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1.
Br J Cancer ; 122(10): 1518-1524, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205863

RESUMO

BACKGROUND: Patients with desmoplastic (angiogenic) histopathological growth pattern (HGP) colorectal liver metastases (CLM) might derive more benefit from bevacizumab-based chemotherapy than those with replacement (non-angiogenic) HGP. This study investigated the association of HGP with the immune phenotype (IP) and clinical outcome after liver resection. METHODS: CLM of patients treated with perioperative bevacizumab-based chemotherapy and liver resection were investigated. Association of HGP and IP with response, recurrence-free survival (RFS) and overall survival (OS) was investigated. RESULTS: One hundred and eighteen patients (M/F 66/52, median age 62.3 (31.0-80.4) years, median follow-up 32.2 (5.0-92.7) months) were enrolled. The inflamed IP was associated with the desmoplastic HGP. The desmoplastic HGP was associated with better radiological and histological response compared to the replacement HGP, respectively. The replacement HGP was associated with shorter RFS (8.7 versus 16.3 months, HR 2.60, P = 0.001) and OS (36.6 months versus not reached, HR 2.32, P = 0.027), respectively. The non-inflamed IP was associated with shorter RFS (10.8 versus 16.5 months, HR 1.85, P = 0.029). The HGP but not the IP remained significant in multivariable analysis for RFS. CONCLUSIONS: The desmoplastic HGP is associated with the inflamed IP and HGP may be a potential biomarker for adjuvant treatment that includes targeting the immune contexture.


Assuntos
Bevacizumab/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Fenótipo
2.
Nat Commun ; 9(1): 4672, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405103

RESUMO

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/secundário , Receptor TIE-2/sangue , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Angiopoietina-2/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neovascularização Patológica/sangue , Prognóstico , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Adv Anat Pathol ; 24(5): 235-251, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28777142

RESUMO

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Linfócitos do Interstício Tumoral/patologia , Segunda Neoplasia Primária/patologia , Animais , Biomarcadores Tumorais/análise , Humanos , Patologistas
4.
Adv Anat Pathol ; 24(6): 311-335, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28777143

RESUMO

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.


Assuntos
Neoplasias Encefálicas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias do Endométrio/imunologia , Neoplasias Gastrointestinais/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Mesotelioma/imunologia , Neoplasias Ovarianas/imunologia , Patologia/métodos , Neoplasias Cutâneas/imunologia , Neoplasias Urogenitais/imunologia , Biomarcadores Tumorais/análise , Biópsia , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias do Endométrio/patologia , Feminino , Neoplasias Gastrointestinais/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/patologia , Melanoma/patologia , Mesotelioma/patologia , Neoplasias Ovarianas/patologia , Patologia/normas , Fenótipo , Valor Preditivo dos Testes , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias Urogenitais/patologia
5.
Mol Cancer Ther ; 16(1): 228-238, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27811012

RESUMO

HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx FISH and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4,674 patients in a central laboratory for eligibility (1,995 cases) and for confirmation of local HER2 results (333 cases). Of 1,995 adenocarcinomas screened centrally, 322 (16.1%) had HER2-amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%), 487 patients (89%) were centrally confirmed as having HER2-amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2 In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low. Mol Cancer Ther; 16(1); 228-38. ©2016 AACR.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lapatinib , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Resultado do Tratamento , Adulto Jovem
6.
Mol Cancer Ther ; 15(11): 2814-2821, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27535973

RESUMO

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected before bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, and KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P < 0.05). High ACVRL1 levels predicted favorable 3-year OS (P = 0.041) and radiologic response (PR = 1.093, SD = 0.539, P = 0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P < 0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 months; HR = 2.83, P = 0.038). High VEGFB (46% vs. 85%; HR = 5.75, P = 0.009) and low FLT1 (55% vs. 100%; P = 0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers. Mol Cancer Ther; 15(11); 2814-21. ©2016 AACR.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Vasos Sanguíneos/embriologia , Vasos Sanguíneos/metabolismo , Expressão Gênica , Morfogênese/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacologia , Terapia Combinada , Feminino , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do Tratamento
7.
Br J Cancer ; 115(2): 228-35, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27351218

RESUMO

BACKGROUND: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use. METHODS: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined. RESULTS: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P<1 × 10(-9)). CONCLUSIONS: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers.


