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2.
J Immunother Cancer ; 8(2)2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33199511

RESUMEN

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC). Due to the absence of targets such as HER2 or hormone receptors, early TNBC is treated with surgery and chemotherapy. Since TNBC is also considered the most immunogenic type of BC with tumor infiltrating lymphocytes that are predictive for chemotherapy response and prognostic for patients' survival, many different immunotherapeutic strategies are currently explored in clinical trials for the treatment of this disease. In order to efficiently combine chemotherapy with immunotherapy, it is important to evaluate the effect of chemotherapy on immune cells in vivo. METHODS: Peripheral blood was taken from 56 patients with TNBC undergoing neoadjuvant chemotherapy with nanoparticle albumin-bound paclitaxel (Nab-Pac) followed by epirubicin and cyclophosphamide (EC) at three different time points. Multicolor flow cytometry was used to characterize the immune cell composition and functional properties along neoadjuvant chemotherapy. RESULTS: Whereas the first phase of the neoadjuvant chemotherapy did not significantly alter the patients' immune cell composition, after the second phase of chemotherapeutic administration most B cells (>90%) were lost and the frequency of natural killer (NK) cells and CD4+ T lymphocytes decreased approximately to 50%. In contrast, the frequency of CD8+ T cells were less affected. CONCLUSIONS: Despite late consequences of Nab-Pac cannot be ruled out, these data suggest that different chemotherapeutics might have distinct effects on the immune cell repertoire and that different immune cell populations exhibit a specific susceptibility to these chemotherapies with B and NK cells being more affected than T cells. This might also have an impact on the combination of chemotherapies with immunotherapies. TRIAL REGISTRATION NUMBER: NCT02685059.

5.
Clin Cancer Res ; 26(8): 1896-1904, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-31932495

RESUMEN

PURPOSE: In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. EXPERIMENTAL DESIGN: We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays. RESULTS: We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21-2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28-4.51; P = 0.006) with a significant interaction with bevacizumab treatment (P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P = 0.025). CONCLUSIONS: Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab, which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.

6.
Breast Cancer Res ; 21(1): 142, 2019 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-31829264

RESUMEN

BACKGROUND: Clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. HLA class I molecules present antigens to CD8+ cytotoxic cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis. METHODS: We evaluated HLA class I heavy chain expression by immunohistochemistry in 863 biopsies (GeparTrio trial). Patients received neoadjuvant chemotherapy and adjuvant endocrine treatment if tumors were hormone receptor-positive (HR+). In parallel, the expression of HLA-A was analyzed using a microarray cohort of 320 breast cancer patients from the MD Anderson Cancer Center. We evaluated its association with clinical outcome, tumor-infiltrating lymphocytes (TILs), and immune cell metagenes. RESULTS: In HR+/HER2- breast cancer, HLA class I heavy chain expression was associated with increased TILs and better response to chemotherapy (7% vs. 14% pCR rate, P = 0.029), but worse disease-free survival (hazard ratio (HR) 1.6 (1.1-2.4); P = 0.024). The effect was significant in a multivariate model adjusted for clinical and pathological variables (HR 1.7 (1.1-2.6); P = 0.016) and was confirmed by analysis of HLA-A in a microarray cohort. HLA-A was correlated to most immune cell metagenes. There was no association with response or survival in triple-negative or HER2+ disease. CONCLUSIONS: The study confirms the negative prognostic role of lymphocytes in HR+ breast cancer and points at a complex interaction between chemotherapy, endocrine treatment, and tumor immunogenicity. The results point at a subtype-specific and potentially treatment-specific role of tumor-immunological processes in breast cancer with different implications in triple-negative and hormone receptor-positive disease.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/mortalidad , Femenino , Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Terapia Neoadyuvante , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/deficiencia , Resultado del Tratamiento , Microambiente Tumoral
7.
Br J Cancer ; 121(12): 1009-1015, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31728025

