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Concomitant high gene copy number and protein overexpression of IGF1R and EGFR negatively affect disease-free survival of surgically resected non-small-cell-lung cancer patients

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Abstract

Background

Insulin-like growth factor 1 receptor (IGF1R) represents a novel molecular target in non-small-cell-lung cancer (NSCLC). IGF1R and epidermal growth factor receptor (EGFR) activation are essential to mediate tumor cell survival, proliferation, and invasion. This study investigates the prognostic role of IGF1R and EGFR in surgically resected NSCLC.

Materials and methods

IGF1R and EGFR copy number gain (CNG) were tested by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) in 125 stage I–II–IIIA NSCLC patients.

Results

Fourty-six tumors (40.3 %) were IGF1R FISH-positive (FISH+), and 76 (67.2 %) were EGFR FISH+. Tumors with concomitant IGF1R/EGFR FISH+ were observed in 34 cases (30.1 %). IGF1R and EGFR FISH+ were associated with SCC histology (p = 0.01 and p = 0.04, respectively). IGF1R and EGFR protein over-expression (IHC+) were detected in 45 (36.0 %) and 69 (55.2 %) cases, respectively. Tumors with concomitant IGF1R/EGFR IHC+ were detected in 31 (24.8 %) patients. IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were significantly associated (χ2 = 4.02, p = 0.04). Patients with IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were associated with shorter disease-free survival (DFS) (p = 0.05 and p = 0.05, respectively). Patients with concomitant IGF1R/EGFR FISH+/IHC+ had a worse DFS and overall survival (p = 0.005 and p = 0.01, respectively). The multivariate model confirmed that IGF1R/EGFR FISH+/IHC+ (hazard ratio (HR), 4.08; p = 0.01) and tumor stage (II–III vs I) (HR, 4.77; p = 0.003) were significantly associated with worse DFS.

Conclusions

IGF1R/EGFR FISH+ correlates with IGF1R/EGFR IHC+. IGF1R/EGFR FISH+/IHC+ is an independent negative prognostic factor for DFS in early NSCLC. These features may have important implications for future anti-IGF1R therapeutic approaches.

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Acknowledgments

The authors acknowledge the technical assistance of the Cytogenetics Core of the University of Colorado Cancer Center for all FISH analyses. The authors thank the patients who participated in this study. This work was supported in part by a grant from the Italian Association for Cancer Research (AIRC) to A.F. and from Umbria Association Against Cancer (AUCC) for IHC reagents.

Conflict of interest

The author(s) indicated no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, S. Maria Della Misericordia Hospital, 1, G. Dottori Street, 06132, Perugia, Italy

    V. Ludovini, A. Flacco, R. Chiari, V. Minotti, L. Pistola, F. R. Tofanetti, A. Siggillino, E. Baldelli & L. Crinò

  2. Department of Electronic and Information Engineering, Perugia University, Perugia, Italy

    F. Bianconi

  3. Department of Thoracic Surgery, Perugia University, Perugia, Italy

    M. Ragusa, J. Vannucci, N. Daddi & F. Puma

  4. Institute of Pathological Anatomy and Histology, Division of Cancer Research, Perugia University, Perugia, Italy

    G. Bellezza & A. Sidoni

  5. Department of Medicine/Medical Oncology, University of Colorado Cancer Center, Aurora, CO, USA

    M. Varella-Garcia

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  1. V. Ludovini
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Correspondence to V. Ludovini.

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Ludovini, V., Flacco, A., Bianconi, F. et al. Concomitant high gene copy number and protein overexpression of IGF1R and EGFR negatively affect disease-free survival of surgically resected non-small-cell-lung cancer patients. Cancer Chemother Pharmacol 71, 671–680 (2013). https://doi.org/10.1007/s00280-012-2056-y

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