title: A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors.
abstract: A critical requirement in neuroendocrine tumor (NET) management is a blood biomarker test that is sensitive, specific and reproducible. We evaluated a PCR-based 51-transcript signature to detect tumors, compared it with chromogranin A (CgA) and examined the confounding effect of proton pump inhibitors (PPIs), which cause falsely elevated CgA levels. The multigene signature was evaluated in two groups. Group 1: 125 prospectively collected NETs: gastroenteropancreatic NETs (n=91, including 42 pancreatic and 40 small intestinal), carcinoids of unknown primary (n=18) and other sites (n=16). Group 2: prospectively collected non-NET patients receiving PPIs (>1 month; dyspepsia, n=19; GERD, n=6; and pancreatitis, n=4) and 50 controls. All samples were analyzed by PCR (marker genes) and ELISA (DAKO-CgA). Sensitivity comparisons included χ(2), non-parametric measurements, and receiver operating characteristic (ROC) curves. Group 1: 123 NETs were PCR-positive (98.4%) compared with 50 (40%) CgA-positive (χ(2)=97.3, P<10(-26)). Significant differences (P<0.001) were noted between pancreas: PCR 95% vs CgA 29.2% (P<10(-9)) and small intestine: 100 vs 58% (P<10(-4)). The multigene test was elevated in all grades (G1-G3), in both local and disseminated disease, and was not normalized by somatostatin analog therapy. It was also elevated in 97% of CgA normal NETs. Group 2: PPI administration increased CgA in 83% and CgA was elevated in 26% of controls. PCR values were not elevated in either group. PCR performance metrics were as follows: sensitivity 98.4%, specificity 100%, positive predictive value 100%, negative predictive value 97.8%, and the ROC-derived area under the curve (AUC) was 0.997. These were significantly better than CgA (all metrics <60%; AUC, 0.54; Z-statistic, 10.44, P<0.0001). A 51-panel multigene blood transcript analysis is significantly more sensitive than plasma CgA for NET detection and is unaffected by acid suppression therapy.
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA imodlin@optonline.net.
authors.forename: Irvin M
authors.initials: IM
authors.lastname: Modlin
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Aslanian
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bodei
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA.
authors.forename: Ignat
authors.initials: I
authors.lastname: Drozdov
authors.affiliation: Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
keywords: NET; PCR; biomarker; carcinoid; chromogranin A; gastroenteropancreatic; multigene transcript; neuroendocrine; proton pump inhibitor