Pre-Therapeutic VEGF Level in Plasma Is a Prognostic Bio-Marker in Head and Neck Squamous Cell Carcinoma (HNSCC)

Julia Siemert; Theresa Wald; Marlen Kolb; Isolde Pettinella; Ulrike Böhm; Markus Pirlich; Susanne Wiegand; Andreas Dietz; Gunnar Wichmann

doi:10.3390/cancers13153781

Pre-Therapeutic VEGF Level in Plasma Is a Prognostic Bio-Marker in Head and Neck Squamous Cell Carcinoma (HNSCC)

Cancers (Basel). 2021 Jul 27;13(15):3781. doi: 10.3390/cancers13153781.

Authors

Julia Siemert¹, Theresa Wald¹, Marlen Kolb¹, Isolde Pettinella¹, Ulrike Böhm¹, Markus Pirlich¹, Susanne Wiegand¹, Andreas Dietz¹, Gunnar Wichmann¹

Affiliation

¹ Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstr, 10-14, 04103 Leipzig, Germany.

Abstract

Vascular endothelial growth factor (VEGF) is centrally involved in cancer angiogenesis. We hypothesized that pre-therapeutic VEGF levels in serum and plasma differ in their potential as biomarkers for outcomes in head and neck squamous cell carcinoma (HNSCC) patients. As prospectively defined in the study protocols of TRANSCAN-DietINT and NICEI-CIH, we measured VEGF in pretreatment serum and plasma of 75 HNSCC test cohort (TC) patients. We analyzed the prognostic value of VEGF concentrations in serum (VEGF_Serum) and plasma (VEGF_Plasma) for event-free survival (EFS) utilizing receiver-operating characteristics (ROC). Mean VEGF concentrations in plasma (34.6, 95% CI 26.0-43.3 ng/L) were significantly lower (p = 3.35 × 10^-18) than in serum (214.8, 95% CI 179.6-250.0 ng/L) but, based on ROC (area under the curve, AUC_Plasma = 0.707, 95% CI 0.573-0.840; p = 0.006 versus AUC_Serum = 0.665, 95% CI 0.528-0.801; p = 0.030), superiorly correlated with event-free survival (EFS) of TC patients. Youden indices revealed optimum binary classification with VEGF_Plasma 26 ng/L and VEGF_Serum 264 ng/L. Kaplan-Meier plots demonstrated superiority of VEGF_Plasma in discriminating patients regarding outcome. Patients with VEGF_Plasma < 26 ng/L had superior nodal (NC), local (LC) and loco-regional control (LRC) leading to significant prolonged progression-free survival (PFS) and EFS. We successfully validated VEGF_Plasma according the cut-off <26 ng/L as predictive for superior outcome in an independent validation cohort (iVC) of 104 HNSCC patients from the studies DeLOS-II and LIFE and found better outcomes including prolonged tumor-specific (TSS) and overall survival (OS). Outcomes in TC and iVC combined again was related to VEGF_Plasma, and multivariate Cox regression revealed that VEGF_Plasma was an independent outcome predictor. In HNSCC, pre-therapeutic VEGF_Plasma is prognostic for outcomes.

Keywords: angiogenesis; anti-angiogenesis; biomarker validation; head and neck cancer (HNC); head and neck squamous cell carcinoma (HNSCC); multivariate Cox proportional hazard regression; outcome research; prognostic biomarker; survival; vascular endothelial growth factor (VEGF).