Personalized and Tumor Informed Circulating Tumor DNA Assay for Molecular Residual Disease Monitoring of Solid Malignancies

ABSTRACT Emerging evidence suggests that minimal residual disease (MRD) monitoring in solid tumors has implications for prognosis, treatment response, and therapeutic intervention. However, detecting MRD requires highly sensitive and specific circulating tumor DNA (ctDNA) assays. Therefore, we developed an innovative MRD monitoring assay that offers superior performance and cost advantage. Our approach utilizes a comprehensive genomic profiling panel to characterize the patient‐specific mutational landscape of tumor tissue and selects up to 20 top‐ranked variants to design a personalized panel, which is integrated with a tumor‐naive cancer‐type‐specific fixed panel for ultra‐deep sequencing of plasma ctDNA to monitor MRD in common solid tumors. Its limit of detection at the sample level reaches as low as 0.005%, with a specificity of 100%. Furthermore, when applied to colorectal, breast, and lung cancer patients, the ctDNA‐MRD assay accurately predicted postoperative recurrence, prior to radiographic imaging by a median of 112 days for breast cancer and 83 days for lung cancer. In the tracked variants, clonal mutations demonstrated superior prognostic value compared to subclonal variants. This personalized MRD monitoring assay has the potential to enhance early detection of residual or recurrent disease, enable patient prognostic stratification, and inform clinical decision‐making for patients with common solid tumors.