Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

Kidd, Mark; Drozdov, Ignat; Modlin, Irvin M.

doi:10.1530/erc-15-0092

Cited by 88 publications

(132 citation statements)

References 61 publications

(84 reference statements)

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“…The NETest assesses biological activity using gene inference technology and cancer hallmark prediction [26]. Details of the PCR methodology, mathematical analysis and validation have been published in detail [24,26,28,29].…”

Section: Methodsmentioning

confidence: 99%

“…Details of the PCR methodology, mathematical analysis and validation have been published in detail [24,26,28,29]. The procedure utilizes a 2-step protocol (RNA isolation, cDNA production and PCR) [24,28] from EDTA-collected whole blood [24,28].…”

Section: Methodsmentioning

confidence: 99%

“…Currently, the most widely investigated biomarker tool is represented by blood-based multianalyte transcript analysis [24,25]. Blood gene expression closely correlates with tumor tissue expression levels, and inferential gene analysis of relevant clusters captures the biology of neuroendocrine neoplasia facilitating the accurate definition of clinical status [26]. …”

Section: Introductionmentioning

confidence: 99%

“…This is then scaled to a disease/tumor activity (0-100%) score [26], using expressions that specifically capture the hallmarks of neoplasia [27], and may be used to provide direct information about the tumor, its pathophysiology, and its state of evolution from stability to progression. To assess this, we prospectively collected blood samples from NET disease patients at a single center (ENETS Center of Excellence - Charité, Berlin) over a ∼5-year time period and appraised the utility of biomarkers and imaging in defining the bandwidth of the disease spectrum that embraces that most critical clinical decision-making fulcrum: when stability and disease remission become progression.…”

Section: Introductionmentioning

confidence: 99%

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NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive

et al. 2016

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Background/Aims: A key issue in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is early identification and prediction of disease progression. Clinical evaluation and imaging are limited due to the lack of sensitivity and disease indolence. We assessed the NETest as a predictive and prognostic marker of progression in a long-term follow-up study. Methods: GEP-NETs (n = 34) followed for a median 4 years (2.2-5.4) were evaluated. WHO tumor grade/stage grade 1: n = 17, grade 2: n = 14, grade 3: n = 1 (for 2, no grade was available); 31 (91%) were stage IV. Baseline and longitudinal imaging and blood biomarkers were available in all, and progression was defined per standard clinical protocols (RECIST 1.0). The NETest was measured by quantitative PCR of blood and multianalyte algorithmic analysis (disease activity scaled 0-100% with low <40% and high activity risk cutoffs >80%); chromogranin A (CgA) was measured by radioimmunoassay (normal <150 µg/l); progression-free survival (PFS) was analyzed by Cox proportional-hazard regression and Kaplan-Meier analysis. Results: At baseline, 100% were NETest positive, and CgA was elevated in 50%. The only baseline variable (Cox modeling) associated with PFS was NETest (hazard ratio = 1.022, 95% confidence interval = 1.005-1.04; p < 0.012). Using Kaplan-Meier analyses, the baseline NETest (>80%) was significantly associated (p = 0.01) with disease progression (median PFS 0.68 vs. 2.78 years with <40% levels). The NETest was more informative (96%) than CgA changes (>25%) in consistently predicting disease alterations (40%, p < 2 × 10^-5, χ² = 18). The NETest had an earlier time point change than imaging (1.02 ± 0.15 years). Baseline NETest levels >40% in stable disease were 100% prognostic of disease progression versus CgA (χ² = 5, p < 0.03). Baseline NETest values <40% accurately (100%) predicted stability over 5 years (p = 0.05, χ² = 3.8 vs. CgA). Conclusion: The NETest correlated with a well-differentiated GEP-NET clinical status. The NETest has predictive and prognostic utility for GEP-NETs identifying clinically actionable alterations ∼1 year before image-based evidence of progression.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive

et al. 2016

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“…This test has been applied to identify candidate marker genes in peripheral circulation of patients with NETs with high performance (Modlin et al 2014b) independent of age, gender, ethnicity, fasting or proton pump inhibitor treatment and identified affected patients with high sensitivity and specificity (Modlin et al 2014c). Along the same line, Kidd et al (2015b), matched the results of the evaluation of the 51 circulating transcripts identified by MAAA with the analysis of tumour tissue transcripts, divided into different gene clusters, and applied an MAAA/cluster integrated algorithm. The latter was capable of accurately separate NETs with progressive disease from those displaying stable disease after different lines of therapy, predicting the disease status by means of a disease activity NET score, the NETest.…”

Section: Circulating Markersmentioning

confidence: 99%

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Zatelli¹,

Fanciulli²,

Malandrino³

et al. 2015

Endocrine-Related Cancer

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Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

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Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow‐up after curative surgical resection of well‐differentiated pancreatic neuroendocrine tumors

Genc

Jilesen

Dijkum

et al. 2018

Journal of Surgical Oncology

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Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

Abstract: A multianalyte algorithmic assay (MAAA) identifies circulating neuroendocrine tumor (NET) transcripts (nZ51) with a

Cited by 88 publications

References 61 publications

NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive

NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow‐up after curative surgical resection of well‐differentiated pancreatic neuroendocrine tumors

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