Driver Mutation Variant Allele Frequency in Circulating Tumor DNA and Association with Clinical Outcome in Patients with Non–Small Cell Lung Cancer and EGFR- and KRAS-Mutated Tumors

• Published in: The Journal of molecular diagnostics : JMD Vol. 24; no. 5; pp. 543 - 553
• Main Authors: Li, Meijuan, Yang, Lei, Hughes, Jason, van den Hout, Allison, Burns, Christine, Woodhouse, Ryan, Dennis, Lucas, Hegde, Priti, Oxnard, Geoffery R., Vietz, Christine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2022
• Subjects: Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell-Free Nucleic Acids; Circulating Tumor DNA - genetics; ErbB Receptors - genetics; Gene Frequency; High-Throughput Nucleotide Sequencing - methods; Humans; Lung Neoplasms - diagnosis; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mutation; Proto-Oncogene Proteins p21(ras) - genetics
• ISSN: 1525-1578; 1943-7811
• DOI: 10.1016/j.jmoldx.2022.02.002

Clinical implementation of mutational analysis for next-generation sequencing–based assays has largely been of a binary nature, with pathogenic mutations being reported as either positive or negative. Actionability on the continuous output of variant allele frequency (VAF) has not been well characterized in the clinical setting, thus limiting its use. In this study, analytical validity and performance of the short variant VAF based on a next-generation sequencing–based liquid biopsy assay, FoundationOne Liquid CDx, were evaluated through assessment of precision, analytical accuracy, limit of blank, and limit of detection. Analytical validation of VAF values measured by using FoundationOne Liquid CDx supports that these values are accurate, precise, robust, and linear with the true VAF value. The association of allele frequency of clinically relevant short variants in circulating-free DNA and the association with overall survival for patients using real-world data were also assessed. The results of the association analysis indicate that VAF of the predictive biomarker mutation negatively correlates with overall survival of patients with non–small cell lung cancer.