Prognostic Impact of Elevation of Vascular Endothelial Growth Factor Family Expression in Patients with Non-small Cell lung Cancer: an Updated Meta-analysis

Background: The vascular endothelial growth factor family has been implicated in tumorigenesis andmetastasis. The prognostic value of each vascular endothelial growth factor family member, particular VEGF/VEGFR co-expression, in patients with non-small lung cancer remains controversial. Materials and
Methods:Relevant literature was identified by searching PubMed, EMBASE and Web of Science. Studies evaluatingexpression of VEGFs and/or VEGFRs by immunohistochemistry or ELISA in lung cancer tissue were eligiblefor inclusion. Hazard ratios (HRs) and 95% confidence intervals (CIs) from individual study were pooled byusing a fixed- or random-effect model, heterogeneity and publication bias analyses were also performed.
Results:74 studies covering 7,631 patients were included in the meta-analysis. Regarding pro-angiogenesis factors, theexpression of VEGFA (HR=1.633, 95%CI: 1.490-1.791) and VEGFR1 (HR=1.924, 95%CI: 1.220-3.034) wasassociated separately with poor survival. Especially, VEGFA over-expression was an independent prognosticfactor in adenocarcinoma (ADC) (HR=1.775, 95%CI: 1.384-2.275) and SCC (HR=2.919, 95%CI: 2.060-4.137).Co-expression of VEGFA/VEGFR2 (HR=2.011, 95%CI: 1.405-2.876) was also significantly associated with worsesurvival. For lymphangiogenesis factors, the expression of VEGFC (HR=1.611, 95%CI: 1.407-1.844) predicteda poor prognosis. Co-expression of VEGFC/VEGFR3 (HR=2.436, 95%CI: 1.468-4.043) emerged as a preferableprognostic marker.
Conclusions: The expression of VEGFA (particularly in SCC and early stage NSCLC),VEGFC, VEGFR1 indicates separately an unfavorable prognosis in patients with NSCLC. Co-expression VEGFA/VEGFR2 is comparable with VEGFC/VEGFR3, both featuring sufficient discrimination value as preferable asprognostic biologic markers.