Abstract
Non-small cell lung cancer (NSCLC) metastasizes fairly often to the brain, but identifying which patients will develop brain metastases is problematic. The phosphoinositide 3-kinase (PI3K)-AKT-mTOR signaling pathway is important in the control of cell growth, tumorigenesis, and cell invasion. We hypothesized that genotype variants in this pathway could predict brain metastasis in patients with NSCLC. We genotyped 16 single-nucleotide polymorphisms (SNP) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) by using DNA from blood samples of 317 patients with NSCLC, and evaluated potential associations with the subsequent development of brain metastasis, the cumulative incidence of which was estimated with Kaplan-Meier analysis. Multivariate Cox regression analysis was used to analyze correlations between genotype variants and the occurrence of brain metastasis. In analysis of individual SNPs, the GT/GG genotype of AKT1: rs2498804, CT/TT genotype of AKT1: rs2494732, and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of brain metastasis at 24-month follow-up [respective HRs, 1.860, 95% confidence interval (CI) 1.199-2.885, P = 0.006; HR 1.902, 95% CI 1.259-2.875, P = 0.002; and HR 1.933, 95% CI 1.168-3.200, P = 0.010]. We further found that these SNPs had a cumulative effect on brain metastasis risk, with that risk being highest for patients carrying both of these unfavorable genotypes (P = 0.003). Confirmation of our findings, the first to indicate that genetic variations in PI3K-AKT-mTOR can predict brain metastasis, in prospective studies would facilitate stratification of patients for brain metastasis prevention trials.
Highlights
Every year, about 150,000 patients with cancer in the United States develop brain metastasis (BM) [1], with the lung being the most common primary site for secondary brain metastases (BM) [2, 3]
In analysis of individual single nucleotide polymorphisms (SNPs), the GT/GG genotype of AKT1: rs2498804, Computed tomography (CT)/TT genotype of AKT1: rs2494732 and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of BM at 24 months’ follow-up
We previously reported that genetic variations in the transforming growth factor (TGF) -β-Smad-dependent pathway are associated with increased risk of BM in patients with Non-small cell lung cancer (NSCLC) [18]
Summary
About 150,000 patients with cancer in the United States develop brain metastasis (BM) [1], with the lung being the most common primary site for secondary BM [2, 3]. In most trials conducted to date, the use of prophylactic cranial irradiation (PCI) has reduced the cumulative incidence of BM compared with that in control groups, but far use of PCI has not affected overall survival [6,7,8,9]. Findings from a recent trial by the Radiation Therapy Oncology Group (RTOG 0214) that PCI decreased the rate of BM but did not improve overall or disease-free survival for patients with stage III disease imply that not all such patients would benefit from PCI and it should not be recommended routinely for patients with stage III NSCLC [10]. The ability to predict which patients are at higher risk of developing BM would help in selecting patients for future prospective studies to establish appropriate cancer management strategies to reduce or prevent the occurrence of BM, improving the clinical outcome for such patients
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