NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease

Background: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript “liquid biopsy” (NETest) in BPC for diagnosis and monitoring of the disease status. Aim: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study. Material and Methods: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means ± SD. Results: NETest levels were significantly increased in BPC (45 ± 25) versus controls (9 ± 8; p < 0.0001). The area under the ROC curve was 0.96 ± 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 ± 32) and LCNEC (28 ± 7). NETest accurately distinguished progressive (61 ± 26) from stable disease (35.5 ± 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 ± 21) and SCC (12 ± 11) and benign disease (IPF) (18 ± 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25–0.31). Conclusions: Elevated NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.

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Molecular identification of bronchopulmonary neuroendocrine tumours and neuroendocrine genotype in lung neoplasia using the NETest liquid biopsy

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa018 ◽

2020 ◽

Vol 57 (6) ◽

pp. 1195-1202

Author(s):

Pier Luigi Filosso ◽

Kjell Öberg ◽

Anna Malczewska ◽

Anna Lewczuk ◽

Matteo Roffinella ◽

...

Keyword(s):

Gene Expression ◽

Liquid Biopsy ◽

Large Cell ◽

Small Cell ◽

Enzyme Linked Immunosorbent Assay ◽

Small Cell Lung ◽

Lung Cancers ◽

Bronchopulmonary Carcinoid ◽

Neuroendocrine Carcinomas

Abstract OBJECTIVES Diagnosing 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). METHODS We 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. RESULTS The 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. CONCLUSIONS A 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.

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NETest liquid biopsy is diagnostic of lung neuroendocrine tumors and identifies progressive disease

Endocrine Abstracts ◽

10.1530/endoabs.60.p15 ◽

2018 ◽

Author(s):

Anna Malczewska ◽

Beata Kos-Kudla ◽

Pier-Luigi Filosso ◽

Harry Aslanian ◽

Anna Lewczuk ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Liquid Biopsy ◽

Progressive Disease

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A Novel Method for Microsatellite Instability Detection by Liquid Biopsy Based on Next- Generation Sequencing

Current Bioinformatics ◽

10.2174/1574893615666200324133451 ◽

2020 ◽

Vol 15 ◽

Author(s):

Zheng Jiang ◽

Hui Liu ◽

Siwen Zhang ◽

Jia Liu ◽

Weitao Wang ◽

...

Keyword(s):

Next Generation Sequencing ◽

Microsatellite Instability ◽

Liquid Biopsy ◽

Tumor Tissue ◽

High Sensitivity ◽

Next Generation ◽

Tissue Samples ◽

Next Generation Sequencing Technology ◽

Medication Selection ◽

Generation Sequencing

Background: Microsatellite instability (MSI) is a prognostic biomarker used to guide medication selection in multiple cancers, such as colorectal cancer. Traditional PCR with capillary electrophoresis and next-generation sequencing using paired tumor tissue and leukocyte samples are the main approaches for MSI detection due to their high sensitivity and specificity. Currently, patient tissue samples are obtained through puncture or surgery, which causes injury and risk of concurrent disease, further illustrating the need for MSI detection by liquid biopsy. Methods: We propose an analytic method using paired plasma/leukocyte samples and MSI detection using next-generation sequencing technology. Based on the theoretical progress of oncogenesis, we hypothesized that the microsatellite site length in plasma equals the combination of the distribution of tumor tissue and leukocytes. Thus, we defined a window-judgement method to identify whether biomarkers were stable. Results: Compared to traditional PCR as the standard, we evaluated three methods in 20 samples (MSI-H:3/MSS:17): peak shifting method using tissue vs. leukocytes, peak shifting method using plasma vs. leukocytes, and our method using plasma vs. leukocytes. Compared to traditional PCR, we observed a sensitivity of 100%, 0%, and 100%, and a specificity of 100.00%, 94.12%, and 88.24%, respectively. Conclusion: Our method has the advantage of possibly detecting MSI in a liquid biopsy and provides a novel direction for future studies to increase the specificity of the method.

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Neuroendocrine Carcinomas of the Digestive Tract: What Is New?

