title: Validation of a blood protein signature for non-small cell lung cancer.
abstract: BACKGROUND
  CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations.
  
  
  RESULTS
  Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation.
  
  
  CONCLUSIONS
  Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
authors.affiliation: SomaLogic, Inc., Boulder, CO, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Mehan
authors.affiliation: SomaLogic, Inc., Boulder, CO, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Williams
authors.affiliation: University of Pittsburgh Cancer Institute, School of Medicine, Pittsburgh, PA, USA ; University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
authors.affiliation: University of Pittsburgh Cancer Institute, School of Medicine, Pittsburgh, PA, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Bigbee
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Joel L
authors.initials: JL
authors.lastname: Weissfeld
authors.affiliation: University of Pittsburgh Cancer Institute, School of Medicine, Pittsburgh, PA, USA.
authors.forename: David O
authors.initials: DO
authors.lastname: Wilson
authors.affiliation: Langone Medical Center and Cancer Center, New York University School of Medicine, New York, NY, USA.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: New York University School of Medicine, New York, NY, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.affiliation: Thoraxklinik at University Hospital Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Thoraxklinik at University Hospital Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Wilbur
authors.initials: W
authors.lastname: Franklin
authors.affiliation: University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA ; Denver Veterans Affairs Medical Center, Denver, CO, USA.
authors.forename: York E
authors.initials: YE
authors.lastname: Miller
authors.affiliation: SomaLogic, Inc., Boulder, CO, USA.
authors.forename: Edward N
authors.initials: EN
authors.lastname: Brody
authors.affiliation: SomaLogic, Inc., Boulder, CO, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Ostroff
keywords: Biomarker; Diagnosis; Lung cancer; Preanalytic variability; Proteomic; SOMAmer; Sample bias; Squamous cell carcinoma
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Mol Cancer Res. 2010 Nov;8(11):1453-65
references.pmid: 20870736
references.citation: PLoS One. 2012;7(7):e39403
references.pmid: 22768300
references.citation: Cancer Res. 2009 Sep 15;69(18):7252-61
references.pmid: 19706765
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683
references.citation: J Am Chem Soc. 2010 Mar 31;132(12):4141-51
references.pmid: 20201573
references.citation: N Engl J Med. 2011 Aug 4;365(5):395-409
references.pmid: 21714641
references.citation: Eur Respir J. 2013 Dec;42(6):1659-67
references.pmid: 23845716
references.citation: N Engl J Med. 2013 May 23;368(21):1980-91
references.pmid: 23697514
references.citation: JAMA. 2012 Jun 13;307(22):2418-29
references.pmid: 22610500
references.citation: J Natl Cancer Inst. 2013 Dec 18;105(24):1871-80
references.pmid: 24249745
references.citation: Sci Transl Med. 2013 Oct 16;5(207):207ra142
references.pmid: 24132637
references.citation: Cancer. 2013 Nov 15;119(22):3976-83
references.pmid: 24037918
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Lancet. 2012 Dec 15;380(9859):2095-128
references.pmid: 23245604
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 May;21(5):786-92
references.pmid: 22374995
references.citation: J Thorac Oncol. 2013 Jul;8(7):866-75
references.pmid: 23612465
references.citation: Chem Cent J. 2013 Feb 25;7(1):38
references.pmid: 23442334
references.citation: Am J Respir Crit Care Med. 2013 Aug 15;188(4):461-5
references.pmid: 23306547
references.citation: J Natl Cancer Inst. 2011 Jul 20;103(14):1112-22
references.pmid: 21685357
references.citation: J Clin Oncol. 2013 Dec 20;31(36):4536-43
references.pmid: 24248694
references.citation: J Proteomics. 2010 Jan 3;73(3):649-66
references.pmid: 19755178
references.citation: Chest. 2013 Apr;143(4):1117-1126
references.pmid: 23546484
references.citation: Am J Respir Crit Care Med. 2008 Nov 1;178(9):956-61
references.pmid: 18635890
references.citation: J Clin Oncol. 2007 Dec 10;25(35):5578-83
references.pmid: 18065730
references.citation: Lancet. 2013 Aug 24;382(9893):709-19
references.pmid: 23972814
references.citation: BMC Cancer. 2005 Aug 23;5:110
references.pmid: 16117833
references.citation: PLoS One. 2010 Dec 07;5(12):e15004
references.pmid: 21165148
references.citation: Nat Rev Drug Discov. 2008 Feb;7(2):168-81
references.pmid: 18167490
references.citation: J Thorac Oncol. 2012 May;7(5):924-33
references.pmid: 22722794
references.citation: J Proteome Res. 2009 Jan;8(1):113-7
references.pmid: 19072545
references.citation: Adv Exp Med Biol. 2013;735:283-300
references.pmid: 23402035
references.citation: PLoS One. 2011;6(10):e26332
references.pmid: 22022604
references.citation: N Engl J Med. 2013 Sep 5;369(10):920-31
references.pmid: 24004119
references.citation: N Engl J Med. 2009 Dec 3;361(23):2221-9
references.pmid: 19955524
references.citation: J Clin Oncol. 2010 Jun 1;28(16):2719-26
references.pmid: 20421535
references.citation: Lung Cancer. 2007 Dec;58(3):384-91
references.pmid: 17728005
references.citation: J Thorac Oncol. 2008 Jul;3(7):781-92
references.pmid: 18594326
references.citation: Clin Proteomics. 2013 Oct 02;10(1):13
references.pmid: 24088261
references.citation: Lancet Oncol. 2014 Jan;15(1):23-34
references.pmid: 24314615
references.citation: JAMA Intern Med. 2014 Feb 1;174(2):269-74
references.pmid: 24322569
references.citation: PLoS One. 2012;7(10):e46091
references.pmid: 23056237
references.citation: PLoS One. 2010 Dec 07;5(12):e15003
references.pmid: 21170350
references.citation: J Natl Cancer Inst. 2001 Jul 18;93(14):1054-61
references.pmid: 11459866
references.citation: J Thorac Oncol. 2013 Sep;8(9):1128-35
references.pmid: 23945383
references.citation: Proc Am Thorac Soc. 2008 Dec 1;5(8):811-5
references.pmid: 19017734
references.citation: Nature. 2012 Sep 27;489(7417):519-25
references.pmid: 22960745
references.citation: J Mol Biol. 2012 Oct 5;422(5):595-606
references.pmid: 22721953
references.citation: Am J Respir Crit Care Med. 2013 Apr 15;187(8):848-54
references.pmid: 23348977
references.citation: J Thorac Oncol. 2013 Jan;8(1):31-6
references.pmid: 23201823
references.citation: J Clin Oncol. 2009 Nov 1;27(31):5287-97
references.pmid: 19738110