A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors

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 chi(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 (chi(2) = 97.3, P < 10(-26)). Significant differences (P < 0.001) were noted between pancreas:PCR 95% vs CgA29.2%(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.