Clinical validation of a blood-based classifier for diagnostic evaluation of asymptomatic individuals with pulmonary nodulesReport as inadecuate

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Clinical Proteomics

, 14:25

First Online: 05 July 2017Received: 06 April 2017Accepted: 10 June 2017


BackgroundThe number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide CT-based lung cancer screening. Given the low specificity of CT screening, non-invasive adjuvant methods are needed to differentiate cancerous lesions from benign nodules to help avoid unnecessary invasive procedures in the asymptomatic population. We have constructed a serum-based multi-biomarker panel and assessed its clinical accuracy in a retrospective analysis of samples collected from participants with suspicious radiographic findings in the Prostate, Lung, Chest and Ovarian PLCO cancer screening trial.

MethodsStarting with a set of 9 candidate biomarkers, we identified 8 that exhibited limited pre-analytical variability with increasing clotting time, a key pre-analytical variable associated with the collection of serum. These 8 biomarkers were evaluated in a training study consisting of 95 stage I NSCLC patients and 186 smoker controls where a 5-biomarker pulmonary nodule classifier PNC was selected. The clinical accuracy of the PNC was determined in a blinded study of asymptomatic individuals comprising 119 confirmed malignant nodule cases and 119 benign nodule controls selected from the PLCO screening trial.

ResultsA PNC comprising 5 biomarkers: CEA, CYFRA 21-1, OPN, SCC, and TFPI, was selected in the training study. In an independent validation study, the PNC resolved lung cancer cases from benign nodule controls with an AUC of 0.653 p < 0.0001. CEA and CYFRA 21-1, two of the markers included in the PNC, also accurately distinguished malignant lesions from benign controls.

ConclusionsA 5-biomarker blood test has been developed for the diagnostic evaluation of asymptomatic individuals with solitary pulmonary nodules.

KeywordsLung cancer screening Indeterminate pulmonary nodules Biomarker Serum Asymptomatic AbbreviationsAUCarea under curve

CTcomputed tomography

CEAcarcinoembryonic antigen-related cell adhesion molecule 5

CMSCenters for Medicare and Medicaid Services

ctDNAcirculating tumor DNA

CYFRA 21-1cytokeratin-19 fragment

ELISAenzyme-linked immunosorbent assay

FDG-PETfluoro deoxy glucose-positron emission tomography


MMP2matrix metalloproteinase-2

NLSTNational Lung Screening Trial

NPVnegative predictive value

NSCLCnon-small cell lung cancer


PLCOProstate, Lung, Chest and Ovarian

PNCpulmonary nodule classifier

PPVpositive predictive value

SCCsquamous cell carcinoma antigen

TFPItissue factor pathway inhibitor

TIMP1tissue inhibitor of metalloproteinases-1

USPSTFUS Preventive Services Task Force

Electronic supplementary materialThe online version of this article doi:10.1186-s12014-017-9158-9 contains supplementary material, which is available to authorized users.

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Author: Charles E. Birse - Jennifer L. Tomic - Harvey I. Pass - William N. Rom - Robert J. Lagier


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