Abstract 4347: Anaplastic lymphoma kinase (ALK) expression is an independent prognostic factor in neuroblastoma patients and correlates well with ALK inhibitor response in vitro

Abstract

Abstract Introduction: ALK mutations are one of the most common genetic aberrations occurring in 3-11% of the neuroblastoma (NBL) patients and are considered oncogenic. We determined the role of ALK protein levels on survival of NBL patients. Secondly, we tested in vitro responsiveness to ALK inhibitors in NBL cell lines with and without ALK mutation. Results: Formalin-Fixed, Paraffin-Embedded material of 71 NBL, 12 ganglioneuroblastoma (GNBL) and 20 ganglioneuroma (GN) patients was stained for total ALK protein by immunohistochemistry (IHC). The percentage of ALK positive cells in IHC was stratified in 4 Ccategories; Category 1 (n=40): < 20% ALK-positive cells, category 2 (n=25): 20-50% ALK positive cells, category 3 (n=25): 50-75% ALK positive cells, and category 4 (n=13): 75-100% ALK positive cells. These categories correlate significantly with overall survival in the spectrum of NBL, GNBL and GN (p=0.002, Logrank test). ALK mutations were identified in 2/63 NBL (3.2%) and 2/11 GNBL (18.2%) patients by sequencing. Importantly, in NBL and GNBL patients, ALK protein expression remains a significant factor in a multivariate model (Cox Proportional Hazard model) including the COG risk stratification (p<0.000), which encompasses stage and NMYC status (see table). Further, we studied the role of ALK levels in the response to ALK inhibitors in vitro in NBL cell lines. ALK inhibitor response (TAE684) correlates well with ALK protein levels (r=−0.813, p=0.001). ALK point mutated cell lines show higher ALK levels and a better ALK inhibitor response (LC50 values 14.9 fold lower, p=0.004) than WT and amplified cell lines. In conclusion: ALK protein expression is an independent predictor of overall survival in NBL patients and ALK inhibitor response in vitro. ICH staining with ALK antibody is reliable and correlates well with prognosis. 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 4347. doi:10.1158/1538-7445.AM2011-4347