treatment and at 6-month follow-up, respectively. In the GAD-7, worrying too much (Q3) consistently showed the highest scores during the treatment and follow-up periods. Of the patients, 7 (5.11%) and 11 (8.03%) patients had a worsened state of depression and anxiety, respectively, after treatment compared with before treatment. CONCLUSION: Most factors associated with depression and anxiety improved after treatment. However, factors such as insomnia and worrying too much still disturbed patients with breast cancer, even at 6-month follow-up. Therefore, serial assessment of depression and anxiety is necessary for such patients.
Assuntos
Ansiedade/diagnóstico , Neoplasias da Mama/psicologia , Depressão/diagnóstico , Registros Eletrônicos de Saúde , Medidas de Resultados Relatados pelo Paciente , Índice de Massa Corporal , Neoplasias da Mama/cirurgia , Fadiga/diagnóstico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Inquéritos e Questionários , Fatores de TempoRESUMO
Background After publication of the findings of the American College of Surgeons Oncology Group Z1071 trial, sentinel lymph node biopsy (SLNB) has been increasingly performed in patients with breast cancer after neoadjuvant chemotherapy (NAC). Purpose To investigate the pretreatment breast MRI and clinical-pathologic characteristics associated with failed sentinel node identification after NAC in patients with breast cancer. Materials and Methods Patients who underwent SLNB after NAC between January 2015 and January 2019 were retrospectively identified. Two radiologists independently reviewed the characteristics of axillary nodes (number, perinodal infiltration, cortical thickness, and maximal diameter) at pretreatment breast MRI. The associations of the clinical-pathologic and imaging characteristics of the axillary nodes with sentinel node identification were assessed by using the χ2 test and/or the χ2 test for trend and multivariable logistic regression with odds ratio (OR) calculation. Results A total of 276 women (mean age ± standard deviation, 48 years ± 9; range, 27-68 years) were included. Sentinel nodes were identified in 252 of the 276 patients (91%). Multivariable analysis showed that higher (stage 3 or 4) clinical T stages (OR = 5.2, P = .004 for radiologist 1; OR = 4.6, P = .01 for radiologist 2), use of a single tracer (OR = 4.3, P = .04 for radiologist 1; OR = 3.9, P = .046 for radiologist 2), a greater number (10 or more) of suspicious axillary nodes (OR = 11.5, P = .002 for radiologist 1; OR = 8.3, P = .01 for radiologist 2), and the presence of perinodal infiltration (OR = 7.0, P = .002 for radiologist 1; OR = 7.5, P = .003 for radiologist 2) were associated with failed sentinel node identification. Conclusion A greater number of suspicious axillary nodes and the presence of perinodal infiltration at pretreatment MRI, higher clinical T stages, and use of a single tracer were independently associated with failed sentinel node identification after neoadjuvant chemotherapy in patients with breast cancer. © RSNA, 2020 See also the editorial by Imbriaco in this issue.
Assuntos
Axila/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Metástase Linfática/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Axila/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Metástase Linfática/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is a predictor of improved outcomes in breast cancer. In patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative breast cancer, the response to NAC is variable and mostly limited. This study was an investigation of the predictive relevance of parameters of 18F-FDG PET/CT for the pCR to NAC in patients with HR-positive, HER2-negative breast cancer. METHODS: AH total of 109 consecutive HR-positive and HER2-negative breast cancer patients who were treated with NAC were enrolled in this prospective cohort study. The relationships between pretreatment 18F-FDG PET/CT and clinical outcomes including pathologic response to NAC were evaluated. RESULTS: All patients finished their planned NAC cycles and eight patients (7.3%) achieved pCR. In the receiver operating characteristic (ROC) curve analysis, pSUVmax exhibited high sensitivity and specificity for predicting pCR. Furthermore, multivariate logistic regression analysis revealed pSUVmax as a predictive factor for pCR (hazard ratio = 17.452; 95% CI = 1.847-164.892; p = 0.013). CONCLUSION: The results of this study suggest that 18F-FDG PET/CT pSUVmax is a predictive factor for pCR of HR-positive, HER2-negative breast cancer to NAC.