Cancers ◽

10.3390/cancers13153766 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3766

Author(s):

Anna Pellat ◽

Anne Ségolène Cottereau ◽

Benoit Terris ◽

Romain Coriat

Keyword(s):

Peptide Receptor Radionuclide Therapy ◽

Large Cell ◽

Current Data ◽

World Health ◽

High Grade ◽

Ki 67 ◽

Lung Cancers ◽

Platinum Based Chemotherapy ◽

Line Setting ◽

Neuroendocrine Carcinomas

Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.

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Detecting an ALK Rearrangement via Liquid Biopsy Enabled a Targeted Therapy-based Approach for Treating a Patient with Advanced Non-small Cell Lung Cancer

Oncology & Hematology Review (US) ◽

10.17925/ohr.2018.14.1.38 ◽

2018 ◽

Vol 14 (1) ◽

pp. 38 ◽

Cited By ~ 2

Author(s):

Alejandro R Calvo ◽

Gabriel H Ibarra ◽

Cecile Rose T Vibat ◽

Veena M Singh

Keyword(s):

Liquid Biopsy ◽

Clinical Utility ◽

Tumor Tissue ◽

Molecular Testing ◽

Tissue Analysis ◽

Alk Rearrangement ◽

Blood Draw ◽

Diagnostic Biopsy

Initial diagnostic biopsy procedures often yield insufficient tissue for molecular testing, and invasive surgical biopsies can be associated with significant cost as well as risk to the patient. Liquid biopsy offers an alternative and economical means for molecular characterization of tumors via a simple peripheral blood draw. This case report describes the ability of liquid biopsy to detect an ALK translocation where tissue analysis by fluorescence in situ hybridization was negative for the genetic alteration. Identification of an ALK rearrangement in circulating tumor cells from a blood specimen led to sequential targeted therapies that included crizotinib followed by alectinib. The patient demonstrated outstanding clinical response during treatment with each of the prescribed ALK inhibitors. This case demonstrates the clinical utility of Biocept’s liquid biopsy to detect actionable biomarkers by surveying the systemic landscape of a patient’s disease where identification of the same genetic drivers may be missed in analyses of heterogeneous tumor tissue.

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Primary lymphoma of bone in children.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.9.1275 ◽

1989 ◽

Vol 7 (9) ◽

pp. 1275-1280 ◽

Cited By ~ 54

Author(s):

W L Furman ◽

S Fitch ◽

H O Hustu ◽

T Callihan ◽

S B Murphy

Keyword(s):

Progressive Disease ◽

Large Cell ◽

Initial Therapy ◽

National Institutes Of Health ◽

Primary Lymphoma ◽

Histologic Subtype ◽

Lymphoma Treatment ◽

Local Radiation ◽

Multiagent Chemotherapy ◽

Cessation Of Treatment

Primary lymphoma of bone (PLB) occurs infrequently in children. Between January 1962 and November 1988, 395 children with non-Hodgkin's lymphoma (NHL) were treated at St. Jude Children's Research Hospital. Eleven of these patients (2.8%) presented with a bone primary, usually in the femur (eight of 11 patients). The median age of these seven boys and four girls at presentation was 13 years (range, 5.5 to 19 years). Seven patients had one or more additional bones involved. All patients had high-grade lymphomas based on the National Institutes of Health (NIH) Working Formulation. The histologic subtypes included six large-cell lymphomas, three lymphoblastic lymphomas, one small-noncleaved, non-Burkitt's lymphoma, and one unclassifiable lymphoma. Treatment consisted of multiagent chemotherapy combined with local radiation therapy in seven of 11 patients. Six of 10 children who received chemotherapy as a component of their initial therapy, including all who presented with localized tumor, are alive with no evidence of disease 2+ to 85+ months (median, 42.5 months) after cessation of treatment; one patient has just completed chemotherapy. Each of the four patients who died showed leukemic conversion 5 to 11 months after diagnosis, and three died of progressive disease. One patient died of sepsis during chemotherapy-induced neutropenia with no evidence of disease at necropsy. We conclude that optimal therapy for PLB, as with all other forms of NHL, should focus on the histologic subtype and stage of disease.

