Complementing Tumor Tissue Profiling with Plasma-based Global Resolution

In the era of precision medicine, liquid biopsies are being increasingly integrated into clinical trial design, translational research studies, and clinical testing regimens. Solid tumor biopsies remain the gold-standard for the interrogation of the cancer genome, however the advent of liquid biopsies and multi-region tissue sampling has demonstrated that there can be more to a cancer’s genomic profile than that found in a single site biopsy.1 Moreover, the ease and non-invasive nature of the liquid biopsy facilitates multi-timepoint sampling to observe tumor evolution in real time.

However, the liquid biopsy alone may not capture all tumor variants if healthy cancer cells do not shed their contents into blood circulation.

NeXT Liquid Biopsy™, a first-of-its-kind, high-performance, exome-wide liquid biopsy assay, is designed to complement Personalis’ flagship tissue-based immunogenomics platform, ImmunoID NeXT™, providing a comprehensive platform to further enhance the development of more efficacious cancer therapies in later-stage solid tumor indications. By combining NeXT Liquid Biopsy with ImmunoID NeXT, researchers now have a powerful tool to overcome the complexities of spatial and temporal heterogeneity, longitudinally monitor clonal and subclonal dynamics, and interrogate mechanisms of acquired resistance at or before cancer progression (Figure 1).

Additionally, by virtue of a whole-exome approach, NeXT Liquid Biopsy provides researchers a unique ability to explore key areas of tumor biology that may not be accessible through focused, targeted panels.

Figure 1:

Enabling Multiple Applications Exome-Wide

  • Assess tumor heterogeneity

    A predominant hallmark of cancer is heterogeneity, which can occur both across and within disease sites (spatial) as well as during the course of its evolution (temporal). As a result, tumors (and their metastases) are composed of a diverse collection of cells that may harbor distinct molecular signatures, differing driver and passenger mutations, and biomarker statuses, all of which can contribute to the development of therapy resistance. Therefore, an accurate assessment of tumor heterogeneity can prove essential to the development of effective therapies.

    NeXT Liquid Biopsy exploits the inherent biology associated with cellular turnover in the tumor by capturing circulating DNA molecules shed into the blood. This DNA is potentially representative of multiple regions of the primary tumor and/or distant metastases, thus complementing results from ImmunoID NeXT.

  • Monitor clonal evolution and tumor dynamics in response to therapy

    Serial sampling of the tumor genome is required to determine why certain patients respond well to therapy, while others do not2. However, serial tissue biopsies are invasive and often unattainable, and even if serial biopsies are obtained, these are limited both spatially and temporally. Following a comprehensive assessment of the mutational landscape with ImmunoID NeXT at baseline, NeXT Liquid Biopsy enables the exome-wide monitoring of both clonal and sub-clonal variants so that investigators have an extensive view of how the cancer evolves in response to therapy (Figure 2).

Figure 2: Typical Study Configuration

  • Interrogate mechanisms of intrinsic and acquired resistance

    Insights into the genomic landscape of some cancers have fueled a shift in the treatment paradigm towards the use of personalized (genotype and/or tumor microenvironment-guided) approaches. Yet, in the cases where these therapeutic modalities produce dramatic initial responses, the majority of these tumors develop resistance and ultimately progress.3

    Interrogating resistance mechanisms at cancer progression with a cfWES approach has led to the discovery of novel resistance pathways, with profound implications for new therapeutic strategies.3 NeXT Liquid Biopsy provides a non-invasive approach which can be used before, at, and after progression to comprehensively analyze the landscape of alterations that can lead to resistance.

  • Go beyond targeted panels

    The majority of commercially-available liquid biopsy panels employ a targeted genomic footprint to interrogate a collection of known, well-established oncogenic driver and tumor suppressor genes. While monitoring these genes is important in many therapeutic strategies, these panels often do not capture key areas of tumor biology responsible for conferring survival advantages, for the emergence of subclones, and ultimately for the development therapeutic resistance and relapse. Thus, a global understanding of tumor dynamics is essential for the development of effective and durable therapeutic strategies. NeXT Liquid Biopsy overcomes these challenges by capturing all ~20,000 protein-coding genes of the human genome, providing oncology translational and clinical researchers with a unique opportunity to explore important areas of tumor biology not accessible through targeted panel approaches (Figure 3).

Figure 3: 

Deep Sequencing
~2,000X mean coverage across the entire ~20,000-gene DNA footprint, as well as boosted
~5,000 mean coverage across ~247 cancer-related genes to deliver enhanced sensitivity.
Augmented Coverage
NeXT Liquid Biopsy utilizes our proprietary ACE Technology to provide augmented coverage of difficult-to-sequence gene regions across the entire ~20,000-gene footprint.
Advanced Error Suppression
Our robust variant filtration process integrates both proprietary and publicly-available tools to generate high-confidence variant calls and reduce background noise attributed to normal circulating DNA.
Fully Integrated with ImmunoID NeXT
Variants detected from both the tissue and plasma, and at all timepoints, are integrated into a single report, facilitating the interrogation of the entire mutational landscape at baseline, and the longitudinal analysis of both plasma-specific and tissue-specific alterations.
De Novo and Monitoring Analysis Modes
De Novo mode reports plasma-specific variants at all time points, while Monitoring mode reports variants found in the solid tumor and/or at previous timepoints, which is important for longitudinally tracking therapy response and tumor evolution.
Compatible Sample Requirements
Personalis’ protocols enable flexible sample formats – blood, plasma, or cell-free DNA – to be processed within the lab, requiring as little as 50ng cfDNA per sample.
  • Brochure, NeXT Liquid Biopsy
  • Spec Sheet, NeXT Liquid Biopsy
  • ASCO 2020 Poster: Exome scale liquid biopsy characterization of putative neoantigens and genomic biomarkers pre- and post anti-PD-1 therapy in squamous cell carcinoma of the head and neck
  • AACR 2020 Poster: Enhanced Whole Exome Profiling of Tumor Circulating Cell-Free DNA Enables Sensitive Assessment of Tumor Mutations

References

  1. Tumor Heterogeneity and Resistance to Cancer Therapies. Dagogo-Jack et al. Nature Reviews, 2017.
  2. The Implications of Clonal Genome Evolution for Cancer Medicine. Apraricio et al., New England Journal of Medicine, 2013.
  3. Polytherapy and Targeted Cancer Drug Resistance. Chatterjee N, et al. Trends Cancer. 2019.
  4. Liquid Versus Tissue Biopsy for Detecting Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers. Parikh et al. Nature Medicine. 2019.

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