Assuntos
Neoplasias da Mama/patologia , Fluordesoxiglucose F18/metabolismo , Terapia Neoadjuvante/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Compostos Radiofarmacêuticos/metabolismo , Taxa de SobrevidaRESUMO
OBJECTIVES: To investigate the effect of neoadjuvant chemotherapy (NAC) on breast tissue composition with mammographic automated volumetric measurement. METHODS: This retrospective study included 168 breast cancer patients who were treated with NAC and underwent serial mammography (pre-treatment, mid-treatment, and post-treatment) between January 2015 and October 2018. Automated volumetric measurements of the contralateral breast volume (BV), fibroglandular volume (FGV), and breast density (BD) were performed using Volpara software. BD grades were divided into 4 groups by Volpara density grade (VDG). The longitudinal changes in BV, FGV, BD, and their associated factors were evaluated. RESULTS: Repeated-measures analysis of variance demonstrated a significant reduction in BV, FGV, and BD over time (p < 0.001, p < 0.001, and p = 0.002, respectively). BV showed a greater reduction in the second half than in the first half (- 28.6 cm3 vs. - 15.2 cm3), BD showed a greater reduction in the first half than in the second half (- 0.8% vs. - 0.1%), and FGV steadily decreased (- 4.6 cm3 and - 3.9 cm3 in the first and second halves). On multivariable linear regression analysis, chemotherapy regimen was associated with BV change between pre- and post-treatment (p = 0.002); age (p = 0.024) and VDG (p = 0.027) were associated with FGV change; age (p = 0.037), VDG (p = 0.002), and chemotherapy regimen (p = 0.003) were associated with BD change. CONCLUSIONS: NAC affects breast tissue composition, reflected as reductions in BV, FGV, and BD. Mammography with automated volumetric measurement can capture quantitative changes in these breast tissue parameters during NAC. KEY POINTS: ⢠Neoadjuvant chemotherapy (NAC) affects breast tissue composition with different patterns of reduction in breast volume, fibroglandular volume, and breast density. ⢠Age, Volpara density grades, and NAC regimen were independent factors associated with breast density change between pre-treatment and post-treatment. ⢠Mammography with automated volumetric measurement enables identification of longitudinal changes in breast tissue composition.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Mama/efeitos dos fármacos , Quimioterapia Adjuvante , Terapia Neoadjuvante , Adulto , Idoso , Mama/diagnóstico por imagem , Densidade da Mama/efeitos dos fármacos , Feminino , Humanos , Estudos Longitudinais , Mamografia , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Análise de Regressão , Estudos Retrospectivos , SoftwareRESUMO
BACKGROUND: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. METHODS: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. RESULTS: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable. CONCLUSIONS: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01730677.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Lapatinib/administração & dosagem , Trastuzumab/administração & dosagem , Vinorelbina/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/genéticaRESUMO
PURPOSE: We conducted an exploratory biomarker study from a phase II clinical trial of eribulin plus gemcitabine (EG) versus paclitaxel plus gemcitabine (PG) in HER2-negative metastatic breast cancer (BC) patients. METHODS: We performed targeted deep sequencing with a customized cancer gene panel and RNA expression assay. Tumor mutation burden (TMB) and mutation signatures were determined based on genetic alteration in targeted regions. Gene set variation analysis was performed with PanCancer Immune Profiling and PanCancer Pathway Panels. Statistical analyses were conducted to identify the associations between genetic alterations and clinical outcomes. RESULTS: Of 119 patients, 40 had available biomarker data. Among the 40 patients, 4 supported their post-treatment tissues. In targeted deep sequencing, FAT3 (48%) was the most frequently mutated gene, followed by PKHD1, TP53, GATA3, PARP4, and PIK3CA. In terms of gene expression, low expression of epithelial-mesenchymal transition (EMT) pathway genes was associated with prolonged progression-free survival (PFS) in the EG group, while high expression of the EMT pathway was associated with good prognosis in the PG group. Median TMB was 6.5 (range 2.44-46.34) and there was no relationship between TMB and patient prognosis. Analysis of mutation signatures showed that signatures 3, 20, and 26 were frequently observed in our cohort. Further survival analysis according to mutation signature showed that mutation signature 3, as a homologous recombinant deficiency-related signature, was highly associated with disease progression (hazard ratio (log2 scale) 8.21, 95% confidence interval 2.93-13.48, p = 0.002). Kaplan-Meier plot also showed that BCs with signature 3 had short PFS compared to those without these signatures (median PFS (months) for signature 3 (low vs. high): 17.2 vs. 8.1, p = 0.0026). CONCLUSIONS: Mutation signature 3, found in about 30% of MBCs regardless of hormone receptor status, was associated with short PFS for patients with cytotoxic chemotherapy. TRIAL REGISTRY: ClinicalTrials.gov number: NCT02263495.