title: Assessment of a Combined Panel of Six Serum Tumor Markers for Lung Cancer.
abstract: BACKGROUND
  We have previously identified six serum tumor markers (TMs) (carcinoembryonic antigen, carbohydrate antigen 15.3, squamous cell carcinoma-associated antigen, cytokeratin-19 fragment, neuron-specific enolase, and pro-gastrin-releasing peptide) related to the presence of lung cancer (LC).
  
  
  OBJECTIVE
  To validate their individual performance in an independent cohort, and to explore if their combined assessment (≥1 abnormal TM value) is a more accurate marker for LC presence.
  
  
  METHODS
  We determined these six TMs in 3,144 consecutive individuals referred to our institution by their primary care physician because of the clinical suspicion of LC.
  
  
  RESULTS
  LC was excluded in 1,316 individuals and confirmed in 1,828 patients (1,563 with non-small cell LC and 265 with small cell LC). This study validated the previously reported performance of each individual TM. We also showed that their combined assessment (≥1 abnormal TM) had a better sensitivity, specificity, negative predictive value, and positive predictive value (88.5, 82, 83.7, and 87.3%, respectively) than each TM considered individually and that it increased the diagnostic performance (area under the curve) of a clinical model that included tumor size, age, and smoking status. In patients with radiographic nodules less than 3 cm, the negative predictive value of the TM panel was 71.8%, hence providing some support for a more conservative diagnostic approach. Finally we identified two TMs (neuron-specific enolase and pro-gastrin-releasing peptide) that differentiate the risk of non-small cell LC from that of small cell LC.
  
  
  CONCLUSIONS
  The combined assessment of a panel of six serum TMs is a more accurate marker for LC presence than these same TMs considered individually. The potential of these TMs in the diagnostic and screening settings deserves further research.
authors.affiliation: 1 Laboratory of Biochemistry (Oncobiology Unit), Biomedical Diagnostic Center (CDB).
authors.forename: Rafael
authors.initials: R
authors.lastname: Molina
authors.affiliation: 2 Respiratory Institute.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Marrades
authors.affiliation: 1 Laboratory of Biochemistry (Oncobiology Unit), Biomedical Diagnostic Center (CDB).
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Augé
authors.affiliation: 1 Laboratory of Biochemistry (Oncobiology Unit), Biomedical Diagnostic Center (CDB).
authors.forename: Jose M
authors.initials: JM
authors.lastname: Escudero
authors.affiliation: 3 Medical Oncology Department, and.
authors.forename: Nuria
authors.initials: N
authors.lastname: Viñolas
authors.affiliation: 3 Medical Oncology Department, and.
authors.forename: Noemi
authors.initials: N
authors.lastname: Reguart
authors.affiliation: 4 Pathology Department, CDB, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; and.
authors.forename: Jose
authors.initials: J
authors.lastname: Ramirez
authors.affiliation: 1 Laboratory of Biochemistry (Oncobiology Unit), Biomedical Diagnostic Center (CDB).
authors.forename: Xavier
authors.initials: X
authors.lastname: Filella
authors.affiliation: 2 Respiratory Institute.
authors.forename: Laureano
authors.initials: L
authors.lastname: Molins
authors.affiliation: 2 Respiratory Institute.|5 CIBERES (Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias), Spain.
authors.forename: Alvar
authors.identifier: http://orcid.org/0000-0003-3271-3788
authors.initials: A
authors.lastname: Agustí
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000097:blood; D015331:Cohort Studies; D005260:Female; D006801:Humans; D053539:Keratin-19 / Q000097:blood; D008175:Lung Neoplasms / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood; D010751:Phosphopyruvate Hydratase / Q000097:blood; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D011994:Recombinant Proteins / Q000097:blood; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015843:Serpins / Q000097:blood
chemical_list: D000951:Antigens, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D053539:Keratin-19; D010446:Peptide Fragments; D011994:Recombinant Proteins; D015843:Serpins; C087079:pro-gastrin-releasing peptide (31-98); C051072:squamous cell carcinoma-related antigen; D010751:Phosphopyruvate Hydratase
keywords: CA15.3; CEA; CYFRA 21-1; NSE; ProGRP