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Liquid biopsy guided precision therapy for lung cancers

Journal of Thoracic Disease ◽

10.21037/jtd.2018.11.02 ◽

2018 ◽

Vol 10 (S33) ◽

pp. S4173-S4175 ◽

Cited By ~ 1

Author(s):

Chongrui Xu ◽

Michael Offin ◽

Paul K. Paik ◽

Bob T. Li

Keyword(s):

Liquid Biopsy ◽

Lung Cancers ◽

Precision Therapy

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The Translational Status of Cancer Liquid Biopsies

Regenerative Engineering and Translational Medicine ◽

10.1007/s40883-019-00141-2 ◽

2019 ◽

Cited By ~ 6

Author(s):

Sinisa Bratulic ◽

Francesco Gatto ◽

Jens Nielsen

Keyword(s):

Treatment Outcomes ◽

Liquid Biopsy ◽

Tumor Tissue ◽

Body Fluids ◽

Precision Oncology ◽

Liquid Biopsies ◽

Non Invasive ◽

Biomarker Research ◽

Successes And Challenges

Abstract Precision oncology aims to tailor clinical decisions specifically to patients with the objective of improving treatment outcomes. This can be achieved by leveraging omics information for accurate molecular characterization of tumors. Tumor tissue biopsies are currently the main source of information for molecular profiling. However, biopsies are invasive and limited in resolving spatiotemporal heterogeneity in tumor tissues. Alternative non-invasive liquid biopsies can exploit patient’s body fluids to access multiple layers of tumor-specific biological information (genomes, epigenomes, transcriptomes, proteomes, metabolomes, circulating tumor cells, and exosomes). Analysis and integration of these large and diverse datasets using statistical and machine learning approaches can yield important insights into tumor biology and lead to discovery of new diagnostic, predictive, and prognostic biomarkers. Translation of these new diagnostic tools into standard clinical practice could transform oncology, as demonstrated by a number of liquid biopsy assays already entering clinical use. In this review, we highlight successes and challenges facing the rapidly evolving field of cancer biomarker research. Lay Summary Precision oncology aims to tailor clinical decisions specifically to patients with the objective of improving treatment outcomes. The discovery of biomarkers for precision oncology has been accelerated by high-throughput experimental and computational methods, which can inform fine-grained characterization of tumors for clinical decision-making. Moreover, advances in the liquid biopsy field allow non-invasive sampling of patient’s body fluids with the aim of analyzing circulating biomarkers, obviating the need for invasive tumor tissue biopsies. In this review, we highlight successes and challenges facing the rapidly evolving field of liquid biopsy cancer biomarker research.

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Establishment and Application of Prostate Cancer Circulating Tumor Cells in the Era of Precision Medicine

BioMed Research International ◽

10.1155/2017/7206307 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Yoon Seok Suh ◽

Jae Young Joung ◽

Sung Han Kim ◽

Ho Kyung Seo ◽

Jinsoo Chung ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Liquid Biopsy ◽

Disease Status ◽

Minimal Invasive ◽

Future Directions ◽

Advantages And Disadvantages ◽

Potential Tool ◽

Selection Of

Prostate cancer (PC) is the second most common cancer in men and is the fifth leading cause of cancer-related deaths worldwide. Additionally, there is concern for overdiagnosis and overtreatment of PC. Thus, selection of an appropriate candidate for active surveillance as well as more accurate and less invasive tools for monitoring advanced PC is required. Circulating tumor cells (CTCs) have emerged as a liquid biopsy tool; there have been several reports on its role, technologies, and applications to various cancers, including PC. Liquid biopsy using CTCs has been gaining attention as a minimal invasive tool for investigation of biomarkers and for prognosis and assessment of response to therapies in patients with PC. Because of the lower invasiveness of liquid biopsy using CTCs, it can be performed more frequently; accordingly, personalized disease status can be successively determined at serial time points. CTC analysis enables detection of genomic alterations, which is drug-targetable, and it is a potential tool for monitoring response to therapeutic agents in patients with PC. This review focuses on the characteristics, technologies for analysis, and advantages and disadvantages of CTCs as a liquid biopsy tool and their application in PC. Finally, we propose future directions of CTCs.

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