Prognostic Significance of High VEGF-C Expression for Patients with Breast Cancer: An Update Meta Analysis

Zhang, Zhiqiao; Luo, Guanying; Tang, Hongfeng; Cheng, Ching‐Li; Wang, Peng

doi:10.1371/journal.pone.0165725

Cited by 15 publications

(14 citation statements)

References 29 publications

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“…A number of recent meta-analyses that summarize the results of these clinical investigations preferentially indicate positive VEGFC/D and VEGFR3 immunostaining in tumor cells and a positive correlation between the expression level and lymph node involvement or disease progression (48,49). Similar data were obtained for breast, colorectal and esophageal cancer patients (50)(51)(52). However, in all the reports, significant discrepancies across particular studies have been highlighted.…”

Section: Discussionmentioning

confidence: 73%

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer

Kowalczuk

Laudański

et al. 2018

Oncol Lett

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The present study aimed to verify a possibility of ongoing lymphangiogenesis in non-small cell lung cancer (NSCLC) via examination of mRNA levels of a number of lymphangiogenesis-associated genes in tumors. It was hypothesized that transcriptional activation of these genes would occur in tumors that stimulate new lymphatic vessel formation. The study was performed on 140 pairs of fresh-frozen surgical specimens of cancer and unaffected lung tissues derived from NSCLC stage I-IIIA patients. mRNA levels were evaluated with the reverse transcription-quantitative polymerase chain reaction method and expressed as fold change differences between the tumor and normal tissues. Possible associations between expression and patient clinicopathological characteristics and survival were analyzed. In the NSCLC tissue samples, vascular endothelial growth factor (VEGF) C, VEGFD, VEGFR3, VEGFR2, VEGFR1, lymphatic vessel endothelial hyaluronan receptor 1, integrin subunit α 9, FOX2, neuropilin 2, fibroblast growth factor 2 genes were significantly downregulated (P<0.001 for all) compared with matched normal lung tissues, whereas mRNA levels for VEGFA, spleen associated tyrosine kinase, podoplanin, and prospero homeobox 1 genes were similar in both tissues. Neither lymph node status, nor disease pathological stage influenced expression, whereas more profound suppression of gene activities appeared to occur in squamous cell carcinomas compared with adenocarcinomas. The VEGFR1 mRNA expression level was significantly connected with patient survival in the univariate analysis, and was an independent prognostic factor for overall survival in the multivariate Cox's proportional hazards model (HR 2.103; 95% confidence interval: 1.005-4.401; P=0.049). The results support a hypothesis of absence of new lymphatic vessel formation inside growing NSCLC tumor mass, however do not exclude a possibility of lymphangiogenesis in narrow marginal tumor parts.

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Section: Discussionmentioning

confidence: 73%

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer

Kowalczuk

Laudański

et al. 2018

Oncol Lett

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“…The contradiction among the original studies, as well as among some interesting recent meta-analyses[ 43 – 44 ], concerning the prognostic significance of most of the angiogenesis-related proteins has hindered their clinical utility in breast cancer patients. One has to remember however, that in most of the existing studies, including ours, the findings are not purely prognostic, since most if not all studies included some type of treatment (hormonal treatment or chemotherapy).…”

Section: Discussionmentioning

confidence: 99%

Associations of angiogenesis-related proteins with specific prognostic factors, breast cancer subtypes and survival outcome in early-stage breast cancer patients. A Hellenic Cooperative Oncology Group (HeCOG) trial

