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EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients.

ABSTRACT: Although clinically relevant, the detection rates of EpCAM positive CTCs in non-small cell lung cancer (NSCLC) are surprisingly low. To find new clinically informative markers for CTC detection in NSCLC, the expression of EGFR and HER3 was first analyzed in NSCLC tissue (n = 148). A positive EGFR and HER3 staining was observed in 52.3% and 82.7% of the primary tumors, and in 62.7% and 91.2% of brain metastases, respectively. Only 3.0% of the brain metastases samples were negative for both HER3 and EGFR proteins, indicating that the majority of metastases express these ERBB proteins, which were therefore chosen for CTC enrichment using magnetic cell-separation. Enrichment based on either EGFR or HER3 detected CTCs in 37.8% of the patients, while the combination of EGFR/HER3 enrichment with the EpCAM-based CellSearch technique detected a significantly higher number of 66.7% CTC-positive patients (Cohen's kappa = -0.280) which underlines the existence of different CTC subpopulations in NSCLC. The malignant origin of keratin-positive/CD45-negative CTC clusters and single CTCs detected after EGFR/HER3 based enrichment was documented by the detection of NSCLC-associated mutations. In conclusion, EGFR and HER3 expression in metastasized NSCLC patients have considerable value for CTC isolation plus multiple markers can provide a novel liquid biopsy approach.

SUBMITTER: Scharpenseel H

PROVIDER: S-EPMC6520391 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients.

Scharpenseel Heather H Hanssen Annkathrin A Loges Sonja S Mohme Malte M Bernreuther Christian C Peine Sven S Lamszus Katrin K Goy Yvonne Y Petersen Cordula C Westphal Manfred M Glatzel Markus M Riethdorf Sabine S Pantel Klaus K Wikman Harriet H

Scientific reports 20190515 1

Although clinically relevant, the detection rates of EpCAM positive CTCs in non-small cell lung cancer (NSCLC) are surprisingly low. To find new clinically informative markers for CTC detection in NSCLC, the expression of EGFR and HER3 was first analyzed in NSCLC tissue (n = 148). A positive EGFR and HER3 staining was observed in 52.3% and 82.7% of the primary tumors, and in 62.7% and 91.2% of brain metastases, respectively. Only 3.0% of the brain metastases samples were negative for both HER3 a ...[more]

PMID: 31092882

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Project description:BackgroundEarly-stage non-small cell lung cancer (NSCLC) has a high recurrence rate despite proper management, including curative surgery. Circulating tumor cells (CTCs) are believed to play a key role in the distant metastasis of lung cancer. Immunofluorescence imaging studies of CTCs have revealed that they are associated with the prognosis of NSCLC. However, the mutational profiling of CTCs from early-stage NSCLC has not been extensively explored. We hypothesized that CTCs could be detected by mutational analysis using panel sequencing and would have distinct mutations associated with distant metastasis compared to those of primary cancer tissue in early-stage NSCLC. Thus, this study examined the DNA from CTCs using targeted panel sequencing to identify mutations and compared them with mutations found in primary cancer tissue in patients with resectable early-stage NSCLC.MethodsOverall, 45 patients with resectable NSCLC were prospectively enrolled from September to December 2023. Matched whole blood samples and primary cancer tissues were collected during curative surgery. Then, 405-gene targeted panel sequencing was performed on DNA from primary cancer tissues and CTCs.ResultsIn this study, 37 patients (82%) had adenocarcinoma, and 30 (67%) were classified as having pathologic stage 1 disease. Mutated genes were detected in all (100%) and 31 patients (69%) for primary cancer tissue and CTCs from panel sequencing, respectively. The partial concordance rate of mutations between primary cancer tissue and CTCs was 17.8%, with the top 10 mutated genes differing significantly. Among primary cancer tissue samples, mutated genes differed by stage and histologic type; these findings were not observed in CTCs. CTCs predominantly displayed mutations in tumor suppressor genes, whereas primary cancer tissues exhibited mutations in both oncogenes and tumor suppressor genes.ConclusionsCTCs exhibited unique mutations, showing low concordance with mutations found in primary cancer tissue. CTCs may possess specific mutations independent from those of primary cancer tissue in early-stage NSCLC.

