Abstract 2251: High VEGFA pathway expression predicts good prognosis in stage I squamous cell carcinoma of the lung
Authors: Agorreta Jackeline , Pajares Maria J. , Larrayoz Marta , Vesin Aurelien , Exponda Teresa , Zudaire Isabel , Torre Wenceslao , Lozano Maria D. , Gurpide Alfonso , Brambilla Elisabeth , Brambilla Christian , Wistuba Ignacio I. , Behrens Carmen , Timsit Jean-Francois , Pio Ruben , Field John , Montuenga EU-ELC Consortium, Luis M. 
Published: June 2012

Abstract
Vascular endothelial growth factor A (VEGFA) mediates its effects through VEGFR1 and VEGFR2, regulating angiogenesis in healthy and tumor tissues. Hence, an anti-VEGFA therapy has been approved, in combination with platinum-based chemotherapy, as first line treatment in unresectable advanced non-small cell lung cancer (NSCLC). This antiangiogenic therapy is based on the inactivation of the VEGFA pathway in endothelial cells. However, tumor cells also express VEGFA and its receptors. In fact, the relationship between NSCLC prognosis and the expression of VEGFA and its receptors has been widely studied. However, the results are controversial. The lack of agreement may be due to variations in gene expression, response to therapy or outcome between the different NSCLC histological subtypes. Moreover, different oxygen requirements in early versus late stages of the disease may profoundly influence the relevance of the VEGFA pathway in NSCLC.
The aim of this study was to analyze the prognostic significance of the activation of the VEGFA pathway in early NSCLC by means of the development of a VEGFA signaling score that reflects the activation of VEGFA pathway in tumor cells. A second objective was to clarify the prognostic relevance of this pathway in the two main histological subtypes, adenocarcinoma (ADC) and squamous cell carcinoma (SCC), separately. To this purpose, we analyzed the VEGFA signaling score in three series of NSCLC patients: 1) a series of 298 stage I-IIIA NSCLC patients recruited in the context of the European Early Lung Cancer (EUELC) project; 2) a first validation series of 173 stage I-IIIA NSCLC patients from the MD Anderson Cancer Center; and 3) a second validation series of 50 patients stage I SCC from the CHU Hospital. Immunohistochemistry was used to detect VEGFA, VEGFR1, VEGFR2, and results were analyzed by semiquantitative methods. The VEGFA signaling score was calculated as the sum of VEGFA, VEGFR1 and VEGFR2 scores. In the EUELC series, the multivariate analysis, using the Fine & Gray adaptation of Cox proportional hazard model, revealed that high VEGFA signaling score is an independent good prognostic factor for progression-free survival (HR=0.61 [0.41-0.91], p=0.01). Sub-group analysis revealed that the favorable prognostic value of VEGFA signaling score was restricted to SCC patients (HR=0.40 [0.20-0.78], p=0.007). Conversely, this association was not observed in ADC cases (HR=0.83 [0.48-1.45], p=0.52). The strong association between high VEGFA signaling score and longer recurrence-free survival among stage I SCC patients was validated in the MD Anderson series (HR=0.05 [0.004-0.62], p=0.02). In the stage I SCC series of the CHU Hospital the same tendency was found (p=0.08). In conclusion, these data point to different roles of VEGFA and its receptors in the biology of the two main histological types of lung cancer, and suggests a paradigm shift in the role of the VEGFA pathway in SCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2011-2251