Abstract 2225: Limitations on mutation detection for early detection of cancer

Introduction: Cell-free DNA (cfDNA) has potential utility for early non-invasive detection of cancer. We assess the feasibility of cfDNA mutational assays for early detection based on their physiological and economic requirements. We further review alternative biological signals of early cancer and the potential of machine learning to integrate these signals into reliable diagnostics. Methods: A binomial model was used to assess depth and input requirements, with parameters derived from published data on cfDNA sequencing. Alternative strategies for early detection were assessed by literature review. Results: 30,000x unique coverage is required for 95% sensitivity for 1 mutant read at 0.01% variant allele frequency, requiring 180ng cfDNA input at 50% process efficiency; current sequencing costs and reimbursement levels may make such tests economically infeasible (Table). 5th percentile plasma cfDNA concentration in the screening population is ~2.3 ng/mL, requiring >140mL blood collection for test failure rate Conclusions: Mutation-detection assays may not be feasible for early cancer detection due to limited sensitivity arising from low concentrations of cfDNA, heterogeneity leading to specificity challenges, and prohibitive cost. Integrating markers beyond mutations with modern machine learning may provide a potential route to statistically robust biomarker development for early cancer detection. Table. Assay requirements for tumor liquid biopsy and mutation-based early cancer detection. Citation Format: Imran S. Haque, Gabriel Otte, Olivier Elemento. Limitations on mutation detection for early detection of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2225.