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Context Early cancer detection is critical to optimize treatment. This is particularly problematic in neuroendocrine tumors (NETs), which exhibit an ∼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 68Gallium 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/68Gallium 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/68Gallium 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.

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