Vascular endothelial growth factor receptor-2 (VEGFr-2) genetic polymorphisms as predictors to antiangiogenic therapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14561-e14561
Author(s):  
J. Jurado ◽  
J. A. Ortega ◽  
P. Iglesias ◽  
J. L. García-Puche ◽  
J. Belon
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Overall Survival ◽  
Growth Factor ◽  
Antiangiogenic Therapy ◽  
Venous Blood ◽  
Metastatic Breast ◽  
Severe Toxicity ◽  
Vascular Endothelial ◽  
Significant Difference ◽  
Endothelial Growth Factor

e14561 Background: Vascular endothelial growth factor (VEGF) and its receptors (VEGFr-2) have important roles in angiogenesis, predicting risk and prognosis in several solids tumor. VEGFr-2 located on chromosome 4 (4q11-q12) is organized into 30 exons separated by 29 introns. Recently the VEGF-2578 AA and VEGF-1154 AA genotypes were associated with a superior median overall survival when using bevacizumab in metastatic breast cancer. We investigated the association of VEGFr-2 polymorphisms to efficacy and toxicity in patients with antiangiogenic therapy. Methods: We performed genotype for selected VEGFr-2 polymorphisms in promoter regions 5’UTR, 3’UTR; in exons 7, 8, 9, 11, 16, 17, 18, 21, 27, 30 and introns 9, 17, 20. DNA was extracted from venous blood of 44 patients with non-curable solid tumors who have received treatment with bevacizumab (B) N=20 (45%) or raf kinase inhibitors 55%; vatalanib (PTK-787) N=3, sunitinib (SU011248) N=6, sorafenib (BAY 43–9006) N= 13, ZD6474 N=1 and AMG706 N= 1. Kaplan-Meier survival analysis was used to assess the association between VEGFr-2 staining and either progression-free survival (PFS) or overall survival (OS). Results: 44 patients have received a median of 6 (1–19) cycles of treatment, 72% was used simultaneously with QT. According to the criteria of NCI-CTC the severe toxicity G3–4 occurred in 47%, 9% with a definite suspension of the drug. The toxicity was not associated with VEGFr-2 genotypes. Efficacy; 5/44 patients (11%) had complete response and 11/ 44 (22%) partial responses by RECIST criteria. With a median follow up of 12 months, the ILP was 8.5 months dt (5.8). The analysis of VEGFr-2 polymorphisms identifies the variant AA of the intron-20 rs2219471 with a significant difference in PFS and OS regarding their ancestral variant AG. Conclusions: Our data suggest that VEGFR polymorphism can be a predictor of clinical outcomes in antiangiogenic therapy. No significant financial relationships to disclose.

scholarly journals Increased expression of adenosine 2A receptors in metastatic renal cell carcinoma is associated with poorer response to anti-vascular endothelial growth factor agents and anti-PD-1/Anti-CTLA4 antibodies and shorter survival

2021 ◽  
Author(s):  
Takao Kamai ◽  
Toshiki Kijima ◽  
Toyonori Tsuzuki ◽  
Akinori Nukui ◽  
Hideyuki Abe ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Vascular Endothelial Growth Factor ◽  
Overall Survival ◽  
Cell Death ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Primary Tumors ◽  
Anti Vegf ◽  
Programmed Cell Death 1 ◽  
Endothelial Growth Factor

Abstract Background Adenosine and its adenosine 2A receptors (A2AR) mediate the immunosuppressive mechanism by which tumors escape immunosurveillance and impede anti-tumor immunity within the tumor microenvironment. However, we do not know whether the adenosine pathway (CD39/CD73/A2AR) plays a role in renal cell carcinoma (RCC). Therefore, we studied the role of immunosuppression in RCC by assessing the adenosine pathway in patients with RCC treated with anti-vascular endothelial growth factor (anti-VEGF) agents or immune checkpoints inhibitors (ICIs) or both. Methods In 60 patients with metastatic RCC, we examined the expression of CD39, CD73, A2AR, and programmed cell death 1 ligand 1 (PD-L1) immunohistochemically in surgically resected tumor tissues and studied the clinicopathological characteristics of these patients. Patients were treated by cytoreductive nephrectomy with systemic therapy with anti-VEGF agent or a combination of the ICIs anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody and programmed cell death 1 (PD-1) antibody. Results Increased expression of A2AR in the primary tumors was associated with metastatic profiles. Patients treated with anti–PD-1 antibody in monotherapy, a combination of anti-PD-1 and anti-CTLA4 antibodies, or anti-VEGF agents showed better response and longer overall survival if the primary tumor had higher PD-L1 expression and lower A2AR expression. In Cox multivariate regression analysis, higher expression of A2AR was associated with shorter overall survival. Conclusions Our findings suggest that the expression of A2AR and PD-L1 in the primary tumors in RCC might predict the outcomes of treatment with anti-VEGF agents and ICIs and that the A2AR pathway might be a molecular target for immunotherapy.

