Abstract
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.
Highlights
The number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide computed tomography (CT)-based lung cancer screening
We evaluated the influence of clotting time in order to deselect candidate biomarkers affected by this key step in the pre-analytical processing pathway
We investigated the effect of clotting time on the serum levels of the 9 candidate lung cancer biomarkers, determining levels in six healthy individuals after clot formation for: 0.5, 4 or 24 h
Summary
The number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide CT-based lung cancer screening. Category 4 nodules are considered “suspicious”: ≥8 to 15 mm nodules (Category 4B) have a cancer risk ≥15% and should be managed with a chest CT with/ without contrast, PET/CT and/or biopsy, depending on the risk of malignancy and comorbidities Despite these updated recommendations, invasive procedures are still performed on 44% of subjects with low-risk nodules (
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