Development of a Multiplexed Tumor-Associated Autoantibody-Based Blood Test for the Detection of Non–Small Cell Lung Cancer

Abstract

Purpose: Non-small cell lung cancer (NSCLC) has an overall 5-year survival of <15%; however, the 5-year survival for stage I disease is over 50%. Unfortunately, 75% of NSCLC is diagnosed at an advanced stage not amenable to surgery. A convenient serum assay capable of unambiguously identifying patients with NSCLC may provide an ideal diagnostic measure to complement computed tomography-based screening protocols.Experimental Design: Standard immunoproteomic method was used to assess differences in circulating autoantibodies among lung adenocarcinoma patients relative to cancer-free controls. Candidate autoantibodies identified by these discovery phase studies were translated into Luminex-based "direct-capture" immunobead assays along with 10 autoantigens with previously reported diagnostic value. These assays were then used to evaluate a second patient cohort composed of four discrete populations, including: 117 NSCLC (81 T 1-2 N 0 M 0 and 36 T 1-2 N 1-2 M 0 ), 30 chronic obstructive pulmonary disorder (COPD)/ asthma, 13 nonmalignant lung nodule, and 31 "normal" controls. Multivariate statistical methods were then used to identify the optimal combination of biomarkers for classifying patient disease status and develop a convenient algorithm for this purpose.Results: Our immunoproteomic-based biomarker discovery efforts yielded 16 autoantibodies differentially expressed in NSCLC versus control serum. Thirteen of the 25 analytes tested showed statistical significance (Mann-Whitney P < 0.05 and a receiver operator characteristic "area under the curve" over 0.65) when evaluated against a second patient cohort. Multivariate statistical analyses identified a six-biomarker panel with only a 7% misclassification rate.Conclusions: We developed a six-autoantibody algorithm for detecting cases of NSCLC among several high-risk populations. Population-based validation studies are now required to assign the true value of this tool for identifying early-stage NSCLC. Clin Cancer Res; 16(13); 3452-62. ©2010 AACR.Lung cancer remains the leading cause of cancer death nationwide, with ∼160,000 deaths predicted in the United States in 2009 (1). Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers and has a poor overall 5-year survival rate of ∼15% (2-4). This low survival rate is largely attributed to the fact that >75% of patients present with local or distant metastasis at diagnosis, which are associated with a 21% and 3% 5-year survival, respectively (2,3,5). In contrast to these dismal figures, stage I disease is associated with a 50% to 67% 5-year survival but accounts for only 15% of patients (2). This suggests that if patients could be diagnosed at an earlier stage, when a complete surgical resection offers the greatest potential for a cure, the mortality associated with this disease could be reduced.To that end, considerable efforts have been undertaken to produce an effective screening method for early NSCLC. In the 1950s, trials of chest X-rays alone or in combination with sputum analysis were com...

Pentraxin-3 Is a Novel Biomarker of Lung Carcinoma

“…Recently, we and others have used proteomic approaches to identify biomarkers for various cancer types (14)(15)(16)(17)(18)(19)(20). In our own proteomic effort, we identified 5 candidate markers that appear to be elevated in serum of lung cancer patients, in comparison to control subjects (6).…”

Serum-based protein biomarkers for detection of lung cancer

“…It has also been applied to early detection and treatment of cancers of the ovary, pancreas, prostate, oesophagus, breast, liver and rectum [21][22][23][24].…”

“…However, despite many leads, little has been done to validate these findings and to translate these promising antibodies into clinically usable tests. Farlow et al [23] identified and validated a large number of potential tumor autoantibodies for NSCLC. Three of these autoantibodies (MTAP, fumarate hydratase and endoplasmic reticulum protein 29) represent new autoantigen targets for distinguishing NSCLC from control populations.…”

Development of Autoantibody Signatures as Biomarkers for Early Detection of Colorectal Carcinoma

“…Autoantibodies to known or unknown tumor-associated antigens (TAA) are present in sera of patients with some malignancies (7)(8)(9)(10)(11)(12)(13)(14). Various technologies such as serologic analysis of recombinant cDNA expression libraries (SEREX), phage display, and protein arrays have been used to identify autoantibody signatures for cancer diagnosis (14)(15)(16)(17)(18)(19).…”