Predicting brain metastasis in early stage non-small cell lung cancer patients by gene expression profiling

Abstract

Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-death due to early metastatic spread, in many cases primarily to the brain. Organ-specific pattern of spread of disease might be driven by the activity of a specific signaling pathway within the primary tumors. We aimed to identify an expression signature of genes and the relevant signaling associated with the development of brain metastasis (BM) after surgical resection of NSCLC.Methods: Rapidly frozen NSCLC surgical specimens were procured from tumor banks. RNA was extracted and analyzed by RNA-sequencing (Illumina HiSeq 2500). Clinical parameters and gene expression were examined for differentiating between patients with BM, patients with metastases to sites other than brain, and patients who did not develop metastatic disease at a clinically significant follow up. Principal component analysis and pathway enrichments studies were done.Results: A total of 91 patients were included in this study, 32 of which developed BM. Stage of disease at diagnosis (P=0.004) and level of differentiation (P=0.007) were significantly different between BM and control group. We identified a set of 22 genes which correlated specifically with BM, and not with metastasis to other sites. This set achieved 93.4% accuracy (95% CI: 86.2-97.5%), 96.6% specificity and 87.5% sensitivity of correctly identifying BM patients in a leave-one-out internal validation analysis. The oxidative phosphorylation pathway was strongly correlated with BM risk.Conclusions: Expression level of a small set of genes from primary tumors was found to predict BM development, distinctly from metastasis to other organs. These genes and the correlated oxidative phosphorylation pathway require further validation as potentially clinically useful predictors of BM and possibly as novel therapeutic targets for BM prevention.

Identification of a high-risk group for brain metastases in non-small cell lung cancer patients

“…Risk factors for BM in NSCLC reported previously comprise: Age(9)(10)(11), gender (11), non-squamous cell carcinoma/ adenocarcinoma(9)(12)(13)(11), clinical stage (13), number of extracranial metastases(10), malignant pleural effusion(10), nodal involvement (12), EGFRm or ALKr(13)( 14), high CEA(8), neutrophil-lymphocyte ratio (15), elevated neuro-speci c enolase (9),and high CA125 (9), with the exception of the latest two, all were analyzed in the present study. Although several clinical markers have been explored, no adequate model has a proven capability of predicting which patients with NSCLC will have BM (5) or failing to identify a group who would bene t from prophylactic cranial irradiation as a measure of extending overall survival (16), there is a window of opportunity exploring molecular markers (7). Previous authors have de ned a high-risk group for BM according to particular characteristics, to mention some: a) Age < 70 years, adenocarcinoma or large cell histology, tumor size > 3 cm, tumor grade ≥ II, and node positive disease(6), b) Adenocarcinoma, EGFRm + or ALKr + and CEA > 20 pg/mL (8).…”

“…Predictor variables had to be either studied or present in at least 10% of the studied population for inclusion in the model. Missing data occurred in tumor grade (15%), tumor size (18%), CEA (58%) and NLR (52%), imputation of such large amount of missing data was considered unreliable, and the missing values were included in a separate category as previously done (6); therefore, regarding parameters missing for some of the cohort, statistical tests were calculated for the available data similar to previous reports (7), after these adjustments, complete information used for analysis is reported for 277 patients in the TD and 293 patients in the VD.…”

Brain metastases: It takes two factors for a primary cancer to metastasize to brain

“…Based on this, we predict that the physical features define largely the types of metastasizing cells can go through the BBBs to reach the internal parts of a brain and the enzymes may define the characteristics of primary cancer cells that survive and thrive in the brain microenvironment. Compared with published studies on prediction of brain metastasis for primary tumors, our model shows higher or comparable accuracy ( 56 , 57 ), but has two key superiorities: (i) the features used in our model are strongly supported by published studies and provide strong information about the key mechanisms of brain metastasis; and (ii) the primary locations of BMPs are not limited to one organ instead any organs, strongly suggesting that our predicted mechanism captures something fundamental.…”

Emerging Biomarkers for Diagnosis, Prevention and Treatment of Brain Metastases—From Biology to Clinical Utility

“…Nonetheless, it identified few crucial genes which might lead to BrM development. Kamer et al discovered a similarly indicated signature for lung cancer, which additionally predicted metastatic spread with and without brain involvement [ 29 ]. The genes involved metastatic spread to the brain from the lungs were mainly oxidative phosphorylation pathway genes, indicating that perhaps in BrM, a more efficient way of utilising glucose which is highly available in this microenvironment is necessary to meet the demands of the rapidly growing metastasis.…”