title: Gene transcript analysis blood values correlate with ⁶⁸Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status.
abstract: OBJECTIVE
  Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between (68)Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs.
  
  
  METHODS
  We utilized two independent patient groups with positive (68)Ga-SSA PET: data set 1 ((68)Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 ((68)Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUVmax), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships.
  
  
  RESULTS
  SUVmax measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ(2) = 20.1, p < 2.5×10(-6)). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUVmax (R (2) = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUVmax. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUVmax [ROC-derived AUC (R (2) = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters was evident.
  
  
  CONCLUSIONS
  (68)Ga-SSA PET imaging parameters (SUVmax) correlated with a circulating NET transcript signature. Disease status could be predicted by an elevated quotient of gene expression (MORF4L2) and SUVmax. These observations provide the basis for further exploration of strategies that combine imaging parameters and disease-specific molecular data for the improvement of NET management.
authors.affiliation: Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bodei
authors.forename: M
authors.initials: M
authors.lastname: Kidd
authors.forename: I M
authors.initials: IM
authors.lastname: Modlin
authors.forename: V
authors.initials: V
authors.lastname: Prasad
authors.forename: S
authors.initials: S
authors.lastname: Severi
authors.forename: V
authors.initials: V
authors.lastname: Ambrosini
authors.forename: D J
authors.initials: DJ
authors.lastname: Kwekkeboom
authors.forename: E P
authors.initials: EP
authors.lastname: Krenning
authors.forename: R P
authors.initials: RP
authors.lastname: Baum
authors.forename: G
authors.initials: G
authors.lastname: Paganelli
authors.forename: I
authors.initials: I
authors.lastname: Drozdov
mesh_terms: D000328:Adult; D000368:Aged; D053379:Chromogranin A / Q000378:metabolism; D005260:Female; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000097:blood; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives*; D014057:Tomography, X-Ray Computed
chemical_list: D053379:Chromogranin A; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D013004:Somatostatin