Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung

Abstract

Purpose: Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non-small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC).

Patients and methods: We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC.

Results: The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC.

Conclusion: Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.

Fig 1.

The expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) 1, and VEGFR2 is higher in adenocarcinoma (ADC) compared with squamous cell carcinoma (SCC). Representative immunostaining for (A, D) VEGF, (B, E) VEGFR1, and (C, F) VEGFR2 in (A-C) ADC and (D-F) SCC tumors. VEGF, VEGFR1, and VEGFR2 are predominantly found in the cytoplasm of tumor cells. Scale bar: 25 μm.

Fig 2.

High vascular endothelial growth factor signaling score (VSS) is a good prognostic factor in patients with squamous cell carcinoma (SCC) in the European Early Lung Cancer project cohort. Cumulative incidence plots of disease progression were grouped by VSS for (A) all patients, (B) patients with adenocarcinoma (ADC), (C) patients with SCC, (D) patients with stage I disease, (E) patients with stage I ADC, and (F) patients with stage I SCC. A competing risk analysis of disease progression was performed to analyze the cumulative competing risks of progression.

Fig 3.

The MD Anderson (MDA) and Grenoble Centre Hospitalier Universitaire (CHU) Albert Michallon validation series confirm that high vascular endothelial growth factor signaling score is associated with longer survival in patients with stage I squamous cell carcinoma (SCC). Cumulative incidence plots are shown for (A) all patients with stage I disease, (B) patients with stage I adenocarcinoma, and (C) patients with stage I SCC in the MDA series. (D) Cumulative incidence plot is shown for patients with stage I SCC in the CHU series.