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.
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.
From an updated multicenter study, including patients with
mutated (
+), Kirsten rat sarcoma
and
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
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.
In 73/335 (32%
, 49%
, 19%
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.
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.
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.
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.
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.
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.
•In 7% of patients brain metastases are detected on the staging dedicated contrast enhanced–computed tomogram.•After a negative brain computed tomography, brain magnetic resonance imaging (MRI) detects 4.7% of patients brain metastases.•7% of patients with a negative staging MRI develop brain metastases within a year.
Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. ...However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens. Interestingly, reconstitution of wild-type
E
-
cadherin
cDNA in a E-cadherin negative cell line that had undergone EMT (MDA-MB-231) did not revert the spindle morphology back to an epithelial morphology. Neither were changes observed in the expression of several markers known to be involved in the EMT process. Similarly, upregulation of E-cadherin via global DNA demethylation in eleven cell lines that had undergone EMT did not induce a change in cell morphology, nor did it alter the expression of EMT markers in these cells. Next, we extracted genes differentially expressed between cell lines that had undergone EMT versus cell lines that had not undergone EMT. Caveolin-1 was identified to be an excellent marker for EMT, irrespective of E-cadherin status (specificity and sensitivity of 100 %). Consistent with our observations in the breast cancer cell lines, expression of Caveolin-1 identified a subset of basal breast cancers, particularly of metaplastic pathology, and only 50 % of these lacked E-cadherin expression. The discrepancy between E-cadherin loss and EMT was thus reproduced in clinical samples. Together, these results indicate that in human breast cancer loss of E-cadherin is not causal for EMT and even not a necessity.
The identification of transcriptomic alterations of HER2+ ductal carcinoma in situ (DCIS) that are associated with the density of tumor-infiltrating lymphocytes (TILs) could contribute to optimizing ...choices regarding the potential benefit of immune therapy. We compared the gene expression profile of TIL-poor HER2+ DCIS to that of TIL-rich HER2+ DCIS. Tumor cells from 11 TIL-rich and 12 TIL-poor DCIS cases were micro-dissected for RNA isolation. The Ion AmpliSeq Transcriptome Human Gene Expression Kit was used for RNA sequencing. After normalization, a Mann–Whitney rank sum test was used to analyze differentially expressed genes between TIL-poor and TIL-rich HER2+ DCIS. Whole tissue sections were immunostained for validation of protein expression. We identified a 29-gene expression profile that differentiated TIL-rich from TIL-poor HER2+ DCIS. These genes included CCND3, DUSP10 and RAP1GAP, which were previously described in breast cancer and cancer immunity and were more highly expressed in TIL-rich DCIS. Using immunohistochemistry, we found lower protein expression in TIL-rich DCIS. This suggests regulation of protein expression at the posttranslational level. We identified a gene expression profile of HER2+ DCIS cells that was associated with the density of TILs. This classifier may guide towards more rationalized choices regarding immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy.
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