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/diagnóstico , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Furanos/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Cetonas/administração & dosagem , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Mutação , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Fatores de Risco , Resultado do Tratamento , Adulto Jovem , GencitabinaRESUMO
OBJECTIVES: Anti-angiogenic agents are reported to exert clinical activity on epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancers. We evaluated the clinical outcomes of nintedanib and docetaxel in refractory NSCLC according to EGFR mutation status during the Korean nintedanib named patient program. METHODS: Docetaxel was administered either 75 or 37.5 mg/m2 on D1, D8 q every 3 weeks for 4-6 cycles plus nintedanib 200 mg orally twice daily until disease progression or unacceptable toxicity. RESULTS: Sixty-two patients were enrolled for study. Twenty-eight patients with activating EGFR mutations progressed after EGFR-tyrosine kinase inhibitors (TKI) therapy and 25 out of 28 patients showing progression after platinum doublet chemotherapy were enrolled. The objective response rate was 29% and median PFS and OS were 3.9 months and 11.7 months. Based on the EGFR mutation status, the objective response rate was 39.3 vs. 21.9% (EGFR mut(+) vs. EGFR mut(-), p = 0.142) and median PFS was 6.5 vs. 3.3 months (EGFR mut(+) vs. EGFR mut(-), p = 0.009). No treatment-related deaths were reported. The most frequent drug-related adverse events (AE) were neutropenia (53.2%) and diarrhea (37.1%). Treatment in 12 patients (19.3%) was permanently discontinued due to AEs without disease progression. CONCLUSIONS: Our data indicated that nintedanib-docetaxel combination could be considered to be effective treatment in EGFR TKI-resistant EGFR mutant NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Terapia Combinada , Docetaxel/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Indóis/administração & dosagem , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Retratamento , Resultado do TratamentoRESUMO
BACKGROUND: Hormone receptor-positive breast cancer accounts for nearly two-thirds of breast cancer cases; it ultimately acquires resistance during endocrine treatment and becomes more aggressive. This study evaluated the role of developmental endothelial locus (Del)-1 in tamoxifen-resistant (TAM-R) breast cancer. METHODS: Del-1 expression in recurrent TAM-R breast cancer tissue was evaluated and compared to that in the original tumor tissue from the same patients. Del-1 expression was also evaluated in TAM-R cells by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assay. The effects of Del-1 knockdown on the proliferation, migration, and invasion of TAM-R cells was assessed with wound-healing and Matrigel transwell assays. RESULTS: Del-1 was more highly expressed in recurrent breast cancer as compared to the original tumor tissues before initiation of endocrine treatment. Del-1 mRNA was upregulated in TAM-R and small interfering RNA-mediated knockdown of Del-1 suppressed the migration and proliferation of TAM-R cells while partly restoring TAM sensitivity. And the TAM resistance was recovered by knockdown of Del-1. CONCLUSIONS: TAM-R breast cancer is characterized by Del-1 overexpression and tumor progression can be inhibited by Del-1 depletion, which restores TAM sensitivity. Thus, therapeutic strategies that target Del-1 may be effective for the treatment of hormone-resistant breast cancer.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Proteínas de Transporte/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Tamoxifeno/farmacologia , Neoplasias da Mama/metabolismo , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/metabolismo , Moléculas de Adesão Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interferência de RNA , RNA Interferente PequenoRESUMO
