title: A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer.
abstract: BACKGROUND
  Bronchoscopy is frequently nondiagnostic in patients with pulmonary lesions suspected to be lung cancer. This often results in additional invasive testing, although many lesions are benign. We sought to validate a bronchial-airway gene-expression classifier that could improve the diagnostic performance of bronchoscopy.
  
  
  METHODS
  Current or former smokers undergoing bronchoscopy for suspected lung cancer were enrolled at 28 centers in two multicenter prospective studies (AEGIS-1 and AEGIS-2). A gene-expression classifier was measured in epithelial cells collected from the normal-appearing mainstem bronchus to assess the probability of lung cancer.
  
  
  RESULTS
  A total of 639 patients in AEGIS-1 (298 patients) and AEGIS-2 (341 patients) met the criteria for inclusion. A total of 43% of bronchoscopic examinations were nondiagnostic for lung cancer, and invasive procedures were performed after bronchoscopy in 35% of patients with benign lesions. In AEGIS-1, the classifier had an area under the receiver-operating-characteristic curve (AUC) of 0.78 (95% confidence interval [CI], 0.73 to 0.83), a sensitivity of 88% (95% CI, 83 to 92), and a specificity of 47% (95% CI, 37 to 58). In AEGIS-2, the classifier had an AUC of 0.74 (95% CI, 0.68 to 0.80), a sensitivity of 89% (95% CI, 84 to 92), and a specificity of 47% (95% CI, 36 to 59). The combination of the classifier plus bronchoscopy had a sensitivity of 96% (95% CI, 93 to 98) in AEGIS-1 and 98% (95% CI, 96 to 99) in AEGIS-2, independent of lesion size and location. In 101 patients with an intermediate pretest probability of cancer, the negative predictive value of the classifier was 91% (95% CI, 75 to 98) among patients with a nondiagnostic bronchoscopic examination.
  
  
  CONCLUSIONS
  The gene-expression classifier improved the diagnostic performance of bronchoscopy for the detection of lung cancer. In intermediate-risk patients with a nondiagnostic bronchoscopic examination, a negative classifier score provides support for a more conservative diagnostic approach. (Funded by Allegro Diagnostics and others; AEGIS-1 and AEGIS-2 ClinicalTrials.gov numbers, NCT01309087 and NCT00746759.).
authors.affiliation: From the Medical University of South Carolina, Charleston (G.A.S.); the University of Pennsylvania School of Medicine, Philadelphia (A.V., N.M.); Allegro Diagnostics (D.W., K.P.S., E.P.) and the Boston University School of Medicine (J.B., M.E.L., A.S.) - both in Boston; Veracyte, San Francisco (D.W., K.P.S.) and Elashoff Consulting, Redwood City (M.E.) - both in California; and the University of Wisconsin School of Medicine and Public Health, Madison (J.S.F.).
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Silvestri
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.forename: Duncan
authors.initials: D
authors.lastname: Whitney
authors.forename: Michael
authors.initials: M
authors.lastname: Elashoff
authors.forename: Kate
authors.initials: K
authors.lastname: Porta Smith
authors.forename: J Scott
authors.initials: JS
authors.lastname: Ferguson
authors.forename: Ed
authors.initials: E
authors.lastname: Parsons
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
authors.forename: Jerome
authors.initials: J
authors.lastname: Brody
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
mesh_terms: D019540:Area Under Curve; D001999:Bronchoscopy; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics; D011446:Prospective Studies; D012372:ROC Curve; D012680:Sensitivity and Specificity; D012907:Smoking