Assuntos
Proteínas Angiogênicas/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neovascularização Patológica , Receptor TIE-2/metabolismo , Teorema de Bayes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem
8.
Br J Cancer ; 114(8): 855-62, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27031850

RESUMO

BACKGROUND: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker. METHODS: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n=387) or placebo (n=387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. RESULTS: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml(-1)) vs non-Asian patients (3193 pg ml(-1)), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml(-1) increase: 1.19; 95% CI 1.10-1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13-1.64; P=0.0010 (Asians). CONCLUSIONS: Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Gástricas/sangue , Neoplasias Gástricas/diagnóstico , Proteínas de Transporte Vesicular/sangue , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Prognóstico , Neoplasias Gástricas/tratamento farmacológico
9.
J Natl Cancer Inst ; 107(3)2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25713148

RESUMO

BACKGROUND: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). METHODS: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. RESULTS: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. CONCLUSIONS: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Expert Rev Mol Diagn ; 15(3): 399-414, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25585649

RESUMO

Bevacizumab is the first anti-angiogenic agent approved for the treatment of metastatic colorectal cancer. The need for patient selection before initiating therapy necessitates the study of various proteins expressed in metastatic colorectal cancer tissue as candidate predictive markers. Immunohistochemistry is a valuable, commonly available and cost-effective method to assess predictive biomarkers. However, it is subject to variations and therefore requires rigorous protocol standardizations. Furthermore, validated quantification methodologies to study these angiogenic elements have to be applied. Based on their function in tumor angiogenesis and their relation to the mechanism of action of bevacizumab, protein markers were divided in four groups: VEGF A-signaling proteins; other relevant angiogenesis factors; factors regarding the tumor microenvironment and tumor intrinsic markers. Conceivably, nimbly selecting a small but relevant group of therapy-guided patients by the appropriate combination of predictive biomarkers may confer great value to this angiogenic inhibitor.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Inibidores da Angiogênese/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Imuno-Histoquímica , Camundongos , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
J Nucl Med ; 56(1): 63-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25476536

RESUMO

UNLABELLED: No validated predictive biomarkers for antiangiogenic treatment of metastatic renal cell carcinoma (mRCC) exist. Tumor vascular endothelial growth factor A (VEGF-A) level may be useful. We determined tumor uptake of (89)Zr-bevacizumab, a VEGF-A-binding PET tracer, in mRCC patients before and during antiangiogenic treatment in a pilot study. METHODS: Patients underwent (89)Zr-bevacizumab PET scans at baseline and 2 and 6 wk after initiating either bevacizumab (10 mg/kg every 2 wk) with interferon-α (3-9 million IU 3 times/wk) (n = 11) or sunitinib (50 mg daily, 4 of every 6 wk) (n = 11). Standardized uptake values were compared with plasma VEGF-A and time to disease progression. RESULTS: (89)Zr-bevacizumab PET scans visualized 125 evaluable tumor lesions in 22 patients, with a median SUV(max) (maximum standardized uptake value) of 6.9 (range, 2.3-46.9). Bevacizumab/interferon-α induced a mean change in tumor SUV(max) of -47.0% (range, -84.7 to +20.0%; P < 0.0001) at 2 wk and an additional -9.7% (range, -44.8 to +38.9%; P = 0.015) at 6 wk. In the sunitinib group, the mean change in tumor SUV(max) was -14.3% at 2 wk (range, -80.4 to +269.9; P = 0.006), but at 6 wk the mean change in tumor SUV(max) was +72.6% (range, -46.4 to +236%; P < 0.0001) above baseline. SUV(max) was not related to plasma VEGF-A at all scan moments. A baseline mean tumor SUV(max) greater than 10.0 in the 3 most intense lesions corresponded with longer time to disease progression (89.7 vs. 23.0 wk; hazard ratio, 0.22; 95% confidence interval, 0.05-1.00). CONCLUSION: Tumor uptake of (89)Zr-bevacizumab is high in mRCC, with remarkable interpatient and intrapatient heterogeneity. Bevacizumab/interferon-α strongly decreases tumor uptake whereas sunitinib results in a modest reduction with an overshoot after 2 drug-free weeks. High baseline tumor SUV(max) was associated with longer time to progression.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/metabolismo , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Transporte Biológico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/sangue , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Pirróis/uso terapêutico , Traçadores Radioativos , Radioisótopos , Cintilografia , Sunitinibe , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue , Zircônio
12.
Angiogenesis ; 17(4): 909-20, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25012543

