Early Identification of Residual Disease After Neuroendocrine Tumor Resection Using a Liquid Biopsy Multigenomic mRNA Signature (NETest)

Published on May 18, 2021in Annals of Surgical Oncology4.061
· DOI :10.1245/S10434-021-10021-1
Irvin M. Modlin81
Estimated H-index: 81
(Yale University),
Mark Kidd66
Estimated H-index: 66
+ 14 AuthorsAlexandra Kitz2
Estimated H-index: 2
Sources
Abstract
Introduction Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence. Methods This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal ≤20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation. Results The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p 20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p Conclusion The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.
References47
Newest
#1Mark KiddH-Index: 66
#1Mark KiddH-Index: 5
Last. Irvin M. ModlinH-Index: 81
view all 4 authors...
BACKGROUND: The NETest is a multi-gene assay comprising 51 circulating neuroendocrine tumor specific transcripts. The quotient of the 51-gene assay is based upon an ensemble of machine learning algorithms. Eight cancer hallmarks or "omes" (apoptome, epigenome, growth factor signalome, metabolome, proliferome, plurome, secretome SSTRome) represent 29 genes. The NETest is an accurate diagnostic (>90%) but its prognostic utility has not been assessed. In this study, we describe expansion of the NET...
2 CitationsSource
#1Lisa Bodei (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 25
#2Heiko Schöder (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 77
Last. Irvin M. Modlin (Yale University)H-Index: 81
view all 8 authors...
Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be e...
10 CitationsSource
#1Marianne PavelH-Index: 52
#2Kjell Öberg (Uppsala University)H-Index: 116
Last. Alfredo Berruti (University of Brescia)H-Index: 66
view all 7 authors...
46 CitationsSource
#2Dennis van der ZeeH-Index: 2
Last. Margot E.T. TesselaarH-Index: 10
view all 11 authors...
Reliable prediction of disease status is a major challenge in managing gastroenteropancreatic neuroendocrine tumors (GEP-NET). The aim of the study was to validate the NETest®, a blood molecular genomic analysis, for predicting the course of disease in individual patients compared to Chromogranin A (CgA). NETest® (normal ≤20%) and CgA (normal 140ng/ml), NPV and PPV were 83% and 52%. CgA could not predict PD in watchful waiting or NED subgroups. The NETest® reliably predicted SD and was the stron...
4 CitationsSource
#1Pier Luigi Filosso (UNITO: University of Turin)H-Index: 38
#1P.L. Filosso (UNITO: University of Turin)H-Index: 10
Last. Lisa Bodei (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 25
view all 7 authors...
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 neuroe...
2 CitationsSource
#1Stefano Partelli (UniSR: Vita-Salute San Raffaele University)H-Index: 43
#2Massimo Falconi (UniSR: Vita-Salute San Raffaele University)H-Index: 105
Source
#1Anna MalczewskaH-Index: 12
Last. Beata Kos-KudłaH-Index: 31
view all 16 authors...
BACKGROUND: There is a substantial unmet clinical need for an accurate and effective blood biomarker for neuroendocrine neoplasms (NEN). We therefore evaluated, under real-world conditions, the clinical utility of the NETest as a liquid biopsy in an ENETS Centre of Excellence and compared its utility with chromogranin A (CgA). Methods Cohorts: Gastroenteropancreatic (GEP)-NEN (n=253), bronchopulmonary (BP)-NEN (n=64), thymic NEN (n=1), colon cancer (n=37), NSCLC (n=63), benign lung disease (n=59...
5 CitationsSource
#1Faidon-Marios Laskaratos (Royal Free Hospital)H-Index: 7
#2Man Liu (SYSU: Sun Yat-sen University)H-Index: 3
Last. Christos Toumpanakis (Royal Free Hospital)H-Index: 27
view all 9 authors...
PURPOSE: Surgical resection is the only effective curative strategy for small intestinal neuroendocrine neoplasms (SINENs). Nevertheless, the evaluation of residual disease and prediction of disease recurrence/progression remains a problematic issue. METHODS: We evaluated 13 SINENs that underwent surgical resection of the primary tumour and/or mesenteric mass. Patients were divided in three groups: (a) Group 1: SINENs that underwent resection with curative intent, (b) Group 2: SINENs treated wit...
1 CitationsSource
#1Stefano Partelli (UniSR: Vita-Salute San Raffaele University)H-Index: 43
#2Valentina Andreasi (UniSR: Vita-Salute San Raffaele University)H-Index: 8
Last. Massimo Falconi (UniSR: Vita-Salute San Raffaele University)H-Index: 105
view all 5 authors...
BACKGROUND: Surgery remains the only treatment for the cure of pancreatic neuroendocrine tumors (PanNETs). Biomarkers to identify the completeness of resection and predict recurrence are lacking. OBJECTIVE: The aims of this study were to evaluate if the blood measurement of neuroendocrine gene transcripts (NETest) was diagnostic of PanNETs, and whether NETest blood levels could identify complete resection. We compared transcript analysis with the biomarker chromogranin A (CgA). METHODS: This was...
7 CitationsSource
#1Kjell ÖbergH-Index: 116
#1Kjell ÖbergH-Index: 1
Last. S. Paulson (Baylor University)H-Index: 1
view all 11 authors...
Background The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy—liquid biopsy—to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). Patients and methods A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analys...
22 CitationsSource
Cited By3
Newest
Source
Abstract Biomarkers that are secretory monoanalyte products of GEP (gastro-entero-pancreatic) and BP (broncho-pulmonary) or lung NETs (neuroendocrine tumors) have significant limitations in clinical utility. The assessment of secretory activity provides little information in regard to tumor biology. Furthermore, ∼50% of NETs have measurable secretory products. Molecular genomic identification in blood (NETest liquid biopsy) of the regulators of tumor biology provide multianalyte, real-time asses...
Source
Abstract In respect of Carcinoid disease, one might well ask – why have we failed so miserably? In 1907, Oberndorfer described “karzinoide” and yet more than a century later, most diagnoses still reflect incurable metastatic disease. Attempts to address the biology and mechanistic basis of NETs have lacked logic, balanced oversight or linearity. Governance appears directed to the support of countless clinical trials, often so underpowered and scientifically improbable as to seem based more on ma...
Source