Project description:PurposeLow-dose computed tomography (LDCT) screening of high-risk patients decreases lung cancer-related mortality. However, high false-positive rates associated with LDCT result in unnecessary interventions. To distinguish non-small-cell lung cancer (NSCLC) from benign nodules, in the present study, we integrated cellular liquid biomarkers in patients with suspicious lung nodules (lung cancer screening reporting and data system [Lung-RADS] 4).MethodsProspectively, 7.5 mL of blood was collected from 221 individuals (training set: 90 nonscreened NSCLC patients, 74 high-risk screening patients with no/benign nodules [Lung-RADS 1-3], and 20 never smokers; validation set: 37 patients with suspicious nodules [Lung-RADS 4]). Circulating tumor cells (CTCs), CTC clusters, and tumor-macrophage fusion (TMF) cells were identified by blinded analyses. Screening patients underwent a median of two LDCTs (range, 1-4) with a median surveillance time of 30 (range, 11-50) months.ResultsIn the validation set of 37 Lung-RADS 4 patients, all circulating cellular biomarker counts (P < .005; Wilcoxon test) and positivity rates were significantly higher in 23 biopsy-proven NSCLC patients (CTCs: 23 of 23 [100%], CTC clusters: 6 of 23 [26.1%], and TMF cells: 15 of 23 [65.2%]) than in 14 patients with biopsy-proven benign nodules (6 of 14 [42.9%], 0 of 14 [0%], and 2 of 14 [14.3%]). On the basis of cutoff values from the training set, logistic regression with receiver operating characteristic and area under the curve analyses demonstrated that CTCs (sensitivity: 0.870, specificity: 1.0, and area under the curve: 0.989) and TMF cells (0.652; 0.880; 0.790) complement LDCT in diagnosing NSCLC in Lung-RADS 4 patients.ConclusionCellular liquid biomarkers have a potential to complement LDCT interpretation of suspicious Lung-RADS 4 nodules to distinguish NSCLC from benign lung nodules. A future prospective, large-scale, multicenter clinical trial should validate the role of cellular liquid biomarkers in improving diagnostic accuracy in high-risk patients with Lung-RADS 4 nodules.

Project description:PurposeMetabolic reprogramming is now characterized as one of the core hallmarks of cancer, and it has already been shown that the altered genomic profile of metabolically rewired cancer cells can give valuable information. In this study, we quantified three Metabolism-Related Gene (MRG) transcripts in the circulating tumor cells (CTCs) of early stage NSCLC patients and evaluated their associations with epithelial and EMT markers.Experimental designWe first developed and analytically validated highly sensitive RT-qPCR assays for the quantification of HK2, MCT1 and PHGDH transcripts, and further studied the expression of MRGs in CTCs that were isolated using a size-dependent microfluidic device (Parsortix, Angle) from the peripheral blood of: (a) 46 NSCLC patients at baseline, (b) 39/46 of these patients one month after surgery, (c) 10/46 patients at relapse and (d) 10 pairs of cancerous and adjacent non-cancerous FFPE tissues from the same NSCLC patients. Epithelial and EMT markers were also evaluated.ResultsMCT1 and HK2 were differentially expressed between HD and NSCLC patients. An overexpression of MCT1 was detected in 15/46 (32.6%) and 3/10 (30%) patients at baseline and at progression disease (PD), respectively, whereas an overexpression of HK2 was detected in 30.4% and 0% of CTCs in the same group of samples. The expression levels of all tested MRGs decreased in CTCs one month after surgery, but a significant increase was noticed at the time of relapse for PHGDH and MCT1 only. The expression levels of HK2 and MCT1 were associated with the overexpression of mesenchymal markers (TWIST-1 and VIM).ConclusionAn overexpression of MRGs was observed at a high frequency in the CTCs isolated from early NSCLC patients, thereby supporting the role of MRGs in metastatic processes. The glycolytic and mesenchymal subpopulation of CTCs was significantly predominant compared to CTCs that were glycolytic but not mesenchymal-like. Our data indicate that MRGs merit further evaluation through large and well-defined cohort studies.

Dataset Information

EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients.

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EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients.

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