Abstract 6292: Highly sensitive detection of circulating-tumor DNA in plasma using whole genome sequencing

Abstract Sensitive detection of circulating-tumor DNA (ctDNA) in plasma is increasingly utilized as a biomarker of minimal residual disease (MRD) in assessing oncology therapy response, relapse detection, and as a surrogate endpoint in clinical trials for solid tumors. Both tumor-naïve and informed MRD strategies have been described in literature, some of which are available commercially. Tumor-naïve MRD assays detect tumor-specific biomarkers in cfDNA without the patient’s tumor. Although tumor-naïve approach is beneficial in non-resectable tumor cases, tumor-informed assays are generally more sensitive. In a tumor-informed approach, the tumor-specific variants (SNV, indels, MNV, CNV, SV, methylation, etc.) are determined from a patient’s tumor and matched-normal, which are subsequently monitored in the patient’s cell-free DNA (cfDNA) using a patient-specific bespoke panel, a fixed panel, or whole genome sequencing (WGS). Amongst the tumor-informed approaches, tracking tumor mutations in cfDNA with patient-specific bespoke probes has become a popular approach due to its potential for high analytical accuracy and low sequencing cost. However, bespoke approaches require high DNA input for high accuracy, longer turnaround times, and operational complexity when running a patient-specific assay. Fixed, small panels have the potential to improve operational efficiency and reduce turnaround time. But creating a panel with high sensitivity across multiple tumor types can be a challenge due to tumor type specific mutational rates and patterns. We have developed a simple tumor-informed multi-cancer WGS method that can detect ctDNA down to 10 ppm with low DNA input requirements. WGS of a patient’s tumor and matched-normal yields a patient and tumor-specific set of somatic variants for MRD detection. These variants can then be monitored in the plasma using low-pass WGS. Because the WGS data inherently contains the genomic signatures of the tumor, additional biomarkers beyond SNVs that may be more salient of certain cancer types may be additionally assessed without the need to redesign the assay. We demonstrate that this technique can work across a range of tumor mutational burden (TMB) and various tumor types, achieving detection in the range of 10-100ppm. Citation Format: Sven Bilke, Alex Buerkle, Christine Eng, Theo Heyns, Yuka Suzuki, Yunjiao Zhu, Yuan Ding, Jacob Gibson, Artem Movsesyan, Heather Talia, Pete Taylor, Jacquelyn Truong, Jeff Tsai, Li Liu, Khai Luong. Highly sensitive detection of circulating-tumor DNA in plasma using whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6292.