Prospective Evaluation of the NETest as a Liquid Biopsy for Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumours: An ENETS Centre of Excellence Experience.

BACKGROUND: There is a substantial unmet clinical need for an accurate and effective blood biomarker for neuroendocrine neoplasms (NEN). We therefore evaluated, under real-world conditions, the clinical utility of the NETest as a liquid biopsy in an ENETS Centre of Excellence and compared its utility with chromogranin A (CgA). Methods Cohorts: Gastroenteropancreatic (GEP)-NEN (n=253), bronchopulmonary (BP)-NEN (n=64), thymic NEN (n=1), colon cancer (n=37), NSCLC (n=63), benign lung disease (n=59) and controls (n=86). GEPNEN: 164 (65%) had image-detectable disease (n=135) or were image-negative but resection-margin/biopsy-positive (n=29). Grading: G1 (n=106), G2 (n=49) and G3 (n=7), no data (n=2). The remainder (n=71) has no evidence of disease. BPNEN: 43 of 64 (67%) were image-positive. HISTOLOGY: TC (n=14), AC (n=14), SCLC (n=11), LCNEC (n=4). Disease status (stable or progressive) (RECIST 1.1). Blood sampling: NETest (n=563) and NETest/CgA matched samples (n=178). NETest (PCR) (0-100 score), positive >/=20; progressive >40. CgA (ELISA). Samples deidentified, measurement blinded. STATISTICS: Kruskal-Wallis or Mann-Whitney, McNemar's test and AUROC. Results GEPNEN: NETest was significantly higher (34.4+/-1.8, p<0.0001) in disease versus disease-free (10.5+/-1, p<0.0001), colon cancer (18+/-4, p<0.0004) or controls (7+/-0.5, p<0.0001). Sensitivity for detecting disease compared to controls was 89%, specificity: 94%. NETest levels were increased in G2 vs. G1 (39+/-3 vs. 32+/-2, p=0.02) and correlated with stage (localized: 26+/-2, vs regional/distant: 40+/-3 p=0.0002) and progression (55+/-5 vs. 34+/-2 in stable disease, p=0.0005). BPNEN: Diagnostic sensitivity was 100% and levels were significantly higher in image-positive bronchopulmonary carcinoids (BPC) (30+/-1.3) vs. controls (7+/-0.5, p<0.0001), no disease evident (24.1+/-1.3, p<0.005) or NSCLC (17+/-3, p=0.0001). NETest levels were higher in poorly-differentiated BPNEN (LCNEC+SCLC) (59+/-7) than BPC (30+/-1.3, p=0.0005), and progressive (57.8+/-7) compared to stable disease (29.4+/-1, p<0.0001). AUCs for differentiating disease from controls: 0.87 (GEPNEN); 0.99 (BPC) (p<0.0001). Matched CgA analyses (n=178): GEPNEN (n=135): NETest was significantly more accurate for detecting disease (99%) than CgA (53%, McNemar's test Chi2=87, p<0.0001). BPNEN (n=43): NETest was significantly more accurate for disease detection (100%) than CgA (26%, McNemar's test Chi2=30, p<0.0001). Conclusions The NETest is an accurate diagnostic for GEP- and BPNEN. It exhibits tumor biology correlation with grading, staging and progression. CgA is significantly less accurate than NETest. The NETest has substantial clinical utility that can facilitate patient management.