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1.
J Neurooncol ; 138(2): 369-382, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29488184

RESUMO

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996-2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan-Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2-/HR+, 24.8% TN, 22.2% HER2+/HR- and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25-85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2-/HR+ 5.3 years (95% CI 4.6-5.9), HER2+/HR+ 4.4 years (95% CI 3.4-5.2), HER2+/HR- 2.6 years (95% CI 2.2-3.1) and TN 2.2 years (95% CI 1.9-2.7) (p < 0.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p < 0.001), and between HER2+ and HER2- tumors (3.2 vs. 3.8 years, p = 0.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio = 1.36 for ER, p = 0.013, 1.31 for PR, p = 0.021, and 1.01 for HER2+ vs. HER2- tumors, p = 0.880). HR- and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Receptores de Peptídeos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Europa (Continente) , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
2.
Breast ; 37: 36-41, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29073498

RESUMO

BACKGROUND: Several prognostic scores have been developed to estimate survival of breast cancer (BC) patients with brain metastases (BM). Modified Breast Graded Prognostic Assessment (GPA), based on a single-institution cohort of 1552 patients, has been proposed as refinement of Breast-GPA. In addition to age, tumour subtype and KPS, Modified Breast-GPA comprises number of BM. This study was designed to validate Modified Breast-GPA. PATIENTS AND METHODS: Clinical data of 668 BC patients diagnosed with BM at four institutions between 1996 and 2016 were reviewed. Patients were classified by Breast-GPA and Modified Breast-GPA. Overall survival (OS) was calculated from time of BM diagnosis to death or last follow-up. Cox proportional models were used to calculate hazard-ratios and their 95% CI. The performances of Breast-GPA and Modified Breast-GPA were compared using Harrell's concordance index. RESULTS: Median age at BM diagnosis was 56 years (range 24-85). At last follow-up, 632 patients (94.6%) had died. Median OS was 8.1 months (95% CI 6.9-9.4). The number of BM (1-3 vs. >3) was significantly associated with OS in univariate analysis (p < 0.001) and having >3 BM was identified as a negative prognostic factor in multivariate analysis. Both Breast-GPA and Modified Breast-GPA accurately predicted OS (p < 0.001 for both scores). Performance of Modified Breast-GPA was better: concordance indices were 0.6390 (95% CI, 0.6381 to 0.6399) and 0.6647 (95% CI, 0.6639 to 0.6655) for Breast-GPA and Modified Breast-GPA, respectively (p < 0.001). CONCLUSIONS: This work provides the first external independent validation of Modified Breast-GPA and confirms its better performance as compared to Breast-GPA.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/terapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Feminino , França , Alemanha , Humanos , Itália , Avaliação de Estado de Karnofsky , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral , Adulto Jovem
3.
BMC Cancer ; 16: 428, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27387327

RESUMO

BACKGROUND: Metastatic breast cancer (MBC) prognosis is highly variable, depending on various factors such as the biological subtype, the performance status, disease extension…. A better evaluation of a patient's prognostic factors could allow for a more accurate choice of treatments. The role of serum tumor markers remains, however, unclear in this population. Considering the recent interest in phenotypic changes and tumor heterogeneity during breast cancer progression, additional tumor markers could be interesting in this setting. METHODS: Two hundred fifty MBC patients treated at the Montpellier Cancer Institute (2008-2015) were retrospectively selected, based on the availability of frozen serum samples. The usual MBC clinical and pathological variables were collected, altogether with Cancer Antigen 15-3 (CA15-3), Carcinoembryonic Antigen (CEA), HER2 extra-cellular domain (ECD), Neuron Specific Enolase (NSE), S100ß protein and Matrix Metalloproteinase 9 (MMP-9) serum levels in order to determine their prognostic value. RESULTS: With a median follow-up of 40.8 months, median overall survival was 16.2 months (95 % CI 12.4-20.6). In multivariate analysis, the performance status, brain or subcutaneous metastases, the number of previous metastatic chemotherapy lines and the tumor biological subtype were independent prognostic factors. Elevated CA 15-3 (HR = 1.95, IC 95 % 1.31-2.93, p = 0.001), HER2 ECD (regardless of tumor HER2 status, HR = 2.51, IC 95 % 1.53-4.12, p < 0.001) and S100ß (HR = 1.93, IC 95 % 1.05-3.54, p = 0.033) serum levels were independently associated with a poor outcome. CONCLUSIONS: Serum CA 15-3, HER2 ECD and S100ß could represent useful independent prognostic factors in MBC. Of particular interest is the independent value of serum HER2 ECD levels, regardless of the tumor HER2 status, possibly linked to metastatic tumor heterogeneity.