et al. 2018

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Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values <0.05), with the exception of the one between VEGF-C and VEGFR1 (chi-square test, p = 0.15). Tumors with high VEGF-A protein expression, as compared to tumors with low expression were more frequently ER/PgR-negative (33.3% vs. 20.8%, chi-square test, p = 0.009) and HER2-positive (44.8% vs. 20.6%, p<0.001). In addition, tumors with high VEGFR1 expression, were more frequently HER2-positive (32.8% vs. 19.6%, p<0.001), while tumors with high VEGFR3 expression were more frequently ER/PgR-negative (24.9% vs. 17.0%, p = 0.024) and HER2-positive (26.9% vs. 14.8%, p = 0.001). High VEGF-A and VEGF-C protein expression was associated with increased DFS in the entire cohort (HR = 0.57, 95% CI 0.36–0.92, Wald’s p = 0.020 and HR = 0.71, 95% CI 0.52–0.96, p = 0.025, respectively), as well as in specific subtypes/subgroups, such as HER2-positive (VEGF-A, HR = 0.32, 95% CI 0.14–0.74, p = 0.008) and triple-negative (VEGF-C, HR = 0.44, 95% CI 0.21–0.91, p = 0.027) patients. High vs. low VEGFR1 expression was an unfavorable factor for DFS in triple-negative patients (HR = 2.74, 95% CI 1.26–5.98, p = 0.011), whereas the opposite was observed among the ER/PgR-positive patients (HR = 0.69, 95% CI 0.48–0.98, p = 0.041). Regarding OS, high VEGF-C protein expression was associated with increased OS in the entire cohort (HR = 0.64, 95% CI 0.46–0.89, Wald’s p = 0.008), as well as in in specific subtypes/subgroups, such as ER/PgR-negative (HR = 0.37, 95% CI 0.20–0.71, p = 0.003) and triple-negative (HR = 0.42, 95% CI 0.19–0.90, p = 0.026) patients. In conclusion, high expression of angiogenesis-related proteins is associated with adverse clinicopathological parameters in early-stage breast cancer patients and may be surrogate markers of biologically distinct subgroups of ER/PgR-negative or triple-negative tumors with superior outcome. Further validation of our findings in independent cohorts is needed.

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“…VEGF-C expression in tumor tissue has been evaluated immunohistochemically in many studies, but the results have not been consistent [ 14 ]. However, a recent meta-analysis that included 21 studies and 2828 patients with breast cancer reported HRs of 1.87 (95% CI 1.25–2.79, p = 0.001) for RFS and 1.96 (95% CI 1.15–3.31, p = 0.001) for OS for patients with high tumor VEGF-C expression [ 5 ]. More recent studies have confirmed the negative prognostic role of VEGF-C based on its mRNA levels in tumor tissue [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, greater expression of VEGF-C (measured by immunohistochemistry in tumor biopsies) is related to poorer relapse-free survival (RFS) and overall survival (OS). A recent meta-analysis that included 21 studies and 2828 patients with breast cancer reported hazard ratios (HRs) of 1.87 (95% confidence interval [CI] 1.25–2.79, p = 0.001) for RFS and 1.96 (95% CI 1.15–3.31, p = 0.001) for OS in patients with high tumor VEGF-C expression [ 5 ]. However, the cut-off values used to define high tumor VEGF-C expression varied considerably among the studies.…”

Section: Introductionmentioning

confidence: 99%

High serum vascular endothelial growth factor C predicts better relapse-free survival in early clinically node-negative breast cancer

et al. 2018

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A recent meta-analysis indicated that higher tumoral expression of vascular endothelial growth factor C (VEGF-C) was related to poorer relapse-free and overall survival in breast cancer patients. However, a retrospective study found that higher circulating VEGF-C levels were associated with better survival in breast cancer patients. In 2009, we initiated a prospective study to determine the utility of preoperative serum VEGF-C levels for predicting the risk of sentinel lymph node involvement in early breast cancer and to assess serum VEGF-C levels as a prognostic factor for relapse-free and overall survival. We analyzed serum samples from 174 patients with early breast cancer who underwent sentinel lymph node biopsies. VEGF-C levels were determined using an ELISA. Serum VEGF-C levels were normally distributed, with a median value of 6561.5 pg/mL, and did not correlate with any other clinical or pathological variables. During a median follow-up period of 58 months, the five-year relapse-free survival rate was higher in patients with VEGF-C levels above the median than in patients with lower levels (95.3% vs. 85.9%, p < 0.04). No association was found between VEGF-C levels and overall survival. Our study demonstrates that the prognosis was better for early breast cancer patients with high serum VEGF-C levels.

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Prognostic Significance of High VEGF-C Expression for Patients with Breast Cancer: An Update Meta Analysis

Cited by 15 publications

References 29 publications

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer

Associations of angiogenesis-related proteins with specific prognostic factors, breast cancer subtypes and survival outcome in early-stage breast cancer patients. A Hellenic Cooperative Oncology Group (HeCOG) trial

High serum vascular endothelial growth factor C predicts better relapse-free survival in early clinically node-negative breast cancer

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