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.
Irvin M Modlin, Harry Aslanian, Lisa Bodei, Ignat Drozdov and Mark Kidd
Ashley K Clift, Omar Faiz, Robert Goldin, John Martin, Harpreet Wasan, Marc-Olaf Liedke, Erik Schloericke, Anna Malczewska, Guido Rindi, Mark Kidd, Irvin M Modlin and Andrea Frilling
Neuroendocrine tumours (NET) are clinically challenging due to their unpredictable behaviour. Nomograms, grading and staging systems are predictive tools with multiple roles in clinical practice, including patient prognostication. The NET nomogram allocates scores for various clinicopathological parameters, calculating percentage estimates for 5- and 10-year disease-specific survival of patients with small bowel (SB) NET. We evaluated the clinical utility of three prognostic systems in 70 SB NET patients: the NET nomogram, the World Health Organisation (WHO)/European Neuroendocrine Tumour Society (ENETS) grading system and the American Joint Commission on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) TNM staging method. Using Kaplan–Meier methodology, neither the WHO/ENETS grade (P = 0.6) nor the AJCC/UICC stage (P = 0.276) systems demonstrated significant differences in patient survival in the cohort. The NET nomogram was well calibrated to our data set, displaying favourable prediction accuracy. Harrel’s C-index for the nomogram (a measure of predictive power) was 0.65, suggesting good prediction ability. On Kaplan–Meier analyses, there were significant differences in patient survival when stratified into nomogram score-based risk groups: low-, medium- and high-risk tumours were associated with median estimated survivals of 156, 129 and 112 months, respectively (P = 0.031). Our data suggest that a multivariable analysis-based NET nomogram may be clinically useful for patient survival prediction. This study identifies the limitations of the NET nomogram and the imperfections of other currently used single or binary parameter methodologies for assessing neuroendocrine disease prognosis. The future addition of other variables to the NET nomogram will likely amplify the accuracy of this personalised tool.
Kjell Oberg, Eric Krenning, Anders Sundin, Lisa Bodei, Mark Kidd, Margot Tesselaar, Valentina Ambrosini, Richard P Baum, Matthew Kulke, Marianne Pavel, Jaroslaw Cwikla, Ignat Drozdov, Massimo Falconi, Nicola Fazio, Andrea Frilling, Robert Jensen, Klaus Koopmans, Tiny Korse, Dik Kwekkeboom, Helmut Maecke, Giovanni Paganelli, Ramon Salazar, Stefano Severi, Jonathan Strosberg, Vikas Prasad, Aldo Scarpa, Ashley Grossman, Annemeik Walenkamp, Mauro Cives, Irene Virgolini, Andreas Kjaer and Irvin M Modlin
The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.