scholarly journals Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway

2010 ◽  
Vol 235 (1) ◽  
pp. 3-9 ◽  
Author(s):  
Grzegorz Korpanty ◽  
Elizabeth Smyth ◽  
Laura A Sullivan ◽  
Rolf A Brekken ◽  
Desmond N Carney
Keyword(s):  
Lung Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Antiangiogenic Therapy ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals The VAD Scheme versus Thalidomide plus VAD for Reduction of Vascular Endothelial Growth Factor in Multiple Myeloma: A Meta-Analysis

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Gan-Lin He ◽  
Duo-Rong Xu ◽  
Wai-Yi Zou ◽  
Sui-Zhi He ◽  
Juan Li
Keyword(s):  
Multiple Myeloma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Meta Analysis ◽  
Biomedical Literature ◽  
Cochrane Library ◽  
Vascular Endothelial ◽  
China National Knowledge Infrastructure ◽  
Significant Difference ◽  
Endothelial Growth Factor

The VAD (vincristine-doxorubicin-dexamethasone) regimen has been used for decades to treat multiple myeloma (MM). Based on reports that vascular endothelial growth factor- (VEGF-) mediated angiogenesis is critical for MM pathogenesis, the antiangiogenic compound thalidomide has been added to VAD (T-VAD). However, it remains unclear whether T-VAD is more efficacious than VAD for serum VEGF reduction or if the difference influences clinical outcome. Pubmed, Cochrane library, China Biomedical Literature (CBM) database, China National Knowledge Infrastructure (CNKI) database, Vip database, and Wanfang database were searched for relevant studies published up to June 2017. RevMan5.2 was used for methodological quality evaluation and data extraction. Thirteen trials (five randomized, seven nonrandomized, and one historically controlled) involving 815 cases were included. Serum VEGF was significantly higher in MM cases than non-MM controls (MD=353.01, [95%CI 187.52–518.51], P<0.01), and the overall efficacy of T-VAD was higher than that of VAD (RR=1.36, [1.21–1.53], P <0.01). Further, T-VAD reduced VEGF to a greater extent than VAD does ([MD=-49.85, [-66.28− -33.42], P<0.01). The T-VAD regimen also reduced VEGF to a greater extent in newly diagnosed MM patients than it did in recurrent patients ([MD=-120.20, [-164.60–-39.80], P<0.01). There was no significant difference in VEGF between T-VAD patients (2 courses) and nontumor controls (MD=175.94, [-26.08–377.95], P=0.09). Greater serum VEGF reduction may be responsible for the superior efficacy of T-VAD compared to VAD.

Measurement of free and complexed soluble vascular endothelial growth factor receptor, Flt-1, in fluid samples: development and application of two new immunoassays

2001 ◽  
Vol 100 (5) ◽  
pp. 567-575 ◽  
Author(s):  
Funmi M. BELGORE ◽  
Andrew D. BLANN ◽  
Gregory Y. LIP
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Plasma Levels ◽  
Biological Significance ◽  
Growth Factor Receptor ◽  
Soluble Form ◽  
Vascular Endothelial ◽  
Significant Difference ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. VEGF interacts with the endothelium via two membrane-spanning receptors, fms-like tyrosine kinase (Flt)-1 and kinase domain receptor. A soluble form of Flt-1 (sFlt-1) was isolated from endothelial cell media; however, its biological significance is still unknown, with limited data on plasma sFlt-1 levels in disease states. We have developed two new ELISAs for detecting free and VEGF-complexed sFlt-1, which were tested in accordance with standard validation and assessment methodologies employed in commercial settings. The intra-and inter-assay coefficients of variation are < 5% and 10% respectively, and results are highly reproducible. Applying these ELISAs in a clinical setting, we measured levels of VEGF, free and complexed sFlt-1 in citrated plasma from 40 patients with cardiovascular disease and 40 healthy controls. Median (interquartile range) plasma levels of VEGF in patients were significantly greater than controls [403 pg/ml (158–925 pg/ml) versus 113 pg/ml (33–231 pg/ml), P ⩽ 0.05]. Free sFlt-1 was significantly lower in patients compared with controls [8 ng/ml (2–22 ng/ml) versus 21 ng/ml (10–73 ng/ml), P ⩽ 0.05]. There was no significant difference in the levels of complexed sFlt-1 between the two groups. Plasma levels of VEGF-complexed sFlt-1 are minimal, despite the presence of excess free sFlt-1. Thus unbound plasma VEGF detected by ELISA may represent the majority of circulating VEGF, and justifies the measurement of plasma VEGF as an indicator of circulating VEGF levels. Furthermore, these results suggest that circulating sFlt-1 may serve as a selective inhibitor of VEGF activity, and that this regulatory mechanism may be altered by pathological conditions.

