title: Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.
abstract: OBJECTIVE
  Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies.
  
  
  METHODS
  Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81).
  
  
  RESULTS
  Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + β), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%.
  
  
  CONCLUSIONS
  Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: John C
authors.initials: JC
authors.lastname: Kubasiak
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Seder
authors.affiliation: Department of Pathology, Rush University Medical Center, Chicago, Ill.
authors.forename: Ravi
authors.initials: R
authors.lastname: Pithadia
authors.affiliation: Department of Preventative Medicine, Rush University Medical Center, Chicago, Ill.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Ill.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fhied
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: William W
authors.initials: WW
authors.lastname: Phillips
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: Shaun
authors.initials: S
authors.lastname: Daly
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: David D
authors.initials: DD
authors.lastname: Shersher
authors.affiliation: Department of Pulmonary and Critical Care, Rush University Medical Center, Chicago, Ill.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Yoder
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: Gary
authors.initials: G
authors.lastname: Chmielewski
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minn.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Edell
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minn.
authors.forename: Fabien
authors.initials: F
authors.lastname: Maldonado
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Ill.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Liptay
authors.affiliation: Department of Pathology, Rush University Medical Center, Chicago, Ill; Department of Biochemistry, Rush University Medical Center, Chicago, Ill. Electronic address: Jeffrey_Borgia@rush.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Borgia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000000981:diagnostic imaging / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D007087:Illinois; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D007335:Insulin-Like Growth Factor II / Q000032:analysis*; D008175:Lung Neoplasms / Q000097:blood* / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D012372:ROC Curve; D015203:Reproducibility of Results; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; C583557:IGF1 protein, human; C035170:IGF2 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II