A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility

Ann Oncol. 2021 Nov;32(11):1425-1433. doi: 10.1016/j.annonc.2021.08.1746. Epub 2021 Aug 11.

Abstract

Background: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period.

Patients and methods: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml).

Statistics: Mann-Whitney U-test, AUROC, chi-square and McNemar' test.

Results: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), 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. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification (chi-square = 180, OR = 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%.

Conclusion: NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.

Keywords: Chromogranin; NET; NETest; biomarker; neuroendocrine tumor.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • Biomarkers, Tumor / genetics
  • Chromogranin A
  • Cross-Sectional Studies
  • Humans
  • Liquid Biopsy
  • Neoplasm Recurrence, Local
  • Neuroendocrine Tumors* / genetics
  • Pancreatic Neoplasms* / diagnosis
  • Pancreatic Neoplasms* / genetics
  • Prospective Studies

Substances

  • Biomarkers, Tumor
  • Chromogranin A