Parallel Serial Assessment of Somatic Mutation and Methylation Profile from Circulating Tumor DNA Predicts Treatment Response and Impending Disease Progression in Osimertinib-Treated Lung Adenocarcinoma Patients

Abstract

Background: Circulating tumor DNA (ctDNA) harboring tumor-specific genetic and epigenetic aberrations allows for early detection and real-time monitoring of tumor dynamics. In this study, we aimed to evaluate the potential of parallel serial assessment of somatic mutation and methylation profile in monitoring the response to osimertinib of EGFR T790M-positive advanced lung adenocarcinoma patients. Methods: Parallel somatic mutation and DNA methylation profiling was performed on a total of 85 longitudinal plasma samples obtained from eight stage IV osimertinib-treated EGFR T790M-positive lung adenocarcinoma patients. Findings: Our results revealed significant correlation between the by-patient methylation level with the maximum allele fraction (maxAF, P=0.0002). The methylation levels were significantly higher in the plasma samples of patients with detectable somatic mutations than patients without somatic mutations (P=0.0003) and healthy controls (P=0.0018). Moreover, analysis of both DNA methylation level and maxAF revealed four trends of treatment response. Collectively, the decrease in methylation level and maxAF reflected treatment efficacy, while the gradual increase reflected impending disease progression. Elevated methylation levels and maxAF were observed in six and five patients in an average lead-time of 3.0 and 1.9 months, respectively, prior to evaluation of disease progression using radiological imaging. Interpretation: DNA methylation profiling has the potential to predict disease relapse prior to being evaluated thru radiological modalities, suggesting that serial assessment of methylation level in combination with somatic mutation profiling are reliable methods for treatment monitoring and should be incorporated with imaging modalities for a more comprehensive work-up of treatment response, particularly for patients treated with targeted therapies. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (grant number 81772471 to S.Xia), Double First-Class University Plan funding of 2016 from Tongji Medical College, Huazhong University of Science and Technology (grant number 5001540022 to S.Xia) and Qinghai Science and Technology Department Funding (grant number 2017-ZJ-709 to S. Xia). Declaration of Interests: J.Ye, A.Lizaso, J.Su, H.Han-Zhang and S. Chuai are employees of Burning Rock Biotech. The other authors declare no potential conflicts of interest. Ethics Approval Statement: This study was performed according to the Helsinki Declaration of 1964 and its current amendments. The study protocol has been approved by the Ethics Committee of Huazhong University of Science and Technology (approval number: 2015L01374/2015L01373). Written informed consent was provided by all the patients included in the study.