Assuntos
Neoplasias da Mama/metabolismo , Mucina-1/sangue , Receptor ErbB-2/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
4.
Int J Cancer ; 139(10): 2299-311, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27464303

RESUMO

Breast cancer (BC) is the second most common cause of brain metastases (BM). Predictive factors for BM have been widely studied in metastatic BC; however, there is no known serum tumor marker to accurately predict BM. Elevated serum S100ß protein and neuron-specific enolase (NSE) could reflect the brain damages induced by BM. Matrix metalloproteinase 9 (MMP-9) is involved in tumor invasion and metastatic dissemination, including BM. Also, HER2-amplified BC were shown to have a particular tropism for central nervous system (CNS). This study evaluated the correlation of these biomarkers with the presence of BM in metastatic BC patients. In this case-control study, 88 consecutive metastatic BC patients with BM (BM group) treated in our institution (2008-2015) were retrospectively selected, based on the availability of frozen serum samples for tumor marker determination. Patients were matched by age, tumor biology and number of previous metastatic chemotherapy lines to 162 metastatic BC patients without CNS involvement (control group). Serum NSE, MMP-9 and HER2 extracellular domain (ECD) levels were significantly higher in the BM group (p = 0.0051, p = 0.0062 and p = 0.0057, respectively). In multivariate analysis, serum HER2 and MMP-9 levels accurately discriminated patients with BM: odds ratios 4.4 (p < 0.001; 95%CI: 1.9-9.6) for HER2 ECD and 3.5 (p = 0.005; 95%CI: 1.5-8.4) for MMP-9. In multivariate analysis, HER2 ECD and NSE serum levels were independent prognostic factors in patients with BM. Serum HER2 ECD and MMP-9 appear to be associated with BM in metastatic BC patients. Their predictive value for BM still needs to be evaluated in further prospective studies.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Metaloproteinase 9 da Matriz/sangue , Fosfopiruvato Hidratase/sangue , Receptor ErbB-2/sangue , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Neoplasias da Mama/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/sangue
5.
Target Oncol ; 10(2): 189-98, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25185646

RESUMO

Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neovascularização Patológica , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Seleção de Pacientes , Valor Preditivo dos Testes , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Breast ; 22(5): 993-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23831232

RESUMO

INTRODUCTION: Brain metastases (BM) from breast cancer are associated with poor prognosis. This study was made to determine the prognostic influence of breast cancer biological subtypes, and to define the best therapeutic options in this setting, with a special focus on the HER2-positive population. PATIENTS AND METHODS: Breast cancer patients with known hormone receptors (HR) and HER2 status presenting with BM treated between 1995 and 2010 in our two institutions were considered for this retrospective study. RESULTS: 250 patients were included. The study population consisted of 25.6% patients categorized as triple-negative (HR-/HER2-), 30.8% as HR+/HER2- and 43.6% as HER2+ breast cancer. Median overall survival (OS) was 8.9 months (95% CI, 6.9-10.3 months). Cerebral progression remained the most frequent cause of death (57.1%). On multivariate analysis, HER2 positivity and the RPA score were the two most important prognostic factors. Local treatment (surgery or stereotactic radiotherapy) and chemotherapy were significantly associated with an increased survival. On multivariate analysis of the RPA1-2 population, local treatment and chemotherapy were independent prognostic factors in addition to biological subtypes, RPA class, liver metastases and clinical signs of intra-cranial hypertension. Anti-HER2 therapies administered after BM diagnosis significantly and independently increased OS. Median OS in patients receiving both trastuzumab and lapatinib after BM diagnosis was significantly better than that the one of patients receiving only one of the 2 targeted therapies (25.7 vs. 9.6 months, p < 0.001). CONCLUSIONS: Biological subtypes are independent prognostic determinants. Chemotherapy and targeted therapies positively affect the prognosis after first BM.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/terapia , Neoplasias Hepáticas/secundário , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/química , Neoplasias Encefálicas/secundário , Neoplasias da Mama/química , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/secundário , Intervalo Livre de Doença , Feminino , Humanos , Hipertensão Intracraniana/etiologia , Estimativa de Kaplan-Meier , Lapatinib , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Radiocirurgia , Receptor ErbB-2/análise , Receptor ErbB-2/antagonistas & inibidores , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Estudos Retrospectivos , Taxa de Sobrevida , Trastuzumab , Adulto Jovem
7.
BMC Cancer ; 13: 70, 2013 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-23394467

RESUMO

BACKGROUND: Several prognostic indexes (PI) have been developed in the brain metastases (BM) setting to help physicians tailor treatment options and stratify patients enrolled in clinical studies. The aim of our study was to compare the clinical relevance of the major PI for breast cancer BM. METHODS: Clinical and biological data of 250 breast cancer patients diagnosed with BM at two institutions between 1995 and 2010 were retrospectively reviewed. The prognostic value and accuracy of recursive partitioning analysis (RPA), graded prognostic assessment (GPA), basic score for BM (BS-BM), breast RPA, breast GPA, Le Scodan's Score and a clinico-biological score developed in a phase I study (P1PS) were assessed using Cox regression models. PI comparison was performed using Harrell's concordance index. RESULTS: After a median follow-up of 4.5 years, median overall survival (OS) from BM diagnosis was 8.9 months (CI 95%, 6.9-10.3 months). All PI were significantly associated with OS. Harrell's concordance indexes C favored BS-BM and RPA. In multivariate analysis, the RPA, Le Scodan's score and GPA were found to be the best independent predictors of OS. In multivariate analysis restricted to the 159 patients with known LDH and proteinemia, RPA 2 and 3, Le Scodan's Score 3 and P1PS 2/3 were associated with worse survival. RPA was the most accurate score to identify patients with long (superior to 12 months) and short (inferior to 3 months) life expectancy. CONCLUSIONS: RPA seems to be the most useful score and performs better than new PI for breast cancer BM.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Carcinoma/mortalidade , Carcinoma/secundário , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida
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