RESUMEN

BACKGROUND: The androgen receptor (AR) is discussed as a prognostic and/or predictive marker in breast cancer patients. METHODS: AR mRNA expression was analysed by RT-qPCR in breast cancer patients treated in the neoadjuvant TECHNO (n = 118, HER2-positive) and PREPARE trial (n = 321, HER2-positive and -negative). In addition, mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured. RESULTS: Regarding subtypes, high AR mRNA levels were frequent in HER2-positive (61.3%, 92/150) and luminal tumours (60.0%, 96/160) but almost absent in triple-negative tumours (4.3%, 3/69) (p < 0.0001). Overall, high AR mRNA levels were found to be associated with lower pathological complete remission (pCR) rates (OR 0.77 per unit, 95% CI 0.67-0.88, p = 0.0002) but also with better prognosis in terms of longer disease-free survival (DFS) (HR 0.57, 95% CI 0.39-0.85, p = 0.0054) and overall survival (OS) (HR 0.43, 95% CI, 0.26-0.71, p = 0.0011). In the PREPARE trial, a survival difference for patients with high and low AR1 mRNA levels could only be seen in the standard chemotherapy arm but not in the dose-dense treatment arm (OS: HR 0.41; 95% CI 0.22-0.74 vs. HR 1.05; 95% CI 0.52-2.13; p = 0.0459). CONCLUSIONS: We provide evidence that AR mRNA predicts response to chemotherapy in breast cancer patients.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Pronóstico , ARN Mensajero/genética , Receptores Androgénicos/genética , Adulto , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Isoformas de Proteínas/sangre , Receptor ErbB-2/genética , Receptores Androgénicos/sangre , Trastuzumab/administración & dosificación
9.
Stud Health Technol Inform ; 260: 138-145, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31118330

RESUMEN

BACKGROUND: This article is based on an ongoing long-term study, in which customary motion trackers measure steps during rehabilitation of geriatric trauma patients (Med=86 years). OBJECTIVES: Exploring steps after 28 days of measurement. Finding similarities in the data by running cluster analysis and formulating linear regressions models to predict steps through time. METHODS: Two types of motion trackers (FitBitAlta HR and Garmin vívofit 3) have been used to measure patients' (N=24) steps after hip fracture in two study groups. Cluster analysis detected three clusters for progress in number of steps that were tested for group differences with ANOVA. Regression analysis tested models for individual patients. RESULTS: Three-cluster solutions showed significant differences for the average amount of steps after 5, 14, 21 and 28 days. Regression models could predict 71 % of the individual patients' progress in study group 2. CONCLUSION: The long-term study will provide more data in the future to examine the three-cluster solution and to find out in what stage of rehabilitation the measurement of the steps could be used to predict individual rehabilitation.


Asunto(s)
Fracturas de Cadera , Locomoción , Monitoreo Fisiológico , Carrera , Dispositivos Electrónicos Vestibles , Anciano , Fracturas de Cadera/rehabilitación , Humanos , Movimiento (Física) , Pacientes
10.
Eur J Cancer ; 114: 76-88, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31075727

RESUMEN

BACKGROUND: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial. PATIENTS AND METHODS: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested. RESULTS: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome. CONCLUSIONS: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC. CLINICAL TRIAL: NCT00196872.


Asunto(s)
Quimioterapia Adyuvante/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/uso terapéutico , Neoplasias de la Mama Triple Negativas/genética , Adulto , Biomarcadores de Tumor/metabolismo , Femenino , Alemania , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología
11.
Clin Cancer Res ; 25(13): 3986-3995, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-30979740

