The use of circulating tumor-derived DNA (ctDNA) as a predictive biomarker for molecular residual disease (MRD) following treatment for solid tumors is rapidly being integrated into clinical trial design, translational research studies, and is at the precipice of use in routine clinical care. While detection methods for ctDNA have rapidly advanced, the limited sensitivity of these detection methods reduces its utility for diagnosing MRD across a variety of clinical applications. Standard-of-care (SOC) radiological-based technologies, including CT, PET and MRI scans, also remain limited in their ability to detect residual disease during or after surgical or systemic therapy due to the minimum tumor volume required.1 Therefore reliable, 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, an advanced, tumor-informed liquid biopsy assay, was developed to deliver industry-leading MRD sensitivity in the range of 1-3 parts per million (PPM) representing a 10X-100X increase over other available methods. NeXT Personal is sample sparing, requiring only a single tube of blood (4mL plasma/15ng cfDNA), and 1mm3 of FFPE tumor tissue (Figure 1, 2).

Figure 1: MRD Sensitivity: Targeting Detection at the Earliest Timepoints

Model Assumptions: Median breast tumor size detected by mammography: 1.3cm, Median shedding per NSCLC TRACERx study6; Residual tumor from surgery: 1%; Volume doubling time (actual VAF time): 2 months

In the biopharma setting, MRD is rapidly emerging as a key biomarker in therapy development, whereby more sensitive detection and quantification of MRD may provide substantial benefits versus less sensitive methods through the reduction of false negative detection of cancer. These benefits include:

  • More efficient cohort enrichment of study participants that are MRD positive
  • Faster time to surrogate endpoint analysis through earlier detection of MRD
  • Enhanced accuracy of recurrence and survival risk
  • Greater resolution of therapy response

Figure 2: NeXT Personal: Advanced, Higher Sensitivity, Personalized, Tumor-Informed Liquid Biopsy for MRD & Variant Tracking

Unique Assay Design Provides Unprecedented Insights Into Longitudinal Disease Monitoring

While the MRD component of NeXT Personal provides a highly sensitive and aggregated measurement of tumor burden in plasma, the ability to simultaneously track individual variants longitudinally can also be utilized to further our understanding of tumor biology and its dynamic response to therapy. Therefore, in addition to MRD, NeXT Personal provides the ability to track and annotate individual variants over the whole evolution of a cancer patient’s trajectory in a single panel design. Variants tracked by NeXT Personal in the blood are derived from those detected in the tissue, as well as those specified for panel inclusion by the user (Figure 3).

Figure 3: NeXT Personal Assay Features: Advanced, higher sensitivity, personalized, tumor-informed liquid biopsy for MRD & Variant Tracking

For every panel, NeXT Personal boasts the capacity to include up to 400 SNVs detected in the tumor to track in plasma. NeXT Personal automatically filters for variants that lie in coding regions of clinically relevant genes, prioritizing those in genes with known relevance to cancer. This ensures that the most biologically and clinically important variants are tracked longitudinally to deliver insights on evolving tumor biology (Figure 3.2).

Similarly, variants not detected in the tumor may also be added during the panel design process. As custom content, users may define their own set of variants that may be representative of known clinical hotspots (ex. EGFR T790M), resistance hotspots, driver mutations (which may allow detection of a second primary tumor), or other therapy-specific and biologically important variants studied or monitored in clinical research. Capacity for user supplied content can include up to thousands of variants. Alternatively, users may also leverage clinically relevant content developed and curated by Personalis in addition to, or instead of, user-supplied content (Figure 3.3).

Combining ImmunoID NeXT™ and NeXT Personal Yields Multidimensional View Into Tumor Biology

In addition to NeXT Personal, Personalis’ flagship tissue-based immunogenomics platform, ImmunoID NeXT, may also be run from the same tissue sample with no additional tumor material required. For the first time, investigators can comprehensively characterize both the tumor- and immune-related components of the tumor microenvironment while still retaining the ability to longitudinally monitor MRD and variants in the blood with industry-leading sensitivity, even in sample-limited scenarios.

Deep Sequencing
~100,000X raw coverage for plasma is performed across 1,800 loci, enabling sequencing dollars to be directed to variants of highest value. >30X WGS coverage for tumor and normal tissue is performed to detect SNVs for targeted panel inclusion.
Industry Leading MRD Performance
1-3 PPM MRD LOD is 10X-100X more analytically sensitive than other MRD solutions on the market, aiding the detection of MRD and recurrence at the earliest timepoints. ≥99.9% specificity minimizes the rate of false positive results.
Assay Multifunctionality
NeXT Personal is not just an MRD solution: In addition to MRD, NeXT Personal tracks and annotates individual variants — those that are detected in the tumor, and those specified for panel inclusion by the user — to advance knowledge of tumor biology and observe emergence of known clinical and resistance hotspots.
Low Input Sample Requirements
NeXT Personal requires only 15ng of cfDNA, or 1 tube of blood (4mL of plasma), to deliver exceptional performance. Additionally, Personalis’ protocols enable flexible sample formats — blood, plasma, and cfDNA — to be processed in the lab. Additionally, as little as 1mm3 of FFPE tumor tissue is required for WGS.
Advanced Error Suppression
Robust, proprietary error suppression techniques reduce the error rate from sequencing, PCR and other sample processing steps.
Panel Identification
Included in every NeXT Personal design, Personalis deploys a SNP-based quality control measure to ensure a patient’s panel is never mixed with another patient’s sample.
Personalis-Provided Panel Content
Personalis provides the option to include a carefully curated list of clinically actionable and resistance hotspots in addition to or in the absence of panel content specified by the user.

References

  1. Minimum lesion detectability as a measure of PET system Adler et al., EJNMMI Physics, 2017
  2. Analytical validation of the Signatera™ RUO assay, a highly sensitive patient-specific multiplex PCR NGS-based noninvasive cancer recurrence detection and therapy monitoring Sethi et al., AACR, 2018, Abstract 4542
  3. Genome-wide circulating tumor DNA monitoring for bladder cancer treatment management and organ Nordentoft et al., ASCO 2021, Abstract e16527
  4. Phylogenic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx Abbosh et al., AACR 2020, Abstract CT023
  5. Analytical development of the RaDaR™ assay, a highly sensitive and specific assay for the monitoring of minimal residual disease. Marsico et al., AACR 2020, Poster 309
  6. Phylogenic ctDNA analysis depicts early-stage lung cancer Abbosh et al., Nature, 2017

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