Abstract LB116: Error-corrected plasma whole-genome sequencing for personalised and tumor-agnostic minimal residual disease detection in NSCLC

Abstract Background: Sensitive and scalable detection of circulating tumour DNA (ctDNA) is essential for minimal residual disease (MRD) assessment following curative-intent treatment in non-small cell lung cancer (NSCLC). While personalised, tumour-guided approaches are highly sensitive, they typically rely on bespoke panel design, limiting scalability and constraining the breadth of biological signals that can be interrogated. Error-corrected whole-genome sequencing (WGS) offers the potential to overcome these limitations by enabling personalised MRD detection without custom sequencing panels, while supporting genome-wide and tumour-agnostic analyses. Methods: We analysed personalised WGS-based ctDNA detection using Ultima Genomics’ ppmSeq in a TRACERx pilot cohort comprising 45 post-operative plasma samples from individuals with early-stage NSCLC during the landmark period. Landmark was previously defined as between days 10 and 120 post-operatively, prior to the start of adjuvant therapy or disease recurrence. Tumour-specific variants derived from tumour WGS were queried in genome-wide matched plasma. Plasma WGS was performed to a target coverage of 150x. Analytical sensitivity, ctDNA fraction distributions, and associations with relapse-free survival were assessed. Results: Error-corrected WGS enabled detection of tumour-informed variants at parts per million (ppm) allele fractions without bespoke panel design. Among MRD-positive samples, 13% exhibited ctDNA fractions below 10 ppm, and 72% were below 100 ppm, highlighting sensitivity across the ultra-low ctDNA range. The lowest ctDNA fraction called was 2. 2 ppm. Landmark ctDNA detection by WGS was significantly associated with relapse-free survival, with a median relapse-free survival of 23. 2 months in landmark-positive individuals (n = 37) compared with 98. 7 months in landmark-negative individuals (n = 8, log-rank p = 0. 042). Conclusions: These data provide early validation of personalised, tumour-guided ppmSeq ctDNA detection in early-stage NSCLC, with ctDNA quantification to parts per million. This approach is now being expanded to include up to 400 individuals from TRACERx (1, 500 plasma timepoints) to evaluate prognostic performance and scalability, positioning plasma WGS as a next-generation MRD platform that unifies personalised and tumour-agnostic monitoring from a single assay, including genome-wide error-corrected mutations, copy number, and fragmentation features for residual disease and relapse monitoring. Citation Format: Jonathan Wan, Sophie Ward, Alexander Azizi, Hila Benjamin, Raju Veeriah, Siân Harries, Jeanette Kittel, Nika Iremadze, Itai Rusinek, Gat Kreiger, Ariel Jaimovich, Jacqui Shaw, Allan Hackshaw, Nnennaya Kanu, Elena Helman, Mariam Jamal-Hanjani, Charles Swanton. Error-corrected plasma whole-genome sequencing for personalised and tumor-agnostic minimal residual disease detection in NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB116.