The Prognostic Value of Plasma YKL-40 in Patients With Chemotherapy-Resistant Ovarian Cancer Treated With Bevacizumab

2016 ◽  
Vol 26 (8) ◽  
pp. 1390-1398 ◽  
Author(s):  
Mogens K. Boisen ◽  
Christine V. Madsen ◽  
Christian Dehlendorff ◽  
Anders Jakobsen ◽  
Julia S. Johansen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Overall Survival ◽  
Growth Factor ◽  
Confidence Interval ◽  
Single Agent ◽  
Vascular Endothelial ◽  
Improved Outcomes ◽  
Median Serum ◽  
Endothelial Growth Factor

ObjectiveYKL-40 is a proangiogenic glycoprotein that is secreted by cancer cells and inflammatory cells. The expression of YKL-40 is induced by vascular endothelial growth factor inhibition. We tested the hypothesis that low baseline plasma YKL-40 is associated with improved outcomes in patients with ovarian cancer treated with bevacizumab.MethodsOne hundred forty patients with chemotherapy-refractory epithelian ovarian cancer were treated with single-agent bevacizumab 10 mg/kg every 3 weeks in a prospective trial. Plasma YKL-40 was determined by enzyme-linked immunosorbent assay before and during treatment. Both raw YKL-40 concentrations and age-corrected percentiles of normal YKL-40 level were used. Associations between plasma YKL-40 level and progression-free survival (PFS) and overall survival were tested using univariate and multivariate Cox proportional hazards models.ResultsBaseline plasma YKL-40 levels were higher in patients with poor performance status, less differentiated tumors, residual disease after primary surgery, higher than the median serum CA-125 level, and higher than the median serum vascular endothelial growth factor level. Age-corrected percentile of normal plasma YKL-40 greater than the lowest quartile (Q1, 85th percentile) was associated with shorter PFS in univariate (hazard ratio, 1.83; 95% confidence interval, 1.15–2.89; P = 0.010) and multivariate analyses and shorter overall survival in univariate analysis (hazard ratio, 1.96; 95% confidence interval, 1.27–3.03; P = 0.003). Increase in plasma YKL-40 during bevacizumab treatment, with correction for baseline plasma YKL-40, was a predictor of shorter PFS. Using normal versus elevated plasma YKL-40 as a cutoff did not provide the same discriminative value.ConclusionsLow plasma YKL-40 at baseline and during treatment is associated with improved outcomes in patients with chemotherapy-refractory advanced ovarian cancer treated with single-agent bevacizumab.

Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma.

1998 ◽  
Vol 16 (9) ◽  
pp. 3121-3128 ◽  
Author(s):  
B Linderholm ◽  
B Tavelin ◽  
K Grankvist ◽  
R Henriksson
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Overall Survival ◽  
Growth Factor ◽  
Breast Carcinoma ◽  
Systemic Therapy ◽  
Prognostic Value ◽  
Vascular Endothelial ◽  
Node Negative ◽  
Endothelial Growth Factor ◽  
Vegf Level

PURPOSE The prognostic value of vascular endothelial growth factor (VEGF) protein, known to stimulate endothelial growth and angiogenesis, was evaluated in node-negative breast carcinoma (NNBC) and compared with established prognostic factors. PATIENTS AND METHODS In 525 consecutive patients with primary invasive NNBC (T1-2N0M0; tumor, node, metastasis stage), of whom 500 patients did not receive any systemic therapy, the cytosolic levels of VEGF165 were measured by using a quantitative enzyme-linked immunosorbent assay. The median follow-up was 46 months. Univariate and multivariate analyses were performed. RESULTS VEGF level was significantly inversely correlated with estrogen receptor (ER) positivity but positively associated with tumor size and histologic grade. Patients with VEGF levels above the median value (2.40 pg/microg of DNA) showed a significantly shorter survival time (P=.0012) than patients with levels less than the median value, also when analyzed as a continuous variable (P=.0277). Tumor size, grade, and ER expression were all statistically significant for overall survival in univariate analyses (P=.0069, P=.014, and P < .001, respectively). Multivariate analysis showed that VEGF level was the strongest predictor of overall survival (P=.0199). Histologic grade was also an independent predictor of survival (P=.0477). Among the 381 patients with ER-positive tumors, a group in general considered to have a good prognosis, we found a significant reduction in survival for those with levels of VEGF greater than the median value (P=.0009). CONCLUSION The results suggest that the level of VEGF165 protein is an independent, strong prognostic factor for survival in patients with NNBC, especially in the subgroup of patients with ER positivity. Thus, cytosolic VEGF165 might be useful to select patients for adjuvant systemic therapy.

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