A multivariate cell-based assay for blood-based diagnostics enhances lung cancer risk stratification

Area of Science:

• Biotechnology
• Molecular Diagnostics
• Cancer Research

Background:

• Blood biomarkers often suffer from low signal-to-noise ratios, hindering accurate disease detection.
• Current methods for managing indeterminate pulmonary nodules in lung cancer screening have limitations.
• There is a need for innovative, scalable, and cost-effective diagnostic tools for early cancer detection.

Purpose of the Study:

• To develop and validate the lung cancer indicator cell assay platform (LC-iCAP) as a blood-based test for early lung cancer detection.
• To assess the clinical utility of LC-iCAP in managing indeterminate pulmonary nodules identified via computed tomography (CT) screening.
• To evaluate the reproducibility and mechanistic relevance of the LC-iCAP assay.

Main Methods:

• Development of the LC-iCAP assay utilizing cultured cells as biosensors to detect cancer signals in patient serum.
• Machine learning analysis of gene expression profiles from indicator cells for disease classification.
• Prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) study design for performance assessment, including analytical optimization and reproducibility testing.
• Integration of LC-iCAP assay readout with CT-based features for enhanced clinical utility assessment.

Main Results:

• LC-iCAP achieved an AUC of 0.64 in ROC curve validation.
• Post-validation integration with CT features improved clinical utility, showing 90% sensitivity, 64% specificity, and 95% negative predictive value.
• The assay demonstrated reproducibility across different cell lineages and identified a lung-cancer specific transcriptional response enriched for hypoxia-responsive genes.
• The LC-iCAP platform showed improved specificity compared to existing tests for lung cancer risk classification.

Conclusions:

• LC-iCAP is a validated, scalable, and cost-effective platform for blood-based diagnostics with potential for early cancer detection.
• The assay demonstrates clinical utility in managing indeterminate pulmonary nodules and shows promise as a next-generation platform for precision medicine.
• The identified lung-cancer specific transcriptional response highlights the platform's mechanistic relevance and potential for multi-cancer screening and drug development.