BACKGROUND: We report on our experience of ultrasound (US)-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy (NAC) with clip and activated charcoal to guide axillary surgery in breast cancer patients. METHODS: Between November 2017 and May 2018, a dual-localization procedure was performed under US guidance for the most suspicious axillary nodes noted at initial staging (before NAC, with clip) and restaging (after NAC, with activated charcoal) in 28 cytologically proven node-positive breast cancer patients. Patients underwent axillary sampling or dissection, which involved removing not only the sentinel nodes (SNs), but also clipped nodes (CNs) and tattooed nodes (TNs). Success (or failure) rates of biopsies of SNs, CNs, and TNs and inter-nodal concordance rates were determined. Sensitivities for the individual and combined biopsies were calculated. RESULTS: SN biopsy failed in four patients (14%), whereas the CN biopsy failed in one patient (4%). All TNs were identified in the surgical field. Concordance rates were 79% for CNs-TNs, 63% for CNs-SNs, and 58% for TNs-SNs. Sensitivity for SN, CN, and TN biopsy was 73%, 67%, and 67%, respectively. Sensitivity was 80% for any combination of biopsies (SN plus CN, SN plus TN, SN plus CN plus TN). CONCLUSIONS: US-guided dual-localization of axillary nodes before and after NAC with clip and activated charcoal was a feasible approach that might facilitate more reliable nodal staging with less-invasive strategies in node-positive breast cancer patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carvão Vegetal/administração & dosagem , Metástase Linfática/diagnóstico por imagem , Biópsia de Linfonodo Sentinela/métodos , Adulto , Idoso , Axila , Neoplasias da Mama/diagnóstico por imagem , Carvão Vegetal/uso terapêutico , Tratamento Farmacológico , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Sensibilidade e Especificidade , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: Gene expression profiling provides key information for prognosis of breast cancer to establish treatment strategy. However, the genetic assessment should be available before induction of treatment to be useful for clinical practice. To evaluate the reliability of using needle biopsy samples for gene assays, we compared gene-expression profiling results between core needle biopsy (CNB) samples and surgical specimens in breast cancer. METHODS: Thirty-one paired, formalin-fixed, paraffin-embedded CNB and surgical specimen samples were selected from patients with hormone receptor-positive breast cancer. Total RNA was extracted from the samples and the risk classifications based on GenesWell BCT scores were compared. RESULTS: The BCT scores correlated between CNB samples and surgical specimens of hormone receptor-positive breast cancer (Pearson r = 0.66). The overall concordance rate of risk classification (high/low risk) was 83.9%. However, when the breast cancer does not contain intratumoral microcalcification, the concordance rate increased as 92.0%. And, when the breast cancer formed a solitary nodule (non-multifocal), the concordance rate increased up to 95.8%. CONCLUSION: Risk classification using the GenesWell BCT multigene kit with CNB samples could be considered reliable, when the breast cancer is a solitary nodule without intratumoral microcalcification. Such genetic profiling results should be helpful for establishing a treatment plan for hormone receptor-positive breast cancer before treatment induction.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Mama/metabolismo , Medição de Risco , Biópsia com Agulha de Grande Calibre , Mama/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Família Multigênica/genética , RNA , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genéticaRESUMO
To evaluate predictive factors for residual metastatic axillary lymph node (ALN) disease in patients with negative imaging findings after neo-adjuvant chemotherapy (NAC) for breast cancer. From January 2011 to December 2015, 206 patients underwent imaging including ultrasonography, MRI, and PET/CT for restaging the axilla after NAC. Data collected included preoperative information regarding histologic grade, hormone receptor (HR) status, and human epidermal growth factor receptor 2 (HER2) status. Multivariate logistic regression analysis was performed to compare patients with and without residual metastatic ALN disease among patients who showed negative imaging findings after NAC. Of the 181 and 25 patients with initially node-positive and node-negative disease, 131 (72.4%) and 23 (92.0%), respectively, showed negative imaging findings after NAC. Among these 131 and 23 patients, 53 (40.5%) and two patients (8.7%), respectively, had residual metastatic ALN disease. Low to moderate tumor grade (odds ratio [OR] = 5.2, P = 0.009), positive HR status (OR = 6.6, P = 0.003), and negative HER2 status (OR = 2.6, P = 0.048) were associated with residual metastatic ALN disease. Low to moderate histologic grade, positive HR status, and negative HER2 status may serve as predictors of residual metastatic ALN disease in patients with negative imaging findings after NAC for breast cancer.
