Blood mRNA Measurement (NETest) for Neuroendocrine Tumor Diagnosis of Image-Negative Liver Metastatic Disease

Context: Early cancer detection is critical to optimize treatment. This is particularly problematic in neuroendocrine tumors (NETs), which exhibit an similar to 5-year diagnostic delay due to covert symptoms, limitations in imaging, and circulating biomarkers. Despite development of continuous monitoring strategies utilizing advanced modalities [CT/MRI or (68)Gallium positron emission tomography (PET)/CT] or a repertoire of monoanalyte biomarkers [e.g., chromogranin A (CgA), pancreastatin, serotonin], detection of minimal residual disease or microrecurrence remains elusive. Emerging molecular liquid biopsies (e.g., NETest) provide a substantially improved threshold for disease detection. Case Description: We describe the utility of a blood-based multigene PCR neuroendocrine measurement (NETest), which is representative of core molecular drivers of neuroendocrine tumorigenesis, to detect hepatic micrometastases in a patient with negative blood biomarkers and negative anatomical/functional imaging. The 52-year-old woman, who had undergone margin-negative resection for a NET of the ileocecal valve, developed persistently elevated NETest levels 8 months later. CT/MRI/(68)Gallium PET and biomarkers remained negative. Blood multigene analysis identified disease, and peptide receptor radionuclide therapy (PRRT) was undertaken. Over 9 months, NETest levels increased (conventional biomarkers/imaging remained normal). Liver biopsy was undertaken, and foci of a 3-mm NET in segment VI were histologically documented. At 3.3 years after PRRT, the disease remained as a microscopic burden and stable biomarker/(68)Gallium PET/MRI occult despite elevated blood levels of NET genes. Conclusions: Blood measurement of NET transcripts can identify image- and CgA-negative disease. A NET liquid biopsy strategy has clinical utility in the early identification of residual or metastatic disease and optimizes consideration of adjuvant therapeutic intervention.