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A liquid biopsy for bronchopulmonary/lung carcinoid diagnosis.

ABSTRACT: No effective blood biomarker exists to detect and clinically manage bronchopulmonary (BP) neuroendocrine tumors (NET). We developed a blood-based 51 NET-specific transcript set for diagnosis and monitoring and evaluated clinical performance metrics. It accurately diagnosed the tumor and differentiated stable from progressive disease as determined by RECIST criteria. Gene expression was evaluated in: a) publicly available BPNET transcriptomes (GSE35679); b) two BPNET cell-lines; and c) BPNET tissue with paired blood (n = 7). Blood gene expression was assessed in 194 samples including controls, benign lung diseases, malignant lung diseases and small bowel NETs. A separate validation study in 25 age- and gender-matched BPNETs/controls was performed. Gene expression measured by real-time PCR was scored (0-100%; normal: < 14%). Regression analyses, Principal Component Analysis (PCA), hierarchical clustering, Fisher's and non-parametric evaluations were undertaken. All 51 genes were identified in BPNET transcriptomes, tumor samples and cell-lines. Significant correlations were evident between paired tumor and blood (R2:0.63-0.91, p < 0.001). PCA and hierarchical clustering identified blood gene expression was significantly different between lung cancers and benign diseases, including BPNETs. Gene expression was highly correlated (R2: 0.91, p = 1.7 × 10-15) between small bowel and BPNET. For validation, all 25 BPNETs were positive compared to 20% controls (p < 0.0001). Scores were significantly elevated (p < 0.0001) in BPNETs (57 ± 28%) compared to controls (4 ± 5%). BPNETs with progressive disease (85 ± 11%) exhibited higher scores than stable disease (32 ± 7%, p < 0.0001). Blood measurements accurately diagnosed bronchopulmonary carcinoids, distinguishing stable from progressive disease. This marker panel will have clinical utility as a diagnostic liquid biopsy able to define disease activity and progression in real-time.

SUBMITTER: Kidd M

PROVIDER: S-EPMC5805546 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A liquid biopsy for bronchopulmonary/lung carcinoid diagnosis.

Kidd Mark M Modlin Irvin M IM Drozdov Ignat I Aslanian Harry H Bodei Lisa L Matar Somer S Chung Kyung-Min KM

Oncotarget 20171229 6

No effective blood biomarker exists to detect and clinically manage bronchopulmonary (BP) neuroendocrine tumors (NET). We developed a blood-based 51 NET-specific transcript set for diagnosis and monitoring and evaluated clinical performance metrics. It accurately diagnosed the tumor and differentiated stable from progressive disease as determined by RECIST criteria. Gene expression was evaluated in: a) publicly available BPNET transcriptomes (GSE35679); b) two BPNET cell-lines; and c) BPNET tiss ...[more]

PMID: 29467960

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Project description:ObjectivesDiagnosing lung neuroendocrine neoplasia (NEN) requires a biopsy or an operation. We evaluated a 'liquid biopsy' (NETest) as an in vitro diagnostic tool for identifying NEN and compared it to chromogranin A (CgA).MethodsWe identified 4 study cohorts: patients with bronchopulmonary carcinoids (n = 99, including 62 typical and 37 atypical carcinoids), lung cancers [n = 101, including 41 adenocarcinomas, 37 squamous carcinomas (SQC), 16 small-cell lung cancers and 7 large-cell neuroendocrine carcinomas]; benign disease (50 idiopathic pulmonary fibrosis) and healthy controls (n = 102). Transcript levels measured quantitatively (activity scores: 0-100) were compared to CgA (enzyme-linked immunosorbent assay; normal < 109 ng/ml) levels.ResultsThe results of the NETest were positive (>20) in 94% of patients with bronchopulmonary carcinoid compared to 8% of the controls (Fisher's exact test; P < 0.001) and were significantly more accurate as a diagnostic test (McNemar's test; P < 0.001, χ2 = 72) than was CgA (positive: 19% bronchopulmonary carcinoid, 15% controls). Small-cell lung cancers (87%), large-cell neuroendocrine carcinomas (86%), adenocarcinoma (42%) and SQC (35%) were also NETest-positive. Increasing the NETest cut-off score to >40 was useful for detecting all NENs and differentiating these tumours from either controls/benign lung diseases (specificity 97%) or adenocarcinoma/SQC (specificity 94%). CgA was positive in 15-44% irrespective of pathology and had no diagnostic value.ConclusionsA gene-based liquid biopsy is an effective and accurate method for diagnosing lung tumours with neuroendocrine gene expression. CgA has no value. An NETest score >40 provides an accurate (94-97%) rule-in for the diagnosis of NEN and a rule-out for benign and other neoplastic diseases. Because neuroendocrine gene expression is associated with a poor prognosis, NETest levels may have utility both in the diagnosis of and the treatment stratification for lung neoplasia.

Project description:IntroductionMolecular profiling of tumor tissue is the gold standard for treatment decision-making in advanced non-small cell lung cancer (NSCLC). Results may be delayed or unavailable due to insufficient tissue, prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma testing in the initial diagnostic workup for patients with suspected advanced lung cancer.MethodsPatients with ⩽15 pack-year smoking history and suspected advanced lung cancer referred to the lung cancer rapid diagnostic program underwent plasma circulating-tumor DNA testing using a DNA-based mutation panel. Tissue testing was performed per standard of care, including comprehensive next-generation sequencing (NGS). The primary endpoint was time from diagnostic program referral to cancer treatment in stage IV NSCLC patients (Cohort A) compared to a contemporary cohort not enrolled in the study (Cohort B) and an historical pre-COVID cohort referred to the program between 2018 and 2019 (Cohort C).ResultsFrom January to June 2021, 20 patients were enrolled in Cohort A; median age was 70.5 years (range 33-87), 70% were female, 55% Caucasian, 85% never smokers, and 75% were diagnosed with NSCLC. Seven had actionable alterations detected in plasma or tissue (4/7 concordant). Fusions, not tested in plasma, were identified by immunohistochemistry for three patients. Mean result turnaround time was 17.8 days for plasma NGS and 23.6 days for tissue (p = 0.10). Mean time from referral to treatment initiation was significantly shorter in cohort A at 32.6 days (SD 13.1) versus 62.2 days (SD 31.2) in cohort B and 61.5 days (SD 29.1) in cohort C, both p < 0.0001.ConclusionLiquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC can lead to faster molecular results and shorten time to treatment even with smaller DNA panels. An expansion study using comprehensive NGS plasma testing with faster turnaround time is ongoing (NCT04862924).

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A liquid biopsy for bronchopulmonary/lung carcinoid diagnosis.

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A liquid biopsy for bronchopulmonary/lung carcinoid diagnosis.

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