Assuntos
Axila/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Metástase Linfática/diagnóstico por imagem , Axila/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Reações Falso-Negativas , Feminino , Humanos , Modelos Logísticos , Linfonodos/patologia , Metástase Linfática/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/metabolismoRESUMO
MicroRNAs (miRNAs) can be used to target a variety of human malignancy by targeting their oncogenes or tumor suppressor genes. The developmental endothelial locus-1 (Del-1) might be under miRNA regulation. This study investigated microRNA-137 (miR-137) function and Del-1 expression in triple-negative breast cancer (TNBC) cells and tissues. Del-1 mRNA and miRNA-137 levels were determined via qRT-PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-137 on cell proliferation, migration, and invasion were determined using MTT assays, wound healing, and Matrigel transwell assays. The luciferase reporter assay revealed direct binding of miR-137 to the 3'-UTR of Del-1. miR-137 inhibited cell proliferation, migration, and invasion of MDA-MB-231 cells. Among the 30 TNBC specimens, miR-137 was downregulated and Del-1 level in plasma was significantly elevated relative to normal controls. It is concluded that miR-137 regulates Del-1 expression in TNBC by directly binding to the Del-1 gene and cancer progression. The results implicate miR-137 as a new therapeutic biomarker for patients with TNBC.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/fisiologia , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Proteínas de Ligação ao Cálcio/genética , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Ensaio de Imunoadsorção Enzimática , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , MicroRNAs/genética , Plasmídeos/genética , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
OBJECTIVE: The aim of this study was to review our experience with ultrasound (US)-guided localization of axillary lymph nodes using activated charcoal for the guidance of axillary surgery after neoadjuvant chemotherapy (NAC) in clinically node-positive breast cancer patients. METHODS: Between April 2016 and April 2017, US-guided localization of the most suspicious axillary lymph nodes at restaging US using activated charcoal (Charcotrace™) was performed in 45 consecutive, clinically node-positive breast cancer patients who had less than two suspicious nodes after NAC and axillary surgery with sentinel node biopsy. Sentinel nodes were defined as radioactive nodes or nodes containing blue dye. The concordance between final pathological results for both the tattooed and sentinel nodes was analyzed. RESULTS: Sentinel node biopsy failed in five patients (11%) in whom axillary surgery was performed under the guidance of the tattooed node. The tattooed nodes were identified in the surgical field in 44 patients (98%). Of the 44 tattooed nodes, 25 (57%) were concordant with the sentinel nodes and 19 (43%) were non-sentinel nodes, including the five nodes with failed sentinel node biopsy. In the final pathological results, 18 patients (40%) had metastatic nodes. The sensitivities for detecting axillary metastasis of the sentinel node biopsy, tattooed node biopsy, and the sentinel and/or tattooed node biopsy were 61% (11/18), 67% (12/18), and 78% (14/18), respectively. CONCLUSION: US-guided localization of axillary lymph nodes using activated charcoal at restaging after NAC in clinically node-positive breast cancer patients is a useful technique to guide axillary surgery, with a high identification rate.
Assuntos
Neoplasias da Mama/patologia , Carvão Vegetal/química , Linfonodos/patologia , Terapia Neoadjuvante , Cirurgia Assistida por Computador/métodos , Ultrassonografia Mamária/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axila , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Linfonodos/cirurgia , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Estudos RetrospectivosRESUMO
OBJECTIVE: A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. METHODS: Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. RESULTS: While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p < 0.036). Furthermore, a correlation was found between Del-1 expression and an aggressive histological grade, nuclear mitosis, and polymorphism, suggesting a possible role in tumor progression. In the survival analysis, a worse distant disease-free survival trend was noted for the group overexpressing Del-1. CONCLUSION: While all the investigated breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients.