Erin Newburn, MS, PhD
Sr. Director, Field Applications Scientist

How Liquid Biopsy Technology is Changing What’s Possible in Cancer Treatment

There’s no doubt that early detection is essential for good outcomes when dealing with cancer treatment, and this is equally true when detecting disease recurrence. Patients who have already undergone extensive treatments like surgery and chemotherapy require highly-sensitive disease detection methods to ensure recurrent or metastatic disease is found as soon as possible. Traditional biopsies can be quite invasive and many patients who are already in a weakened state may not be able to undergo more time under the knife. Further, radiologic detection of disease recurrence or metastasis is non-ideal for early intervention. However, recent research and development in liquid biopsy technology is showing promise as a highly accurate and specifically non-invasive method to detect Molecular Residual Disease (MRD) in patients.

In order to understand the developing role of liquid biopsy technology in clinical trials and drug development, it’s important to have a basic understanding of how these tests work, specifically in the area of monitoring disease post diagnosis. It is well understood that cancer is a genetic disease caused by alterations to DNA, and the field continues to work to understand the biological origin and implications of these abnormalities. Some of these alterations can include mutations and modifications that affect DNA’s ability to replicate and repair itself, or promote its growth. Small portions of this altered DNA are often shed into blood circulation and referred to as circulating tumor-derived DNA, or ctDNA for short.

Researchers have found they can differentiate between ctDNA and nucleic acid from normal cells by identifying the presence of abnormalities such as “mutations, altered methylation patterns, and the presence of viral sequences.” This essentially means that medical professionals now have a second method of detecting and testing tumors aside from the traditional method of cutting into a section of the tumor itself. By testing blood, urine, saliva, pleural effusion, or spinal fluid, doctors can learn a lot about a person’s cancer without actually accessing the tumor.

There are a number of commercially-available assays which have been developed to accomplish this, many of which we refer to as “first generation” or “early generation” of liquid biopsy assays. This current generation of liquid biopsy tests have been shown to be an extremely useful tool for supplementing traditional biopsies to capture tumor heterogeneity and, in some cases, improving outcomes by detecting cancer earlier while minimizing invasiveness. Even though some liquid biopsy tests are less accurate than traditional biopsies, it’s important to remember that because of their ease of use, they can be done more frequently, helping doctors to have the best information possible at any given time in a patient’s care cycle. While these early generation tools have laid a solid foundation, additional technological advances are required to ensure that non-invasive testing has the clinical utility needed to improve patient care.

The Personalis NeXT Personal™ Approach

However, these ctDNA tests have limitations that have challenged the ability to make an impact in clinical practice, arguably the most important of which being sensitivity. Studies have shown that most available liquid biopsy tests increase in sensitivity as patients experience higher stages of malignancy. For example, a 2020 study found that sensitivity doubled from roughly 40% for stage I cancers to 80% in stage III patients. As cancers progress and tumor volumes increase, more mutant ctDNA is shed into the bloodstream, making it easier for tests to detect disease effectively. Additionally, sensitivity varies depending on cancer type, with certain cancers such as glioblastoma resulting in roughly 40% lower prevalence of ctDNA than other varieties such as small cell lung, breast, and colorectal cancers.

NeXT Personal looks to overcome these inherent challenges by providing an ultra high sensitivity MRD assay with a limit of detection at 1 part million (PPM) as shown in Figure 1. With heightened specificity and a sensitivity 10-100x greater compared to both other tumor-naive and tumor-informed MRD solutions, NeXT Personal can help clinicians have the highest chance of success diagnosing and treating patients earlier and with greater accuracy.

Figure 1: A graphic model of tumor variant allele frequency which demonstrates the relationship between ctDNA load and time post-surgery, and the impact of assay sensitivity on detection. Model Assumptions: Median breast tumor size detected by mammography: 1.3cm, Median shedding per NSCLC TRACERx study; Residual tumor from surgery: 1%; Volume doubling time (actual VAF time): 2 months. References for the figure may be found at end of post.

Specificity is also an important factor in the utility of a liquid biopsy assay. A recent study found that even methods with the highest accessible specificity at the time of publication still led to false-positive findings. The NeXT Personal approach has a high specificity in MRD performance of greater than 99.9%. Researchers can utilize NeXT Personal to track thousands of individual tumor-informed variants based on the patient’s unique tumor profile. This heightened level of specificity limits the potential for false positives while allowing physicians to more accurately assess a patient’s condition who may be in even the earliest stages of cancer development.

Lastly, tumor and plasma materials are often difficult to obtain from patients, specifically those in the initial stages of cancer development. NeXT Personal overcomes this barrier by requiring just a small blood, plasma, or cfDNA sample and 1 mm3 of tumor tissue to deliver the highest level of fully cross-referenced data. What’s more, is the ability to use the same data to continue tracking the evolution of disease as the patient’s profile changes in response to treatment or disease recurrence. This simultaneous variant tracking allows for the identification of new patient cohorts based on molecular status during clinical trials, and the tracking of neoantigen response through DNA mutations. It also allows researchers to interrogate resistance mechanisms. In the clinic, this information may enable physicians to further manage the patient’s disease by providing more information for selecting second line therapies (if available).

The next generation of liquid biopsy assays, such as NeXT Personal, are being integrated into clinical studies and trials to demonstrate the ability to solve a number of key challenges in drug development. Through collaborations with biopharmaceutical companies and investigators at leading medical centers, NeXT Personal aims to enable clinicians to provide the highest standard of care available. Whether your goals are earlier detection of recurrence, cohort enrichment of MRD positive patients, variant tracking for treatment decision making, ensuring disease detection in a broader range of indications, or developing a surrogate endpoint for analysis, you’ll find NeXT Personal to be an effective solution.

Contact us to learn more about NeXT Personal and NeXT Liquid Biopsy™.

All products described here are for Research Use Only and not for use in diagnostic procedures (except as specifically noted).

Figure 1 References:

  1. Minimum lesion detectability as a measure of PET system performance. 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 assay. Sethi et al., AACR, 2018, Abstract 4542
  3. Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer. Parikh et al, Clin Can Res. 2021
  4. 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
  5. Phylogenic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study. Abbosh et al., AACR 2020, Abstract CT023
  6. 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