RESUMEN

PURPOSE: Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial. EXPERIMENTAL DESIGN: Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, and PTEN) and 8 genes for copy-number alteration analysis (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, and ZNF703). RESULTS: The most common genomic alterations were mutations of TP53 (38.4%) and PIK3CA (21.5%), and 8 different amplifications (TOP2A 34.9%; ERBB2 30.6%; ZNF703 30.1%; TP53 21.9%; PIK3CA 24.1%; CCND1 17.7%; PAK1 14.9%; FGFR 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in PIK3CA-mutated breast cancer [PIK3CAmut: 23.0% vs. wild-type (wt) 38.8%, P < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24-0.79), P = 0.006]. An increased response to nab-paclitaxel was observed only in PIK3CAwt breast cancer, with univariate significance for the complete cohort (P = 0.009) and the TNBC (P = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction P = 0.0074). CONCLUSIONS: High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. PIK3CA mutations could be a major mediator of therapy resistance in breast cancer.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/genética , Mutación , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Análisis Mutacional de ADN , Femenino , Heterogeneidad Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Tasa de Mutación , Terapia Neoadyuvante , Oportunidad Relativa , Resultado del Tratamiento
12.
BMC Med ; 16(1): 179, 2018 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-30301470

RESUMEN

BACKGROUND: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC). METHODS: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization. RESULTS: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR). CONCLUSION: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.


Asunto(s)
MicroARNs/genética , Receptor ErbB-2/biosíntesis , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Estudios de Casos y Controles , Estudios de Cohortes , Exosomas , Femenino , Humanos , MicroARNs/biosíntesis , Persona de Mediana Edad , Terapia Neoadyuvante , Receptor ErbB-2/genética , Neoplasias de la Mama Triple Negativas/enzimología , Neoplasias de la Mama Triple Negativas/patología
14.
Stud Health Technol Inform ; 248: 226-232, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29726441

RESUMEN

BACKGROUND: This preparatory study accelerates an implementation of individualized monitoring and feedback of physical motion using conventional motion trackers in the rehabilitation process of geriatric trauma patients. Regaining mobility is accompanied with improved quality of life in persons of very advanced age recovering from fragility fractures. OBJECTIVES: Quantitative survey of regaining physical mobility provides recommendations for action on how to use motion trackers effectively in a clinical geriatric setting. METHODS: Method mix of quantitative and qualitative interdisciplinary and mutual complementary research approaches (sociology, health research, philosophy/ethics, medical informatics, nursing science, gerontology and physical therapy). While validating motion tracker use in geriatric traumatology preliminary data are used to develop a target group oriented motion feedback. In addition measurement accuracy of a questionnaire about quality of life of multimorbid geriatric patients (FLQM) is tested. CONCLUSION: Implementing a new technology in a complex clinical setting needs to be based on a strong theoretical background but will not succeed without careful field testing.


Asunto(s)
Retroalimentación , Modalidades de Fisioterapia , Calidad de Vida , Recuperación de la Función , Rehabilitación , Anciano , Geriatría , Humanos , Movimiento (Física) , Examen Físico , Traumatología
15.
J Clin Oncol ; 36(22): 2281-2287, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29791287

RESUMEN

Purpose BRCA1/2 mutations are frequent in patients with triple-negative breast cancer (TNBC). These patients are often treated with primary systemic chemotherapy. The aim of this study was to analyze the effects of BRCA1/2 mutations on pathologic complete response (pCR) and disease-free survival (DFS) in a cohort of patients with TNBC treated with anthracycline and taxane-containing chemotherapy, with or without bevacizumab. Patients and Methods Germline DNA was sequenced to identify mutations in BRCA1 and BRCA2 in 493 patients with TNBC from the GeparQuinto study. The pCR rates were compared in patients with and without mutation, as well as in patients treated with and without bevacizumab. In addition, the influence of BRCA1/2 mutation status and pCR status on DFS was evaluated relative to treatment. Results BRCA1/2 mutations were detected in 18.3% of patients with TNBC. Overall, patients with mutations had a pCR rate of 50%, compared with 31.5% in patients without a mutation (odds ratio [OR], 2.17; 95% CI, 1.37 to 3.46; P = .001). The pCR rate among patients treated with bevacizumab was 61.5% for BRCA1/2 mutation carriers and 35.6% for those without mutations (OR, 2.90; 95% CI, 1.43 to 5.89; P = .004). pCR was a strong predictor of DFS for patients without BRCA1/2 mutations (hazard ratio, 0.18; 95% CI, 0.11 to 0.31) but not for patients with BRCA1/2 mutations (hazard ratio, 0.74; 95% CI, 0.32 to 1.69). Conclusion The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with TNBC with BRCA1/2 mutations. In patients treated with anthracycline and taxane-based chemotherapy (with or without bevacizumab), pCR was a weaker predictor of DFS for BRCA1/2 mutation carriers than for patients without mutations.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Bevacizumab/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Genotipo , Mutación de Línea Germinal , Humanos , Terapia Neoadyuvante , Receptor ErbB-2/metabolismo , Neoplasias de la Mama Triple Negativas/sangre , Neoplasias de la Mama Triple Negativas/patología
16.
J Natl Cancer Inst ; 110(6): 560-567, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29659933

