Originally published as JCO Early Release 10.1200/JCO.2008.19.4233 on May 4 2009

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Connective Tissue-Activating Peptide III: A Novel Blood Biomarker for Early Lung Cancer Detection

From the Division of Thoracic Surgery, Vancouver General Hospital, the University of British Columbia; Genome Science Centre and the Cancer Imaging Department, British Columbia Cancer Agency & the University of British Columbia; The James Hogg iCapture Centre & the Heart and Lung Institute at St Paul's Hospital; and the Department of Medicine, Respiratory Division, University of British Columbia, Vancouver, British Columbia, Canada.

Corresponding author: Stephen Lam, MD, FRCPC, Cancer Imaging Department, British Columbia Cancer Agency, 675 West 10 Ave, Vancouver, BC, Canada V5Z 1L3; e-mail: slam{at}bccancer.bc.ca.

Purpose There are no reliable blood biomarkers to detect early lung cancer. We used a novel strategy that allows discovery of differentially present proteins against a complex and variable background.

Methods Mass spectrometry analyses of paired pulmonary venous-radial arterial blood from 16 lung cancer patients were applied to identify plasma proteins potentially derived from the tumor microenvironment. Two differentially expressed proteins were confirmed in 64 paired venous-arterial blood samples using an immunoassay. Twenty-eight pre- and postsurgical resection peripheral blood samples and two independent, blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls) and 266 participants from the National Heart Lung and Blood Institute Lung Health Study (45 lung cancer and 221 matched controls) determined the accuracy of the two protein markers to detect subclinical lung cancer.

Results Connective tissue-activating peptide III (CTAP III)/ neutrophil activating protein-2 (NAP-2) and haptoglobin were identified to be significantly higher in venous than in arterial blood. CTAP III/NAP-2 levels decreased after tumor resection (P = .01). In two independent population cohorts, CTAP III/NAP-2 was significantly associated with lung cancer and improved the accuracy of a lung cancer risk prediction model that included age, smoking, lung function (FEV₁), and an interaction term between FEV₁ and CTAP III/NAP-2 (area under the curve, 0.84; 95% CI, 0.77 to 0.91) compared to CAPIII/NAP-2 alone.

Conclusion We identified CTAP III/NAP-2 as a novel biomarker to detect preclinical lung cancer. The study underscores the importance of applying blood biomarkers as part of a multimodal lung cancer risk prediction model instead of as stand-alone tests.

Supported in part by the Vancouver Coastal Health Research Institute "In-it-for-Life" grant (J.Y., S.L.), Canadian Institutes of Health Research grant (D.D.S., S.F.P.), Grants No. 1PO1-CA96964 and U01CA96109 from the National Institutes of Health, and National Cancer Institute contract N01-CN-85188 (S.L.), grant No. CA105304 (M.D.S.), and the British Columbia Cancer Agency MDS-Rix Endowment fund (S.L.); the Lung Health Study was sponsored by a N01-HR-46002 contract from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute.

Presented in part the International Lung Cancer Conference, Liverpool, United Kingdom, July 9-12, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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