Abstract 3115: Translational clinical utility of a circulating neuroendocrine tumor transcript measurement
Authors: Irvin Modlin, Mark Kidd, Jaroslaw Cwikla, Ignat Drozdov, Lisa Bodei
Journal: Cancer Research (2016)

Abstract Background: A key issue in the clinical management of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is early identification and the prediction of disease progression or recurrence. Strategies include imaging and biomarker measurement e.g., CgA or NSE. The former is limited by sensitivity and the latter by low specificity and poor reproducibility. We evaluated the role of a blood-based multianalyte gene algorithmic analysis (MAAA) using a 51 NET gene signature (NETest) as an alternative circulating biomarker and assessed its clinical utility in GEP-NET. Patients and Methods: We investigated 180 well-differentiated GEP-NET (small intestine: n = 93, pancreatic: n = 52, colorectal: n = 11, stomach: n = 3, appendix: n = 2 and CUP: n = 19; histological grade: G1: n = 80, G2: n = 86, no data: n = 14). Baseline imaging (SRI: n = 103, CT/MRI: n = 77) were available. Surgery was undertaken in 27 and 28 had somatostatin analog (SSA) therapy. Disease recurrence or progression (RECIST 1.0 criteria) was determined by CT/MRI in treated cohorts. Transcript analysis was by qPCR and multianalyte algorithmic analysis. NETest defines disease activity risk: &amp;lt;14%: negative, &amp;lt;40%: low, &amp;gt;80% high. Transcripts measured by the NETest included genes involved in proliferation e.g., Ki-67, growth factor signaling e.g., RAF pathway and somatostatin receptor expression. Statistical analyses included regression analyses, performance metrics analysis and progression-free survival (PFS: Kaplan-Meier). Results: The NETest was positive in 175 (97%) with image-proven GEP-NET. In the surgical samples, matched blood/ tumor sample were significantly correlated (R2 = 0.7, p&amp;lt;0.0001) and gene expression regulating tumor proliferation, growth factor signaling and somatostatin receptor expression were concordant (R2 = 0.42-0.8, p&amp;lt;0.05). Surgery significantly decreased NETest levels (85%) and tumor volume decreases partially correlated with the NETest (R2 = 0.29, p = 0.02). Elevated post-resection levels (&amp;gt;40%) predicted recurrence (100%). Baseline disease status (RECIST) was concordant with the NETest in 84% of the 62 evaluable patients; metrics were: sensitivity: 100%, specificity: 70%, PPV: 80% and NPV: 100%. In 28 patients treated with SSAs, NETest at baseline predicted treatment response (median PFS: 245 days NETest &amp;gt;80% vs. undetermined, NETest&amp;lt;40%). Clinically actionable elevations (to &amp;gt;80%) in the NETest occurred 105 days (48-252) prior to image-proven disease progression. Conclusions: A blood-based NET MAAA accurately correlated (97%) with image-proven disease. Blood levels were concordant with tissue and correlated with genes regulating tumor activity. NETest levels were decreased by surgery and elevated levels (&amp;gt;40%) were predictive (100%) of recurrence. NETest levels were also correlated (84%) with clinical disease status (RECIST) and values &amp;gt;80% predicted disease progression (100%) on somatostatin analogs. Citation Format: Irvin Modlin, Mark Kidd, Jaroslaw Cwikla, Ignat Drozdov, Lisa Bodei. Translational clinical utility of a circulating neuroendocrine tumor transcript measurement. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3115.