Clinical implications of serum total VEGF-A and VEGF-A isoforms in patients with EGFR-mutated advanced non-small cell lung cancer treated with EGFR-TKIs

Abstract Background Vascular endothelial growth factor (VEGF)-A, which is overexpressed in epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC), has been implicated in resistance to EGFR-tyrosine kinase inhibitors (TKIs). VEGF-A comprises several isoforms, including VEGF 121 and VEGF 165 . However, the clinical potential as blood biomarkers in EGFR-TKI treatment remains unclear. Methods We retrospectively analyzed 64 patients with advanced EGFR -mutated NSCLC who received EGFR-TKI monotherapy at Hiroshima University Hospital between November 2009 and August 2023. Pre-treatment serum levels of total VEGF-A (tVEGF-A), VEGF 121 , and VEGF 165 were measured using enzyme-linked immunosorbent assays. The association of these biomarkers with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was analyzed. Results The ORR was 78.1%, and the median PFS and OS were 7.5 and 31.8 months, respectively. Serum VEGF 121 levels were significantly higher in non-responders than in responders (median, 446.6 vs. 322.1 pg/mL, p = 0.043), whereas no significant differences were observed for tVEGF-A and VEGF 165 levels. Receiver operating characteristic analysis identified an optimal serum VEGF 121 cut-off level of 339.3 pg/mL (AUC: 0.678, sensitivity: 52.0%, specificity: 92.9%). Patients with higher serum VEGF 121 (> 339.3 pg/mL) had significantly lower ORR (64.9% vs. 96.3%, p = 0.003), shorter PFS (median, 6.2 vs. 14.4 months, p = 0.026), and shorter OS (median, 27.6 months vs. not reached, p = 0.040) than those with lower serum VEGF 121 (≤ 339.3 pg/mL). Conclusion Higher levels of serum VEGF 121 were associated with lower EGFR-TKI efficacy and poorer prognosis in patients with EGFR -mutated NSCLC.