RESUMO

BACKGROUND: Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. METHODS: We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. RESULTS: The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. CONCLUSIONS: This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Variação Genética , Neoplasias/genética , Fator A de Crescimento do Endotélio Vascular/genética , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Teorema de Bayes , Bevacizumab , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Fator C de Crescimento do Endotélio Vascular/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
13.
Clin Cancer Res ; 20(17): 4549-4558, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24947924

RESUMO

PURPOSE: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. EXPERIMENTAL DESIGN: Pretreatment training (n=91) and validation (n=114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset. RESULTS: The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica internal endothelial cell kinase 2) concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cutoffs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients in both datasets (median, 23.0 months vs. 16.2; P=0.003) for the interaction of Ang1-Tie2 treatment in Cox regression analysis. The prognostic indices derived from the training set also distinguished high and low probability for progression in the validation set (P=0.008), generating similar values for HR (0.21 vs. 0.27) between treatment and control arms for patients with high Ang1 and low Tie2 values. CONCLUSIONS: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer. These findings need to be validated in larger trials due to the limitation of sample size in this study.


Assuntos
Angiopoietina-1/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Receptor TIE-2/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados/genética , Bevacizumab , Biomarcadores Tumorais , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Células Neoplásicas Circulantes , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neoplasias Ovarianas/patologia , Prognóstico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética
14.
PLoS One ; 9(4): e95983, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24752333

RESUMO

Tumor derived microparticles (TMPs) have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs). Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.


Assuntos
Micropartículas Derivadas de Células , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Bevacizumab , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico
15.
Angiogenesis ; 17(3): 685-94, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24558090

RESUMO

PURPOSE: There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. EXPERIMENTAL DESIGN: Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. RESULTS: Ten SNPs were associated with bevacizumab-induced hypertension (P ≤ 0.05), but none surpassed the threshold adjusted for multiple testing (P < 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). CONCLUSIONS: The genes described in this large genetic analysis using pooled datasets warrant further functional investigation regarding their role in mediating bevacizumab-induced hypertension.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Hipertensão/induzido quimicamente , Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genética , Bevacizumab , Demografia , Determinação de Ponto Final , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipertensão/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Placebos , Transdução de Sinais/genética , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética
16.
Mol Cancer Ther ; 13(1): 202-13, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24150126

RESUMO

We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-VEGF-A therapy in this context has not been fully explored. We, therefore, used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice, including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model, nor were changes in endothelial cell numbers found at metastatic sites. As chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or patients with cancer. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias Pulmonares/terapia , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Animais , Anticorpos Anti-Idiotípicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Fluoruracila , Humanos , Imunoterapia , Leucovorina , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Compostos Organoplatínicos , Fator A de Crescimento do Endotélio Vascular/imunologia
17.
Int J Cancer ; 135(2): 270-81, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24347266

RESUMO

Acute chemotherapy can induce rapid bone-marrow derived pro-angiogenic cell (BMDC) mobilization and tumor homing, contributing to tumor regrowth. To study the contribution of tumor cells to tumor regrowth following therapy, we focused on tumor-derived microparticles (TMPs). EMT/6 murine-mammary carcinoma cells exposed to paclitaxel chemotherapy exhibited an increased number of TMPs and significantly altered their angiogenic properties. Similarly, breast cancer patients had increased levels of plasma MUC-1(+) TMPs following chemotherapy. In addition, TMPs from cells exposed to paclitaxel induced higher BMDC mobilization and colonization, but had no increased effect on angiogenesis in Matrigel plugs and tumors than TMPs from untreated cells. Since TMPs abundantly express osteopontin, a protein known to participate in BMDC trafficking, the impact of osteopontin-depleted TMPs on BMDC mobilization, colonization, and tumor angiogenesis was examined. Although EMT/6 tumors grown in mice inoculated with osteopontin-depleted TMPs had lower numbers of BMDC infiltration and microvessel density when compared with EMT/6 tumors grown in mice inoculated with wild-type TMPs, no significant difference in tumor growth was seen between the two groups. However, when BMDCs from paclitaxel-treated mice were injected into wild-type EMT/6-bearing mice, a substantial increase in tumor growth and BMDC infiltration was detected compared to osteopontin-depleted EMT/6-bearing mice injected with BMDCs from paclitaxel-treated mice. Collectively, our results suggest that osteopontin expressed by TMPs play an important role in BMDC mobilization and colonization of tumors, but is not sufficient to enhance the angiogenic activity in tumors.


