Detecting the undetectable: The rising potential of liquid biopsies in oncology

In the past decade, a vial of blood has become a powerful window into cancer biology. Liquid biopsies, once limited to detecting specific mutations in advanced lung cancer, now offer a dynamic, real-time view of tumor genetics across multiple cancer types. This technique analyzes circulating tumor DNA (ctDNA) shed by cancer cells, providing crucial information without the need for invasive tissue sampling.

The rapid evolution of liquid biopsy technology has expanded its utility from a niche diagnostic tool to a cutting-edge technology to drive precision medicine. Improved sensitivity now allows for the detection of minute amounts of ctDNA, enabling earlier diagnosis, more precise treatment selection and closer monitoring of disease progression. As the field advances, liquid biopsies have the potential to offer personalized treatment strategies and improve patient outcomes.

The evolution of liquid biopsies in clinical practice

Liquid biopsies entered clinical practice approximately a decade ago, initially to identify driver mutations for targeted therapy selection or detect mutations associated with acquired resistance.¹ A notable example was the detection of the T790M mutation in non-small cell lung cancer, indicating the end of response to first-generation EGFR tyrosine kinase inhibitors (TKIs).²

The applications of liquid biopsies have since expanded dramatically. Beyond identifying specific driver mutations or acquired resistance, liquid biopsies now have multiple uses across various cancer types. Recent developments include quantifying disease response by analyzing tumor fraction and facilitating early cancer diagnosis.³

Technological advancements and expanded applications

The evolution of liquid biopsy is closely tied to improvements in test sensitivity. Initially limited to stage four disease where tumor cell-derived DNA is abundant, advancements in technology have enabled more sensitive assays, opening the opportunity for new applications.

One significant development is the ability to assess treatment response by measuring tumor fraction. Circulating DNA comprises tumor-derived ctDNA and DNA from normal cells. By calculating the proportion of tumor-derived DNA relative to normal cell-free DNA, clinicians can evaluate treatment response.⁴ This molecular gauge provides insights comparable to traditional imaging methods like CT scans or MRIs.

Current applications in oncology

The following techniques are among those that have been deployed to evaluate ctDNA/cfDNA:

1. Droplet digital polymerase chain reaction (ddPCR), beads, emulsion, amplification and magnetics (BEAMing)
2. Large-panel hybrid-capture next-generation sequencing (NGS)
3. Tagged-amplicon deep sequencing (TAm-Seq)
4. Cancer personalized profiling by deep sequencing (CAPP-Seq)

Optimizing adjuvant therapy

In the adjuvant setting, liquid biopsies can help determine which patients will benefit from therapy, potentially reducing unnecessary treatment and associated toxicities. This approach allows for treatment intensity adjustment based on molecular evidence of disease persistence or clearance.

Enhanced treatment response assessment

Liquid biopsies offer a more nuanced view of treatment response compared to traditional imaging. While CT scans in clinical trials often report "stable disease," this designation may not fully capture tumor dynamics. Parts of a tumor may be responding to treatment while others continue to grow. Tumor response can also be misread, as the tumor volumes may increase following treatments, associated with cell inflammation or cell death in response to the therapy. Liquid biopsies, by quantifying tumor fraction, can provide a more accurate assessment of patient response, potentially becoming a key factor in treatment decisions.

Advanced surveillance and early detection

Liquid biopsies could complement or potentially replace traditional cancer surveillance methods. Multi-cancer early detection (MCED) tests an emerging approach that utilizes DNA methylation, fragmentomics and other technologies to detect early-stage cancers regardless of their origin. This universal blood test could improve detection rates for cancers currently lacking specific surveillance methods.

Methodologies for detection of MRD

Two primary methodologies can detect minute quantities of tumor-derived DNA in circulation for minimal residual disease (MRD):

1. Tumor-informed approach: This method involves comprehensive sequencing of removed tumor tissue to identify tumor-specific mutations. These mutations serve as targets for designing specific PCR primers, enabling the detection of minimal amounts of tumor-derived DNA in plasma.
2. Tumor-agnostic approach: This technique doesn’t require access to resected tumor tissue. Instead, it relies on a combination of DNA methylation analysis and fragmentomics to identify DNA likely derived from tumors.

A new era of precision oncology

As technologies continue to evolve, liquid biopsies are set to play an increasingly central role in oncology, from early detection through treatment and beyond.

Fortrea can support trials utilizing liquid biopsies, combining therapy and response surveillance. We provide innovative solutions for long-term recurrence/survival follow-up. Using novel technologies such as tokenization, we reduce the number of patients lost to follow-up and minimize site and patient burden. Our full range of support includes assistance in defining endpoints to optimize clinical trial design. We can also help you provide screening access for underserved populations, expanding your trial's reach.

To learn more about how Fortrea can support your precision oncology trials in going from predictive to paradigm changing screening and treatment protocols of the future, contact us.

References

1. Pantel K, & Alix-Panabières C. (2010). Circulating tumour cells in cancer patients: challenges and perspectives. Trends in molecular medicine, 16(9), 398-406. https://doi.org/10.1016/j.molmed.2010.07.001
2. Walter AO, Sjin RTT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. (2013). Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer discovery, 3(12), 1404-1415. https://doi.org/10.1158/2159-8290.CD-13-0314
3. Caputo V, Ciardiello F, Corte CMD, Martini G, Troiani T, & Napolitano S. (2023). Diagnostic value of liquid biopsy in the era of precision medicine: 10 years of clinical evidence in cancer. Exploration of targeted anti-tumor therapy, 4(1), 102–138. https://doi.org/10.37349/etat.2023.00125
4. Suppan C, Brcic I, Tiran V, et al. (2019). Untargeted assessment of tumor fractions in plasma for monitoring and prognostication from metastatic breast cancer patients undergoing systemic treatment. Cancers, 11(8), 1171. https://doi.org/10.3390/cancers11081171