A Blood-Based, Multigenomic Signature is an Effective Diagnostic and Has Clinical Utility in NETs Management

The results of NETest in 1,684 consecutive, prospectively collected neuroendocrine tumours (NETs) assessed over 5 years for diagnostic and surgical utility and additional examination of the NETest directly compared to chromogranin A (CgA) in a sub-cohort of 922 NETs in whom both biomarker measurements were available, showed that NETest is >90% accurate for NET diagnosis. Its concordance with imaging, grade, metastases and disease status significantly outperforms CgA. NETest after surgery predicts residual disease and recurrence with >94% accuracy compared to 11% in case of CgA. The study findings are published by Prof. Kjell Öberg of the Department of Medical Sciences, Uppsala University and Department of Endocrine Oncology, University Hospital in Uppsala, Sweden and colleagues on 11 August 2021 in the Annals of Oncology.  

Prof. Öberg and study team wrote in the background that NET biomarkers have focused on measurements of secretory products, such as gastrin, serotonin or CgA. However, guidelines consider such biomarkers as either not useful or as controversial. In NETs, a NETest is considered as a more accurate biomarker than CgA. The assay has been described in detail and independently validated. It comprises a 51-gene expression-based liquid biopsy for NETs that utilizes PCR and multianalyte algorithmic analyses.

The study team assessed the clinical efficacy of NETest as a multigenomic blood biomarker to CgA over a 5-year period. In cohort 1, a total 1,684 NETs were evaluated by NETest versus 731 benign diseases and controls. In cohort 2, matched analysis of NETest/CgA was performed in a sub-cohort of 922 NETs versus 348 other diseases and controls.

NETest diagnostic accuracy was 91% in cohort 1 (p < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%) NETs. Furthermore, NETest reflected grading. Loco-regional disease levels were lower than metastatic (p < 0.0001). NETest accurately stratified RECIST-assessed disease extent into no disease, stable, and progressive (p < 0.0001). NETest concordance with imaging was 91%. In pre-surgery setting, all NETs (n=153) were positive. After palliative R1/R2 surgery (n=51), all remained elevated. After curative R0-surgery, NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years.

NETest diagnostic accuracy was 87% in cohort 2 and 54% in case of CgA (p < 0.0001). NETest was more accurate than CgA for grading (OR 18.5) and metastatic identification (OR 8.4). NETest identified progressive disease in 95% versus 57% by CgA (p < 0.0001). Imaging concordance for NETest was 91% versus 46% by CgA (p < 0.0001). Recurrence prediction after surgery was positive with NETest in >94% versus 11% by CgA.

The authors concluded that this multigenomic liquid biopsy accurately diagnoses NETs and is an effective surrogate marker. They commented that their results demonstrate in a substantially powered and diverse NETs cohort that NETest provides an accurate, non-invasive strategy to real-time assessment of disease status and surgical treatment efficacy. The consideration of an accurate, non-invasive biomarker to identify disease that can be used as a surrogate, or provide synergistic information with imaging, has attractive clinical and health economic possibilities.


Modlin IM, Kidd M, Falconi M, et al. A Multigenomic Liquid Biopsy Biomarker for Neuroendocrine Tumor Disease outperforms CgA and has Surgical and Clinical Utility. Annals of Oncology; Published online 11 August 2021. DOI: https://doi.org/10.1016/j.annonc.2021.08.1746