title: Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers.
abstract: BACKGROUND
  Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown.
  
  
  METHODS
  Serum NSE, CYFRA 21-1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray's test.
  
  
  RESULTS
  A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19-0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15-0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22-7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size.
  
  
  CONCLUSIONS
  Serum NSE, CYFRA 21-1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time may be applied to independent datasets to identify a patient cohort with a higher biologic propensity for developing brain metastases. Such information may be useful for the study of agents targeting the development of brain metastases.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 E 66th Street, 12th Floor, New York, NY, 10065, United States of America.|Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Bob T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Division of Hematology, Oncology and Transplantation, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN, 55455, United States of America.
authors.forename: Emil
authors.initials: E
authors.lastname: Lou
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, New York, NY, 10017, United States of America.
authors.forename: Meier
authors.initials: M
authors.lastname: Hsu
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 E 66th Street, 12th Floor, New York, NY, 10065, United States of America.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Yu
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 E 66th Street, 12th Floor, New York, NY, 10065, United States of America.
authors.forename: Jarushka
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 E 66th Street, 12th Floor, New York, NY, 10065, United States of America.
authors.forename: Marjorie G
authors.initials: MG
authors.lastname: Zauderer
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, New York, NY, 10017, United States of America.
authors.forename: Camelia
authors.initials: C
authors.lastname: Sima
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 E 66th Street, 12th Floor, New York, NY, 10065, United States of America.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, United States of America.
authors.forename: Mariza
authors.initials: M
authors.lastname: Daras
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, United States of America.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.affiliation: Clinical Chemistry Service, Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 E 66th Street, 12th Floor, New York, NY, 10065, United States of America.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Thoracic Oncology Program, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114-2696, United States of America.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D001932:Brain Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D053539:Keratin-19 / Q000097:blood; D008175:Lung Neoplasms / Q000097:blood* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017063:Outcome Assessment, Health Care / Q000379:methods; D010446:Peptide Fragments / Q000097:blood; D010751:Phosphopyruvate Hydratase / Q000097:blood; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism; D040901:Proteomics; D011994:Recombinant Proteins / Q000097:blood; D012680:Sensitivity and Specificity; D015843:Serpins / Q000097:blood; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D053539:Keratin-19; D010446:Peptide Fragments; D011506:Proteins; D011994:Recombinant Proteins; D015843:Serpins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; C102012:antigen CYFRA21.1; C087079:pro-gastrin-releasing peptide (31-98); C051072:squamous cell carcinoma-related antigen; D010751:Phosphopyruvate Hydratase