RESUMEN

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker. Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided. Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008). Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Valor Predictivo de las Pruebas , Pronóstico , Resultado del Tratamiento
17.
Clin Cancer Res ; 24(14): 3358-3365, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29618617

RESUMEN

Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathologic tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen receptor (ER)-positive/HER2-negative breast cancer. We also compared the prognostic power of the mEPclin with that of the CPS-EG score.Experimental Design: A total of 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cut-off values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS).Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse [HR, 2.16; 95% confidence interval (CI), 1.86-2.51; P < 0.001] and death (HR, 2.28; 95% CI, 1.90-2.75; P < 0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer DFS and overall survival compared with those at low risk. In contrast with CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR, 2.13; 95% CI, 1.73-2.63; P < 0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; P < 0.001).Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies. Clin Cancer Res; 24(14); 3358-65. ©2018 AACR.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Terapia Neoadyuvante , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Medición de Riesgo , Resultado del Tratamiento
18.
BMC Cancer ; 18(1): 265, 2018 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-29514593

RESUMEN

BACKGROUND: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. METHODS: The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. RESULTS: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. CONCLUSIONS: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de Mama Unilaterales/genética , Adulto , Anciano , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Persona de Mediana Edad , Prevalencia , Pronóstico , Neoplasias de la Mama Triple Negativas/epidemiología , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de Mama Unilaterales/epidemiología , Neoplasias de Mama Unilaterales/patología , Adulto Joven
19.
Sci Eng Ethics ; 24(5): 1437-1481, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-28900898

RESUMEN

This paper provides a systematic literature review, analysis and discussion of methods that are proposed to practise ethics in research and innovation (R&I). Ethical considerations concerning the impacts of R&I are increasingly important, due to the quickening pace of technological innovation and the ubiquitous use of the outcomes of R&I processes in society. For this reason, several methods for practising ethics have been developed in different fields of R&I. The paper first of all presents a systematic search of academic sources that present and discuss such methods. Secondly, it provides a categorisation of these methods according to three main kinds: (1) ex ante methods, dealing with emerging technologies, (2) intra methods, dealing with technology design, and (3) ex post methods, dealing with ethical analysis of existing technologies. Thirdly, it discusses the methods by considering problems in the way they deal with the uncertainty of technological change, ethical technology design, the identification, analysis and resolving of ethical impacts of technologies and stakeholder participation. The results and discussion of our literature review are valuable for gaining an overview of the state of the art and serve as an outline of a future research agenda of methods for practising ethics in R&I.


Asunto(s)
Análisis Ético/métodos , Ética en Investigación , Investigación , Tecnología/ética , Humanos
20.
Mod Pathol ; 31(4): 607-615, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29271415

RESUMEN

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P<0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates.


Asunto(s)
Neoplasias de la Mama , Inmunohistoquímica/normas , Hibridación in Situ/normas , Patología Clínica/normas , Receptor ErbB-2/análisis , Adulto , Anciano , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Femenino , Alemania , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto
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