Assuntos
Células da Medula Óssea/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Micropartículas Derivadas de Células/metabolismo , Neovascularização Patológica/metabolismo , Osteopontina/metabolismo , Animais , Antineoplásicos/farmacologia , Células da Medula Óssea/patologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/patologia , Paclitaxel/farmacologia
18.
Clin Cancer Res ; 19(13): 3681-92, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23685835

RESUMO

PURPOSE: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. EXPERIMENTAL DESIGN: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. RESULTS: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. CONCLUSIONS: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Bevacizumab , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/genética , Neoplasias/mortalidade , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo
19.
J Clin Oncol ; 31(9): 1219-30, 2013 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-23401453

RESUMO

Bevacizumab is the first antiangiogenic therapy proven to slow metastatic disease progression in patients with cancer. Although it has changed clinical practice, some patients do not respond or gradually develop resistance, resulting in rather modest gains in terms of overall survival. A major challenge is to develop robust biomarkers that can guide selection of patients for whom bevacizumab therapy is most beneficial. Here, we discuss recent progress in finding such markers, including the first results from randomized phase III clinical trials evaluating the efficacy of bevacizumab in combination with comprehensive biomarker analyses. In particular, these studies suggest that circulating levels of short vascular endothelial growth factor A (VEGF-A) isoforms, expression of neuropilin-1 and VEGF receptor 1 in tumors or plasma, and genetic variants in VEGFA or its receptors are strong biomarker candidates. The current challenge is to expand this first set of markers and to validate it and implement it into clinical practice. A first prospective biomarker study known as MERiDiAN, which will treat patients stratified for circulating levels of short VEGF-A isoforms with bevacizumab and paclitaxel, is planned and will hopefully provide us with new directions on how to treat patients more efficiently.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/análise , Neoplasias/tratamento farmacológico , Bevacizumab , Progressão da Doença , Humanos , Neuropilina-1/análise , Isoformas de Proteínas/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética
20.
Clin Cancer Res ; 19(4): 929-37, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23169435

RESUMO

PURPOSE: We evaluated the prognostic and predictive use of circulating VEGF-A levels in phase III trials of bevacizumab in colorectal cancer, lung cancer, and renal cell carcinoma. METHODS: Baseline plasma samples from 1,816 patients were analyzed for VEGF-A using an ELISA, which recognizes the major isoforms with equivalent sensitivity. HR and 95% confidence intervals (CI) for study end points were estimated using Cox regression analysis. A subset of matched archival tumor samples was analyzed for VEGF-A expression using in situ hybridization. RESULTS: Higher VEGF-A levels showed trends toward adverse prognostic significance in the control arms of multiple trials, reaching statistical significance for overall survival (OS) in AVF2107 (highest vs. lowest 50%: HR = 1.76; 95% CI, 1.28-2.41), AVAiL (HR = 1.52; 95% CI, 1.16-2.00), and AVOREN (HR = 1.67; 95% CI, 1.18-2.36). In predictive analyses, the HRs for progression-free survival were similar across low and high VEGF-A subgroups and favored bevacizumab-containing treatment. In the low VEGF-A subgroups, HRs (95% CIs) were 0.61 (0.43-0.87) in AVF2107, 0.71 (0.43-1.16) in E4599, 0.74 (0.59-0.94) in AVAiL (low-dose), 0.89 (0.70-1.13) in AVAiL (high-dose), and 0.56 (0.40-0.78) in AVOREN. Analyses of OS data have shown similar results. No correlation between primary tumor VEGF-A expression and plasma VEGF-A levels was observed. CONCLUSIONS: In this comprehensive evaluation, pretreatment total circulating VEGF-A was prognostic for outcome in metastatic colorectal, lung, and renal cell cancers, but it was not predictive for bevacizumab-based treatment benefit.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab , Carcinoma de Células Renais/sangue , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/sangue , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
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