Abstract
BackgroundThe National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung) to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT.Recent advances in high throughput (HTP) cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV)).Methods and FindingsSerum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165). Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7).ConclusionThis is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT-Lung test, and so further aid the early detection of lung cancer.
Highlights
The role of the immune system in carcinogenesis remains incompletely understood despite decades of research
This is a practical example of the value of investing resources to develop a high throughput (HTP) technology
Such technology may lead to improvement in the clinical utility of the EarlyCDT--Lung test, and so further aid the early detection of lung cancer
Summary
The role of the immune system in carcinogenesis remains incompletely understood despite decades of research It is known, that a patient may display a specific host immune response to tumor cells and that this may have implications for tumor progression [1]. Humoral responses to cancer-associated antigens are well documented [2] and detecting autoantibodies (AAb) could lead to new insights into this process of carcinogenesis as well as provide biomarkers for early detection of cancer and subsequent patient management. For instance the recently published findings of the National Lung Screening Trial (NLST) in the USA showed that early detection of lung cancer using low dose spiral computed tomography (CT) screening led to a 20% reduction in lung cancer mortality [3]. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and positive predictive value, (PPV))
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