Phil Stafford
VP, Bioinformatics

Overview: Liquid Biopsies

A blood test to decipher the molecular composition of a cancer may have been the makings of a scene in Star Trek some years ago, but today is rapidly becoming a standard-of-care approach to help guide clinical management of patients. Better known as ‘Liquid Biopsies’, these tests leverage highly-sensitive next-generation sequencing techniques for the analysis of circulating tumor DNA & RNA. Liquid biopsies have broad utility covering a wide spectrum of care in clinical oncology. The most popular application to-date has been for molecular profiling and therapeutic monitoring of patients with late-stage/metastatic disease. However emerging applications for the detection of minimal residual disease (MRD) in early-stage cancers, and as a screening modality for cancer detection sets the stage for this technology to make major inroads in improving survival outcomes.

At Caris Life Sciences, we’re very excited to announce that we will soon be launching our new liquid biopsy assay. The Caris assay will be a comprehensive whole exome and transcriptome on both DNA and RNA from plasma as well as white blood cells (buffy coat). This will enable a dual analysis of both somatic and germline alterations illuminating important information for both therapeutic decision-making and genetic predisposition. A unique feature of the assay is the incorporation of RNA which boosts sensitivity for somatic alterations and mitigates against the ‘non-shedder’ problem (i.e. low concentration of circulating tumor DNA which can plague DNA-only tests). Another unique feature is the analysis of the buffy coat which provides the aforementioned germline information but also helps mitigate against a common source of false positives in liquid biopsies; mutations from Clonal Hematopoiesis of Indeterminate Potential (CHIP). CHIP mutations are somatic alterations that occur in white blood cells that increase with age. These mutations occur in hotspot genes, where in some cases can lead to false-positive therapeutic associations. For example, a recent publication had identified that 10% of men with prostate cancer undergoing traditional liquid biopsy testing have CHIP mutations in the gene ATM that would have led to the improper use of PARP inhibitors (Jensen et al. Jama Oncology 2020). In contrast, by sequencing both the plasma and buffy coat in our new assay, we are able to better identify which mutations are true tumor-derived somatic alterations vs. CHIP.

As mentioned, liquid biopsies have had their primarily clinical application for the molecular profiling of patients with metastatic disease. In this setting, it provides a non-invasive methodology to identify actionable alterations, while also being amenable to longitudinal sampling. This longitudinal sampling allows a physician to monitor for the emergence of resistance mutations and/or new actionable alterations that evolve over time. While tissue testing remains the gold standard with its high-sensitivity and the ability to do a histological evaluation, liquid biopsy is a powerful complementary technology. For patients where tissue in not available or it is not safe to biopsy, liquid provides an effective alternative. Coupled with tissue testing, it also provides a methodology to capture genomic heterogeneity. Given that the circulation can act as a “sink” for nucleic acids derived from multiple sites of disease, it allows the potential capture of heterogeneity from different metastases in a scenario where multiple tissue biopsies would not be feasible.

More recently, an exciting application of liquid biopsy is for the detection of minimal residual disease (MRD) in early-stage cancers. Numerous studies across solid tumors have now shown that the detection of ctDNA after completion of curative-intent therapy is a strong predictor of disease recurrence. ctDNA has been shown to be more predictive of relapse beyond standard clinical parameters, including: tumor size, nodal status, grade, etc. The field has now evolved such that interventional trials in which patients are stratified by the presence of ctDNA are now underway. Lastly, liquid biopsy holds the promise of being able to detect a large variety of cancers at its earliest stages. By stage-shifting the detection of cancers, we can improve overall survival, particularly in cancers where an effective screening modality is not currently available.

Taken together the future is bright for liquid biopsies to revolutionize how cancers are diagnosed and treated. Enabling this future is the new Caris liquid biopsy assay with an unprecedented breadth simultaneously analyzing both the exome and transcriptome and versatility to detect both somatic and germline alterations.

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Milan Radovich, PhD
SVP, Chief Precision Medicine Officer
Caris Life Sciences