Yield of Malignant Pleural Effusion for Detection of Oncogenic Driver Mutations in Lung Adenocarcinoma

DeMaio, Antonio; Clarke, Jeffrey; Dash, Rajesh; Sebastian, Siby; Wahidi, Momen M.; Shofer, Scott; Cheng, George Z.; Li, Xuechan; Wang, Xiaofei; Mahmood, Kamran

doi:10.1097/lbr.0000000000000534

Cited by 21 publications

(25 citation statements)

References 21 publications

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“…The ability of sensitive PCR-based techniques to detect a range of driver mutations in NSCLC within cytologically malignant pleural fluid specimens is well established (11,12). However, to our knowledge only two prior studies have applied molecular diagnostic methods to cytologically negative pleural fluids in patients with confirmed driver mutations.…”

Section: Discussionmentioning

confidence: 99%

Sensitive molecular testing methods can demonstrate NSCLC driver mutations in malignant pleural effusion despite non-malignant cytology

Steinfort

Kranz

Dowers

et al. 2019

Transl. Lung Cancer Res.

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Malignant pleural effusion (MPE) may be diagnosed by cytologic evaluation of pleural fluid, though false negative results can occur. Pleural effusions may provide a source of tumour material for genotyping in lung cancer patients. Detection of MPE may be improved through use of highly sensitive molecular techniques. We identified five patients with non-small cell lung cancer (NSCLC) with initial pleural fluid samples that were non-malignant on cytology, but were subsequently clinically confirmed to have MPE. Tumour mutation status was confirmed via routine testing of diagnostic clinical specimens. Cytologically negative pleural fluid cell-block specimens were analysed by amplicon-based parallel sequencing (APS) for somatic mutations commonly detected in NSCLC, and selected cases by improved and complete enrichment CO-amplification at lower denaturation temperature PCR (ICECOLD PCR) for known mutations. Mutations were detected in three out of three (sensitivity 100%) cytologically non-malignant pleural fluids from patients with a known mutation: two patients with known Kirsten rat sarcoma (KRAS) mutation demonstrated the same KRAS mutation in their pleural fluids by APS, both at approximately 2% mutant allele frequency. In one patient with a known KRAS mutation, ICECOLD PCR detected the same KRAS variant at 0.7% frequency. No mutations were detected in patients with wild-type findings from reference samples (specificity 100%). Sensitive DNA sequencing methods can detect cancerdriver mutations in cytologically non-malignant pleural fluid specimens from NSCLC patients with MPE. Our findings demonstrate the feasibility of sensitive molecular diagnostic techniques for improvement of diagnostic assessment of pleural effusions in patients with lung cancer.

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Section: Discussionmentioning

confidence: 99%

Sensitive molecular testing methods can demonstrate NSCLC driver mutations in malignant pleural effusion despite non-malignant cytology

Steinfort

Kranz

Dowers

et al. 2019

Transl. Lung Cancer Res.

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“…15 Although the rate of detection was higher in tissue samples (34%) compared with MPE (30%), the difference was not statistically different. [26][27][28][29] Carter et al analyzed 27 cases of NSCLC with MPE after excluding 14 cases due to inadequate tumor cellularity and detected a genetic aberration in 59% of samples (AKT, BRAF, EGFR, ERBB2, KRAS, NRAS, PIK3CA). 17,30 Liu et al evaluated 192 advanced cases of NSCLC with both primary tumor and MPE samples for EGFR with no difference in detection at 62 and 59%, respectively.…”

Section: Molecular Targets In Pleural Effusionsmentioning

confidence: 99%

“…31 Recently DeMaio et al described the detection of driver mutations in 56 cases of lung-adenocarcinoma-associated MPE including EGFR, KRAS, BRAF, ALK, and ROS1 on pleural fluid cell blocks. 28 EGFR and KRAS were detected by PCR amplification followed by sequencing or next-generation sequencing. FISH was employed for ALK and ROS1 rearrangements.…”

Section: Molecular Targets In Pleural Effusionsmentioning

confidence: 99%

Molecular Testing on Pleural Fluid Samples

Ronaghi

Cai

2019

Semin Respir Crit Care Med

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Pleural effusions are a common manifestation of both malignant and nonmalignant diseases. The sampling of pleural fluid helps categorize effusions as transudative or exudative and helps differentiate paramalignant from malignant disease. Accurate pleural fluid analysis is critical to the appropriate staging of cancers with significant prognostic and treatment implications. However, the etiology of pleural effusions remains unclear in a significant number of cases after routine thoracentesis and pleural fluid analysis. For malignant pleural effusions, cytologic evaluation of pleural fluid has a relatively low sensitivity. We describe the evolving field of molecular pleural fluid analysis in the setting of malignant disease as an active area of investigation with both diagnostic and therapeutic implications.

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“…But only traditional techniques such as fluorescent in situ hybridization, PCR or amplification refractory mutation system, and pyrosequencing have been applied in analyzing pleural effusion supernatant (PES) and pleural effusion cell (PEC) samples. [7][8][9][10][11][12] New techniques with high throughput and sensitivity need to be employed to evaluate the clinical value of pleural effusion.…”

Section: Introductionmentioning

confidence: 99%

Targeted deep sequencing from multiple sources demonstrates increased NOTCH1 alterations in lung cancer patient plasma

Liao

et al. 2019

Cancer Medicine

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Introduction Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer‐associated genes across varying sample sites in lung cancer patients. Materials and Methods Targeted deep sequencing for 48 tumor‐related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin‐fixed paraffin‐embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. Results Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV‐dominated, CNV‐dominated, and codominated groups. Conclusions Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.

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Yield of Malignant Pleural Effusion for Detection of Oncogenic Driver Mutations in Lung Adenocarcinoma

Abstract: Genetic mutation analysis can be performed on malignant pleural effusions secondary to lung adenocarcinoma, independent of fluid volume.

Cited by 21 publications

References 21 publications

Sensitive molecular testing methods can demonstrate NSCLC driver mutations in malignant pleural effusion despite non-malignant cytology

Sensitive molecular testing methods can demonstrate NSCLC driver mutations in malignant pleural effusion despite non-malignant cytology

Molecular Testing on Pleural Fluid Samples

Targeted deep sequencing from multiple sources demonstrates increased NOTCH1 alterations in lung cancer patient plasma

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