Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer.
BACKGROUND
Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin-like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression.


METHODS
We identified all patients with localized TNM stage I-III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS).


RESULTS
Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p<0.0001), subglottic/transglottic localization (HR = 1.756, p = 0.0438) and IGF1R-alpha protein overexpression (HR = 1.475, p = 0.0504).


CONCLUSIONS
IGF1R-alpha protein overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of the IGF1R-alpha prognostic utility is warranted.
Department of Medical Oncology, 251 Airforce General Hospital, Athens, Greece. gmountzios@gmail.com
Giannis
G
Mountzios
Ioannis
I
Kostopoulos
Vassiliki
V
Kotoula
Ioanna
I
Sfakianaki
Elena
E
Fountzilas
Konstantinos
K
Markou
Ilias
I
Karasmanis
Sofia
S
Leva
Nikolaos
N
Angouridakis
Konstantinos
K
Vlachtsis
Angelos
A
Nikolaou
Ioannis
I
Konstantinidis
George
G
Fountzilas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D015870:Gene Expression; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D007822:Laryngeal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
D014408:Biomarkers, Tumor; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D020033:Protein Isoforms; D017527:Receptor, IGF Type 2; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048056:Mitogen-Activated Protein Kinase 9; D017526:Receptor, IGF Type 1; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human