Liquid Biopsies: Paving the Way for More Personalized and Responsive Cancer Care

In the ongoing battle against cancer, early detection remains crucial for improving treatment outcomes and survival rates. Liquid biopsies offer a less invasive, yet highly informative, alternative to traditional diagnostic methods that have primarily relied on tissue biopsies and imaging. This article examines how liquid biopsies are aiding cancer drug development and guiding treatment strategies.

Tumors can shed cells (circulating tumor cells, CTCs), cell-free nucleic acids (circulating tumor DNA, ctDNA, and RNA, ctRNA) as well as tumor-derived extracellular vesicles (EVs) into the blood. The analysis of these cancer traces in blood samples can provide invaluable information about disease recurrence and response to treatment. Advances in technologies such as digital droplet PCR, next-generation sequencing and microfluidics are enabling clinicians to detect and characterize ever-smaller numbers of CTCs and minute amounts of ctDNA and ctRNA in blood.

Professor Klaus Pantel, chairman of the Institute for Tumor Biology at the Medical School of the University of Hamburg, Germany, and Catherine Alix-Panabières, professor of oncology at the University of Montpellier, France, first coined the term “liquid biopsy” in 2010.¹ “We had no idea that it would become so widely used or such a popular field!” Pantel said.

Pantel has been examining the blood of patients with cancer for over 30 years. Some tumors return many years after surgical removal or treatment of the primary tumor, but as he explained, “cancer is not an infectious disease; the cells responsible for recurrence are in the body.” The challenge is detecting them before they form secondary tumors or metastases. Pantel and his team work with methods that are sensitive enough to detect the earliest signs of recurrence or metastasis in blood, before they can be spotted by imaging technologies.

Their early studies showed that the presence of disseminated tumor cells in the bone marrow of patients with breast cancer was associated with an increased risk for local recurrence and distant metastasis.² However, obtaining bone marrow samples requires a trained physician and local anesthesia, and is not without complications, pain being the most frequently reported one.

Compared to a bone marrow biopsy or any other type of tissue biopsy – which often requires surgery and is not always feasible – liquid biopsies entail a simple blood draw. They can be done quickly and are easily repeatable so are better for tracking changes in the tumor over time compared with tissue samples or scans.

Current status of liquid biopsy in cancer

At present, liquid biopsies are used for the early detection of recurrence and monitoring patients with advanced cancer. While the number of CTCs can be indicative of whether a treatment is working, CTC characteristics can aid treatment decisions. For example, the discovery of CTCs expressing the human epidermal growth factor receptor 2 (HER2) protein in patients with HER2-negative tumors suggests that they could benefit from HER2-directed treatment.³

Vivek Subbiah, medical oncologist and chief of early-phase drug development at Sarah Cannon Research Institute (SCRI) in Nashville, USA, has been closely following the concurrent evolution of liquid biopsy technologies and precision cancer medicines. In addition to the non-invasive nature of liquid biopsies and their ability to detect minimal residual disease (MRD), he highlights the benefits of being able to use next-generation sequencing of cell-free DNA (cfDNA) and track tumor evolution in real-time. These features are crucial for selecting, switching or combining specific targeted therapies.

Liquid biopsies also offer insights into emerging genomic alterations and tumor evolution under the selective pressure of immunotherapy. “When the cancer has spread, just looking at the cells from one site will not capture the tumor’s heterogeneity and clonal evolution,” Subbiah explained.

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He is impressed by the possibility of identifying actionable mutations much faster using a liquid biopsy compared to a tissue biopsy. “It can take at least three weeks to schedule and obtain the results of a tissue biopsy, whereas with liquid biopsies, we can identify patients eligible for targeted therapies within five to seven days,” he said. This allows patients to start treatment sooner and could lead to better outcomes in patients with cancers for which there are many approved targeted therapies, such as lung cancer.

Applying ultra-deep sequencing to improve the sensitivity of ctDNA detection and the use of other “omic” approaches, such as proteomics, transcriptomics and epigenomics, is helping researchers build a more comprehensive picture of a patient’s tumor. Subbiah expects the clinical potential of liquid biopsies to expand as omic data is combined in multiomic analyses and AI becomes integrated to enhance the interpretation of liquid biopsy data. “By improving diagnostic accuracy and our understanding of tumor behavior and drug resistance mechanisms, liquid biopsy is pushing the boundaries of oncology,” he said.

Hurdles to integration into clinical workflows

Despite evidence of their clinical utility, liquid biopsies are not routinely used. They are not included in clinical practice guidelines nor refunded by major health providers. Detecting low frequency mutations in early-stage cancer remains challenging. But the biggest issue is standardization.

Both Pantel and Subbiah agree that there is an urgent need for standardized protocols for sample collection, processing and analysis to ensure reproducibility and accuracy across platforms and different types of cancer.

“Regulatory bodies need to provide clear frameworks for the approval and use of liquid biopsy assays in oncology,” Subbiah said. This includes defining their role in the treatment decision-making process alongside traditional imaging and biomarker data.

Subbiah is contributing to these efforts by working with colleagues on the development of Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST).⁴ The current criteria for assessing solid tumor response to chemotherapy and targeted therapy relies on imaging technologies to detect changes in tumor volume. Although there is growing evidence that measuring changes in ctDNA through liquid biopsies can predict tumor responses before gross size changes are evident, regardless of the type of therapy, various issues related to the implementation of LB-RECIST remain.

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In a recent review, Subbiah and colleagues outline some of the biological, clinical and regulatory challenges that need to be addressed to achieve pan-cancer standardization.⁵ Their proposed prospective study design to better understand how ctDNA changes can help prevent the unnecessary continuation of treatment, is increasingly being adopted in clinical trials.

Collaboration is crucial to bridge the gap between the research world and the clinic. Academic researchers, oncologists, regulatory bodies, patients, pharmaceutical and sequencing companies themselves, need to work together to establish standards and guidelines. The European Liquid Biopsy Society (ELBS), founded and chaired by Pantel, comprises over 90 academic and industry partners. In collaboration with healthcare authorities and patient advocacy groups, ELBS is addressing the clinical, technological and regulatory issues preventing the routine use of liquid biopsies.

“The implementation of research findings doesn’t happen by itself, but it is crucial for patients to benefit from our discoveries,” he said. At present, ELBS primarily focuses on cancer, but there are plans to expand its scope to other areas of liquid biopsy research, such as cardiovascular or inflammatory diseases in the future.

Future outlook

As more sensitive technologies and automated workflows enable laboratories to process large numbers of samples efficiently, Subbiah expects that liquid biopsies will become part of the standard care for early cancer detection, diagnosis, prognosis and treatment monitoring.

By combining CTC, ctDNA and ctRNA analyses with EV and immune cell analyses, researchers are starting to glean more details of cancer cell metabolism and of the tumor microenvironment. Such information is helping to identify new therapeutic targets and treatment approaches, including, as reported recently, using the Na⁺/K⁺ ATPase inhibitor digoxin to break down CTC clusters and block metastasis.^6,7

In the next five years, Pantel hopes that liquid biopsies will be used to screen for cancer in high-risk populations. Furthermore, by enabling the detection of early recurrence, liquid biopsies will support new clinical trials in a pre-metastatic stage that could transform the oncology landscape.⁸ “Liquid biopsies are opening a completely new field in early drug studies, that could lead to earlier intervention and improved patient outcomes,” he concluded.