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Journal of Thoracic Oncology:
doi: 10.1097/01.JTO.0000283536.72976.25
Poster Abstracts: BSTB: Prognostic Factors: BSTB: Prognostic Factors Posters, Tue, Sept 4

Angiogenesis gene expression profiling as prognostic marker in non-small cell lung cancer: P2-072

van den Boogaart, Vivian E.1; Thijssen, Victor L.2; De Ruysscher, Dirk3; Wouters, Emiel F.4; van Suylen, Robert Jan5; Griffioen, Arjan W.6; Dingemans, Anne-Marie C.4

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1 University Hospital Maastricht, Dept Pulmonology, Maastricht, The Netherlands 2 University Maastricht, Dept. Pathology, Maastricht, The Netherlands 3 MAASTRO Clinic, Maastricht, The Netherlands 4 University Hospital Maastricht, Dept. Pulmonology, Maastricht, The Netherlands 5 University Hospital Maastricht, Dept Pathology, Maastricht, The Netherlands 6 University Maastricht, Dept Pathology, Maastricht, The Netherlands

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Introduction:

The five-year survival rate of patients with Non-Small Cell Lung Cancer (NSCLC) after surgical resection ranges from 28% (Stage IIB) to 62% (Stage IA). Although gene expression signatures can be used to predict overall survival in NSCLC patients, there is still a need for novel biomarkers that can identify patients who have the highest likelihood of recurrence and thus might benefit most from adjuvant treatment. Since it has recently been shown that chemotherapy in combination with anti-angiogenesis therapy can prolong survival in patients with NSCLC, we evaluated the prognostic value of angiogenesis gene expression signatures for survival in early stage NSCLC.

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Methods:

115 consecutive patients with early stage NSCLC were included based on at least 50% tumour area in the fresh frozen resection specimen and the absence of other malignancies. No patient received postoperative chemotherapy or neo-adjuvant treatment. A training set of 58 patients was selected and divided into short survival (<2 years, n=31) and long survival (>4 years, n=27). Microvessel density (MVD; number of vessels/mm3) was assessed in five randomly selected high power fields following immunohistochemistry. The angiogenesis gene expression signature was determined using real-time PCR covering 24 genes involved in angiogenesis.

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Results:

There was no significant difference in MVD between patients with short or long survival (3.27±1.34 vs. 2.92±1.03, respectively, p=0.293). In addition, there was no correlation between MVD and overall survival (corr. coef. −0.102, p=0.457). For real-time PCR, five reference genes were selected, i.e. β-Actin, cyclophilin-A, GAPDH, HPRT-1 and β-2-Microglobulin. Using correlation analysis and GeNorm analysis, we identified HPRT-1, GAPDH, and β-2-microglobuline as the most stable reference genes. Following angiogenesis gene expression profiling and subsequent univariate analysis, we observed a significant increase in the expression levels of VEGF-C (2.5 fold, p=0.008), Angiopoietin-1 (2.5 fold, p=0.024), and Neuropilin-1 (2.35 fold, p=0.010) in patients with a short survival compared to those with a long survival. Expression levels of VEGF-A/-B/-D, VEGF-R1/-R2/-R3, Angiopoietin-2, Neuropilin-2, Tie-1/-2, PDGF-B, PlGF, EGF, ICAM-1, VCAM, bFGF, TNFα, TGFα/β, IL-8, Trombospondin-1 were not significantly altered. Based on all expression data, we developed a preliminary model that predicts the probability of 2-years overall survival of early stage NSCLC patients. Cross validation and bootstrapping revealed a sensitivity of 60% and a specificity of 70% of this preliminary model.

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Conclusion:

Microvessel density was not a prognostic factor for survival in early stage NSCLC patients. Nevertheless, we found altered expression levels of angiogenesis factors in patients with short survival. Furthermore, we developed a model that predicts the 2-years overall survival of early stage NSCLC patients. Current research aims at increasing the sensitivity and specificity of the model by extending the training set and by model validation of an independent set of samples, these data will be presented.

Copyright © 2007 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.

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