Abstract
Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival (p = 0.012 and p = 0.035, respectively), and with improved overall survival (p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk (p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival (p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy.
Highlights
Lung cancer is one of the most frequent malignancies, and presently the leading cause of cancer-related deaths in Europe [1]
Several studies have evaluated different molecules related to vascular endothelial growth factor (VEGF) pathway in relation to clinical outcomes in patients with non-small-cell lung cancer (NSCLC) treated with CPB regimen, but until now, there are no validated predictive biomarkers in the clinical setting [40]
This prospective study contributes to the body of evidence demonstrating the potential of some biomarkers, including Single-nucleotide polymorphism (SNP) in angiogenic genes and circulating levels of VEGF, as prognostic factors in NSCLC
Summary
Lung cancer is one of the most frequent malignancies, and presently the leading cause of cancer-related deaths in Europe [1]. A crucial aspect for solid tumor growth is vascularization, and various tumors have been found to produce angiogenic factors themselves or benefit from vascularization induced by inflammatory mediators [3]. The major regulator of angiogenesis is vascular endothelial growth factor (VEGF) [4], whose overexpression seems to play a most relevant role in malignant phenotype of solid tumors, including NSCLC [5]. Careful consideration of the results within the study populations points to the need of determining prognostic markers to select those patients that might achieve greater benefit of treatment with these schemes
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