title: A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection.
abstract: A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (n=41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included χ(2), non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96±0.025, CgA: 0.67±0.06, PST 0.56±0.06, NKA: 0.66±0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P<0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest >95% sensitivity and specificity, AUC =0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (>93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy.
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA imodlin@optonline.net.
authors.forename: Irvin M
authors.initials: IM
authors.lastname: Modlin
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA.
authors.forename: Ignat
authors.initials: I
authors.lastname: Drozdov
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Alaimo
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Callahan
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Teixiera
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bodei
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D053379:Chromogranin A / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006403:Hematologic Tests; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000175:diagnosis; D015288:Neurokinin A / Q000097:blood*; D010187:Pancreatic Hormones / Q000097:blood*; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D053379:Chromogranin A; D010187:Pancreatic Hormones; C071102:pancreastatin-52; D015288:Neurokinin A
keywords: NET; PCR; PYY; biomarker; carcinoid; chromogranin A; gastroenteropancreatic; monoanalyte; multianalyte; multigene transcript; neuroendocrine; neurokinin A; pancreastatin; proton pump inhibitor