Astrocyte elevated gene 1 (AEG-1) mRNA expression in non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.

Abstract

10541 Background: NSCLC p with EGFR mutations respond to the oral EGFR tyrosine kinase inhibitors erlotinib and gefitinib, although the duration of response in individual p is unpredictable. In our previous study, we found that erlotinib-treated p with low BRCA1 mRNA levels had a progression-free survival (PFS) of 27 months (m) vs 10 m for p with high levels (P=0.02). AEG-1 is a multifunctional oncogene that plays a role in several carcinogenic processes. Through PI3K/Akt, AEG-1 activates IKK, leading to phosphorylation and destabilization of the NF-kB inhibitor NFKBIA, which is a gatekeeper for EGFR signaling. Methods: Tumor mRNA expression levels of BRCA1 and AEG-1 were assessed by quantitative PCR in 77 erlotinib-treated p with EGFR mutations. Expression levels were dichotomized at the median. Results: PFS was longer in p with low AEG-1 expression (27 vs 12 m; P=0.003). Median survival (MS) was not reached for p with low AEG-1 levels and was 24 m for p with high levels (P=0.08). Based on these results, we generated an AEG-1/BRCA1 risk model: p with high levels of both genes were considered high-risk, p with low levels of both genes were low-risk, and p with high levels of one and low levels of the other gene were intermediate-risk. PFS was not reached in the low-risk group, while it was 18 m for the intermediate-risk group and 8 m for the high-risk group (P=0.00006) (HR for high- vs low-risk groups, 6.6; 95%CI, 2-4-18; P<0.00001). MS was not reached in the low-risk group, while it was 31 m for the intermediate-risk group and 18 m for the high-risk group (P=0.05). In the multivariate analysis for PFS, the only independent prognostic variables were bone metastases (HR, 2.7; 95%CI, 1.1-6.5; P=0.03) and the AEG-1/BRCA1 risk groups (HR for high-risk group, 7.7 (95%CI, 2.8-21.3; P<0.00001). Conclusions: The two-gene risk model based on AEG-1 and BRCA1 mRNA expression was strongly associated with clinical outcome, with significantly shorter PFS and MS in the high-risk group. This model can be useful for the proper individualized management of p with EGFR mutations.