ABSTRACT
Introduction: Bone metastases are frequent in patients with non-small cell lung cancer (NSCLC). The receptor activator of Nuclear Factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is important in bone metastases development. Furthermore, epidermal growth factor receptor (EGFR) signaling promotes osteoclast formation and stimulation. The understanding of the biological mechanism of bone metastases development might have implications for treatment strategies. Therefore, we studied whether there is an association between EGFR, RANKL, RANK and OPG gene expression in the tumor and presence of bone metastases in patients with NSCLC. Methods: From an updated multicenter study, including patients with EGFR mutated (EGFR+), Kirsten rat sarcoma (KRAS+) and EGFR/KRAS wildtype metastatic NSCLC, all patients with available formalin-fixed paraffin-embedded (FFPE) tumor samples were selected. Ribonucleic Acid (RNA) was isolated from these samples and gene expressions of EGFR, RANKL, OPG and RANKL were determined via quantitative Polymerase Chain Reaction (qPCR). Data on demographics, histology and molecular subtyping, sample origin, presence of bone metastasis, SREs and bone progression were collected. Primary endpoint was relation between EGFR, RANK, RANKL, OPG gene expression, RANKL: OPG ratio and bone metastases. Results: In 73/335 (32% EGFR+, 49% KRAS+, 19% EGFR/KRAS wildtype) samples from unique patients, gene expression analysis could be performed. Of these 73 patients, 46 (63%) had bone metastases at diagnosis or developed bone metastases during the disease course. No association was found between EGFR expression and presence of bone metastases. Patients with bone metastases had a significantly higher RANKL expression and RANKL: OPG ratio compared to those without. An increased RANKL: OPG ratio resulted in a 1.65x increased risk to develop bone metastases, especially in the first 450 days after diagnosis of metastatic NSCLC. Conclusion: Increased RANKL gene expression and RANKL: OPG ratio, but not EGFR expression, was associated with presence of bone metastases. Additionally, an increased RANKL: OPG gene ratio was associated with a higher incidence of bone metastases development.
ABSTRACT
Introduction: Despite radical intent therapy for patients with stage III non-small-cell lung cancer (NSCLC), cumulative incidence of brain metastases (BM) reaches 30%. Current risk stratification methods fail to accurately identify these patients. As radiomics features have been shown to have predictive value, this study aims to develop a model combining clinical risk factors with radiomics features for BM development in patients with radically treated stage III NSCLC. Methods: Retrospective analysis of two prospective multicentre studies. Inclusion criteria: adequately staged [18F-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT), contrast-enhanced chest CT, contrast-enhanced brain magnetic resonance imaging/CT] and radically treated stage III NSCLC, exclusion criteria: second primary within 2 years of NSCLC diagnosis and prior prophylactic cranial irradiation. Primary endpoint was BM development any time during follow-up (FU). CT-based radiomics features (N = 530) were extracted from the primary lung tumour on 18-FDG-PET-CT images, and a list of clinical features (N = 8) was collected. Univariate feature selection based on the area under the curve (AUC) of the receiver operating characteristic was performed to identify relevant features. Generalized linear models were trained using the selected features, and multivariate predictive performance was assessed through the AUC. Results: In total, 219 patients were eligible for analysis. Median FU was 59.4 months for the training cohort and 67.3 months for the validation cohort; 21 (15%) and 17 (22%) patients developed BM in the training and validation cohort, respectively. Two relevant clinical features (age and adenocarcinoma histology) and four relevant radiomics features were identified as predictive. The clinical model yielded the highest AUC value of 0.71 (95% CI: 0.58-0.84), better than radiomics or a combination of clinical parameters and radiomics (both an AUC of 0.62, 95% CIs of 0.47-076 and 0.48-0.76, respectively). Conclusion: CT-based radiomics features of primary NSCLC in the current setup could not improve on a model based on clinical predictors (age and adenocarcinoma histology) of BM development in radically treated stage III NSCLC patients.
ABSTRACT
INTRODUCTION: Non-small-cell lung cancer (NSCLC) guidelines advise to screen stage III NSCLC patients for brain metastases (BMs), preferably by magnetic resonance imaging (MRI) or when contraindicated or not accessible a dedicated contrast enhanced-computed tomography (dCE-CT), which can be incorporated in the staging 18Fluodeoxoglucose-positron emission tomography (18FDG-PET-CE-CT). In daily practice, often a dCE-CT is performed instead of a MRI. The aim of the current study is to evaluate the additive value of MRI after dCE-CT, incorporated in the 18FDG-PET-CE-CT. PATIENTS AND METHODS: It is an observational prospective multicentre study (NTR3628). Inclusion criteria included stage III NSCLC patients with a dCE-CT of the brain incorporated in the 18FDG-PET and an additional MRI of the brain. Primary end-point is percentage of patients with BM on MRI without suspect lesions on dCE-CT. Secondary end-points are percentage of patients with BM on dCE-CT and percentage of patients with BM ≤ 1 year of a negative staging MRI. RESULTS: Sixteen (7%) patients with extracranial stage III had BM on dCE-CT and were excluded. One hundred forty-nine patients were enrolled. 7/149 (4.7%) had BM on MRI without suspect lesions on dCE-CT. One hundred eighteen patients had a follow-up of at least 1 year (four with BM on baseline MRI); eight of the remaining 114 (7%) patients developed BM ≤ 1 year after a negative staging brain MRI. CONCLUSION: Although in 7% of otherwise stage III NSCLC patients, BMs were detected on staging dCE-CT, MRI brain detected BMs in an additional 4.7%, which we consider clinically relevant. Within 1 year after a negative staging MRI, 7% developed BM.
