Background While circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, the limited sensitivity of current detection methods reduces its utility for diagnosing Molecular Residual Disease (MRD) across a variety of clinical applications. Sensitive detection and quantification of MRD remains a key challenge, particularly in early-stage cancers, where timely detection of small micrometastatic lesions may enable treatment that prevents progression to advanced metastatic, incurable disease. To address these challenges, NeXT Personal was developed to deliver industry-leading MRD sensitivity in the range of 1–3 parts per million (PPM) representing a 10–100X increase over other available methods, while requiring only a single tube of blood (4 mL plasma/15ng cfDNA), and 1mm³ of FFPE tumor tissue.

Materials and Methods NeXT Personal leverages tumor/normal whole genome sequencing (WGS) to design personalized, targeted MRD liquid biopsy panels for each patient. The MRD portion of the panel is composed of up to 1800 somatic tumor variants, enabling higher sensitivity MRD detection in plasma through tracking of high quality and lower noise variants. Additionally, further content included in the panel design enables simultaneous tracking of clinically-relevant, individual variants longitudinally to enable a deeper understanding of tumor biology and its dynamic response to therapy.

Results Performance characterization using cell line dilution series and clinical samples revealed the linearity of tumor signal down to the 1–3 PPM range. Orthogonal confirmation using droplet digital PCR (ddPCR) demonstrated near-perfect concordance down to ddPCR LOD. Further, an input titration curve showed consistent performance using 5 to 50 ng of input cfDNA material from patient samples. Additionally, NeXT Personal achieved 100% MRD specificity when tested on healthy donor plasma samples.

Conclusions NeXT Personal achieved highly sensitive and specific MRD detection, reproducibly demonstrating a LOD down to 1 PPM in different cancer indications, patient sample dilutions, and cell line dilutions. The high sensitivity of NeXT Personal potentially enables MRD detection across a broad variety of cancers and stages, including typically challenging early stage, low mutational burden, and low shedding cancers. In addition to MRD, NeXT Personal tracks and annotates individual variants to advance knowledge of tumor biology and observe emergence of known clinical and resistance hotspots.

Disclosure Information M. Pruess: A. Employment (full or part-time); Significant; Personalis, Inc. E. Newburn: A. Employment (full or part-time); Significant; Personalis, Inc. S.M. Boyle: A. Employment (full or part-time); Significant; Personalis, Inc. D. Norton: A. Employment (full or part-time); Significant; Personalis, Inc. R.M. Pyke: A. Employment (full or part-time); Significant; Personalis, Inc. F. Navarro: A. Employment (full or part-time); Significant; Personalis, Inc. J. West: A. Employment (full or part-time); Significant; Personalis, Inc.. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Personalis, Inc. R. Chen: A. Employment (full or part-time); Significant; Personalis, Inc.. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Personalis, Inc..