Development of a methylation-based, tissue-free test for the detection of molecular residual disease by circulating tumor DNA.

作者：John Paul Shen, Johannes G. Reiter, Joshua Babiarz, Preethi Srinivasan, Fei Lu, Ehsan Haghshenas, Tzu‐Chun Chen, Nathan L. Liang, Jayashree Joshi, Hsiao‐Yun Huang, Liliana Cerna, Seema Alexander, Boris A. Gutman, Garima Kushwaha, Vasily N. Aushev, Marcia Cruz‐Correa, Matthew Rabinowitz, Trupti Kawli, Alexey Aleshin, Stacey A. Cohen · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco.2025.43.16_suppl.3048 · 被引用次数：1 · 研究领域：Cancer Genomics and Diagnostics、Sarcoma Diagnosis and Treatment、Lung Cancer Treatments and Mutations

3048 Background: Clinical validation studies support tumor-informed molecular residual disease (MRD) as a prognostic biomarker for disease recurrence across multiple solid tumor types. However, these tests are not always feasible due to the occasional lack of tumor tissue for next-generation sequencing. Here, we discuss the design of a test for tissue-free (tf)MRD detection and its application to a cohort of patients with colorectal cancer (CRC). Methods: A targeted panel composed of differentially methylated regions was developed. A machine-learning model was trained on differential methylation patterns in order to classify plasma samples as MRD-positive or MRD-negative. Performance of the trained classifier was assessed in an independent cohort of 246 patients enrolled in the Bespoke CRC trial (NCT04264702). These patients had MRD results available using a tumor-informed circulating tumor DNA (ctDNA) assay (SignateraTM), of whom 163 were persistently MRD-negative without clinical progression, and 83 had MRD-positive results. Tissue-free MRD results were compared to the tumor-informed results by calculating the percent positive agreement (PPA) and negative percent agreement (NPA). Clinical outcomes (recurrence-free survival [RFS]) were evaluated based on tfMRD results in all patients and stratified based on whether the patient received adjuvant chemotherapy (ACT). Results: In this clinical cohort from Bespoke CRC (72% non-Hispanic White, 54% male, mean age 61.4±12.3 years), ...