title: NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive.
abstract: OBJECTIVE
  A key issue in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is early identification and prediction of disease progression. Clinical evaluation and imaging are limited due to the lack of sensitivity and disease indolence. We assessed the NETest as a predictive and prognostic marker of progression in a long-term follow-up study.
  
  
  METHODS
  GEP-NETs (n = 34) followed for a median 4 years (2.2-5.4) were evaluated. WHO tumor grade/stage grade 1: n = 17, grade 2: n = 14, grade 3: n = 1 (for 2, no grade was available); 31 (91%) were stage IV. Baseline and longitudinal imaging and blood biomarkers were available in all, and progression was defined per standard clinical protocols (RECIST 1.0). The NETest was measured by quantitative PCR of blood and multianalyte algorithmic analysis (disease activity scaled 0-100% with low <40% and high activity risk cutoffs >80%); chromogranin A (CgA) was measured by radioimmunoassay (normal <150 µg/l); progression-free survival (PFS) was analyzed by Cox proportional-hazard regression and Kaplan-Meier analysis.
  
  
  RESULTS
  At baseline, 100% were NETest positive, and CgA was elevated in 50%. The only baseline variable (Cox modeling) associated with PFS was NETest (hazard ratio = 1.022, 95% confidence interval = 1.005-1.04; p < 0.012). Using Kaplan-Meier analyses, the baseline NETest (>80%) was significantly associated (p = 0.01) with disease progression (median PFS 0.68 vs. 2.78 years with <40% levels). The NETest was more informative (96%) than CgA changes (<under>></under>25%) in consistently predicting disease alterations (40%, p < 2 × 10-5, χ2 = 18). The NETest had an earlier time point change than imaging (1.02 ± 0.15 years). Baseline NETest levels >40% in stable disease were 100% prognostic of disease progression versus CgA (χ2 = 5, p < 0.03). Baseline NETest values <40% accurately (100%) predicted stability over 5 years (p = 0.05, χ2 = 3.8 vs. CgA).
  
  
  CONCLUSIONS
  The NETest correlated with a well-differentiated GEP-NET clinical status. The NETest has predictive and prognostic utility for GEP-NETs identifying clinically actionable alterations ∼1 year before image-based evidence of progression.
authors.affiliation: Department of Hepatology and Gastroenterology, Campus-Virchow-Klinikum, Berlin, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Pavel
authors.forename: Henning
authors.initials: H
authors.lastname: Jann
authors.forename: Vikas
authors.initials: V
authors.lastname: Prasad
authors.forename: Ignat
authors.initials: I
authors.lastname: Drozdov
authors.forename: Irvin M
authors.initials: IM
authors.lastname: Modlin
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor