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

• Published in: Cancer chemotherapy and pharmacology 2013-03, Vol.71 (3), p.671-680
• Main Authors: Ludovini, V., Flacco, A., Bianconi, F., Ragusa, M., Vannucci, J., Bellezza, G., Chiari, R., Minotti, V., Pistola, L., Tofanetti, F. R., Siggillino, A., Baldelli, E., Sidoni, A., Daddi, N., Puma, F., Varella-Garcia, M., Crinò, L.
• Format: Article
• Language: English
• Subjects: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Cancer Research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - surgery; Cohort Studies; Disease-Free Survival; ErbB Receptors - biosynthesis; ErbB Receptors - genetics; Female; Gene Dosage; Gene Expression - physiology; Humans; Immunohistochemistry; In Situ Hybridization; Kaplan-Meier Estimate; Lung Neoplasms - genetics; Lung Neoplasms - surgery; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pneumology; Prognosis; Receptor, IGF Type 1 - biosynthesis; Receptor, IGF Type 1 - genetics; Sex Factors; Smoking - adverse effects; Tumors; Tumors of the respiratory system and mediastinum
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2056-y

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 (χ 2  = 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.