Liquid biopsy in combination with PET/CT versus PET/CT alone in diagnosis of lung cancer in small nodules.
Authors: Shah Rajesh , Lim Jing Shan , Hum Yee Fang , Ho Jia Min , Manfredi Luisa , Paintal Harman , Segall George , Vasanawala Minal , Das Millie 
Published: June 2023

3072 Background: In the National Lung Screening Trial, almost two-thirds of patients that underwent an invasive procedure for diagnosis had benign findings, suggesting a significant number of patients were exposed to risk that could be avoided. Currently, to help distinguish malignant from benign nodules, Positron Emission Tomography/Computed Tomography (PET/CT) is used. However, PET/CT can be limited in its use for lesions less than 2 cm in size. The detection of circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) in the blood stream via liquid biopsy has demonstrated potential as a non-invasive approach in both screening and diagnostic tests. The purpose of this study is to assess whether combining liquid biopsy with PET/CT findings can better detect malignancy in small lung nodules 6-20 mm in size compared to PET/CT alone, possibly allowing earlier cancer detection and reduction in unneeded invasive diagnostic testing. Methods: This was a single-center prospective observational study for which the primary objective was to compare liquid biopsy plus PET/CT to PET/CT alone for detection of lung cancer in patients with newly discovered or newly growing solid lung nodules. Patients with nodules 6-20 mm in size who were scheduled to undergo 18F-Fluorodeoxyglucose PET/CT also underwent blood collection for plasma ctDNA/cfDNA testing using an amplicon-based next-generation sequencing assay incorporating molecular barcodes for error suppression. Tumor diagnosis was based on resolution of the nodule or tissue biopsy. For liquid biopsy, a multiomic model previously built using (1) cfDNA methylation frequencies, (2) ctDNA abundance, (3) somatic ctDNA mutations, and (4) cfDNA fragment size ratio was used to predict malignancy. For imaging, lesions with a maximum standardized uptake value of 2 or greater were considered malignant. Results: Between December 2021 and November 2022, 24 patients were enrolled. Of these, 13 had a definitive diagnosis and were included in the analysis with the remainder still undergoing serial imaging follow-up. Of the 13 patients, 9 were biopsy or surgically proven to be malignant, and 4 were benign based on biopsy or resolution. The median (IQR) nodule size was 14 mm (8-15). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for PET/CT were 0.67, 1, 1, and 0.57, respectively. For multiomic liquid biopsy alone, these values were the same. However, combining multiomic liquid biopsy and PET/CT, the sensitivity, specificity, PPV, and NPV were 0.89, 1, 1, and 0.8, respectively. Conclusions: Combining multiomic liquid biopsy with PET/CT results in improved sensitivity for the detection of early-stage malignant solid lung nodules by 33% compared to PET/CT alone with no reduction in specificity. This could result in improved selection of patients requiring biopsy. Further evaluation with a larger cohort is needed to confirm the findings.