EFIRM Liquid Biopsy Research Laboratory: Early Lung Cancer Assessment

Computed tomography (CT) is currently the most sensitive test for detecting preclinical lung cancer. The National Lung Screening Trial (NLST) demonstrated that routine low-dose CT screening reduces lung cancer mortality by 20% relative to chest radiography. However, the increased use of CT has also resulted in the discovery of an estimated 2 million screened and incidentally detected indeterminate pulmonary nodules (IPNs). These nodules, less than 30 mm in diameter, are largely benign but a proportion possess malignancy potential. Methods are urgently needed to better differentiate between individuals with benign disease and those should undergo invasive diagnostic testing. Liquid biopsy has found its way into the cancer lexicon as a reference to tumor biomarkers within blood or other readily accessible biospecimens that reflect the presence and biology of cancer. To fully mature liquid biopsy at the forefront of early cancer assessment, two frontiers must be addressed. The first is the development (discovery and validation) of comprehensive personalized cancer-specific omics targets for early detection. The second is the advancement and refinement of technologies that can detect the earliest shedding of these circulating targets. This application is Phase 2 of the EFIRM-Liquid Biopsy Research Laboratory (E-LBRL) aims to advance these two essential frontiers for early cancer assessment of indeterminate pulmonary nodules (IPNs): early detection of lung cancer. Our partnership interweaves the expertise of lung cancer biologists, clinicians, and biostatisticians with industry engineers, converging on the novel liquid biopsy technology “EFIRM-Liquid biopsy (eLB)”. Complementary to the performance of eLB, during the Phase 1 of E-LBRL, we have discovered a novel species of cell-free DNA which are ultrashort and single-stranded (uscfDNA) and contribute to a population of a large pool of Broad Range cfDNA (BRcfDNA). Unlike circulating tumor DNA which are rare or absent in early states, the uscfDNA represent global/systemic changes in cancer and can be harnessed to detect the malignancy status of the IPN. Additionally, due to their physical characteristics, these BRcfDNA biomarkers are optimal for the eLB platform. We hypothesize that signals from malignancy associated BRcfDNAs can be integrated with malignancy associated somatic mutations, differentiated methylated regions, miRNA and radiomic imaging in an integrated model termed IPN.CA to permit the earliest cancer assessment of IPN. Our industry partner together with a Biomarker Reference Lab will convert individual eLB assays to multiplex arrays for CLIA-qualification. The eLBIPN.CA and its associated inputs will be a clinically deployable Laboratory Developed Test (LDT) for early cancer assessment in IPN.