What is Liquid Biopsy? Precision Medicine's Tool of the Future

In the last few years, liquid biopsy technologies have matured rapidly, evolving to the point where they are poised to revolutionize cancer patient management.  

Where tissue biopsy — long the standard of care — can be invasive, painful and even, in many instances, risky, liquid biopsy is a welcome alternative. For many patients, just hearing the word "biopsy" triggers worries of pain or inconvenience, and quite often, an agonizing wait for results.  

Liquid biopsy delivers results in 10 days or less, is less invasive, repeatable, and in cases in which tissue biopsy is unfeasible due to a tumor’s location, multiple metastases, or other health conditions, liquid biopsy is an excellent alternative. Not only that, but liquid biopsy provides a comprehensive tissue profile instead of just a localized one, which is one of the limitations of standard tissue biopsy. On the flip side, liquid biopsy tests are still not as accurate as looking at tissue. But as the technology continues to develop increasing sensitivity, there’s much to be excited about. 

How did we get here?

Over 20 years ago, the International Human Genome Sequencing Consortium made a watershed announcement to the world. A rough draft of the complete human genome had at last been sequenced. 

It was, we have since learned, not quite complete, with approximately 8% left unmapped. 

In the summer of 2021, a team of 99 researchers announced that they had successfully addressed the missing pieces of the genome. They produced the first truly complete 3.055 billion base-pair (bp) sequence of a human genome, representing the largest improvement to the human reference genome since its initial release. We now have a comprehensive roadmap for further discovery of the ways in which human genes function… and sometimes malfunction.

One of the key technologies underpinning all of these great leaps forward is next-generation sequencing (NGS), which essentially provides researchers the means to access, analyze and understand an individual’s genome. To the extent that next-generation sequencing is a survey in search of anomalies, it has dramatically improved our understanding of the underlying genomic alterations and biological pathways that lead to the development and progression of disease.

The Path to Precision Medicine: Follow the Genome

Precision medicine originates out of the simple idea that medical conditions, like cancer, “behave” differently in different people. We are all products of unique genes and environments — i.e., the alchemic interplay of nature vs. nurture.

Precision medicine looks at how a specific gene change (gene mutation) might affect a person's risk of getting a certain cancer or, if they already have cancer, how their genes (or genes in their cancer cells) might affect treatment. 

The more that can be understood about an individual’s genes or the genes in their cancer cells, the more precise, individualized and effective their treatment can be. Precision oncology works to ensure that cancer patients get the right dose of the right treatment at the right time, with minimum ill consequences and maximum efficacy.

The High Cost of Cancer 

Cancer is a leading cause of disease and barrier to increasing life expectancy worldwide. According to recent estimates from the World Health Organization (WHO), cancer is now the first or second leading cause of death before the age of 70 in 112 of 183 countries. In 2018, one in six deaths was a result of cancer. Every year, 17 million new cases are diagnosed, with projections for an increase to 27.5 million new cases annually by 2040. These numbers may be conservative, in light of macro trends such as aging populations combined with the cumulative impacts on health from stress, poor nutrition, environmental toxins and other potential negative consequences of modern society's lifestyle. Across the world, and particularly in the United States, healthcare systems are under tremendous economic strain from the high costs of battling cancer and other chronic diseases. 

Precision Oncology

Precision oncology holds great promise for pushing back on these staggering numbers, both human and economic. The overall aim at the patient/provider level is for a delivery of personalized care that is guided by the specific individual's genetic information. At the broader healthcare ecosystem level, precision oncology will help to prioritize delivery of effective treatments while minimizing expenditure on ineffective therapies.

By individualizing the healthcare process based on each patient's uniquely evolving health status - through genetic analysis, other molecular and cell biology techniques, and imaging procedures — clinicians and healthcare providers can obtain a much more precise diagnosis and tailor the treatment, avoiding costly trial-and-error loops.

Cancer is an extraordinarily dynamic disease. As cancer progresses, tumors typically become more heterogeneous consisting of more diverse cells with a range of molecular signatures and variable sensitivity to treatment. This variability — heterogeneity — forges the armor of cancer's resistance to treatment; it's also not limited to differences between different patients, but also occurs within a single patient.

While the first genome-guided precision oncology therapies relied on the molecular data retrieved from tumor tissue samples, the invasive nature of these tissue biopsies potentially restricts repeated use, thereby limiting insights on a cancer's evolution.

Liquid biopsies leapfrog this limitation, as blood (or other body fluids, such as saliva, urine, seminal fluid, tears and even stool) can be sampled repeatedly. Additionally, the liquid biopsy procedure is much less invasive than tissue-based biopsy, preventing complications such as bleeding, infections and pain. The data from liquid biopsies can be used in place of or alongside that of traditional surgical biopsies.

Combined with improvements in "omics" technologies and artificial intelligence (AI)-enhanced analytics, liquid biopsy opens up a lens for greater insights for directing an individual's cancer treatment while also being a valuable monitor on broader cancer evolution.

Liquid Biopsy: An Alternative to Surgical Biopsy

Liquid biopsies are tests conducted on blood samples (or other body fluids) that examine biomarkers shed by tumors, such as cancer cells or pieces of tumor DNA. Cellular processes lead to a release of cell-free DNA (cfDNA) into the bloodstream. In general, there are between 3 and 9 nanograms (ng) of cfDNA per milliliter of plasma from normal individuals.

In the case of an advanced cancer patient, the amount of cfDNA is increased 10-fold. Additionally, tumor-specific cfDNA can be collected and provide real-time information on the nature of the tumor, enabling oncologists to tailor the therapy and monitor the treatment. Similarly, exosomes are naturally released by cells containing highly stable RNA and DNA. Tumor cells are known to release more exosomes than healthy cells. The exosomes can indicate not only cancers, but also other disease processes like inflammation and neurodegeneration.

The methods used for the detection are Next-Generation Sequencing (NGS), digital Polymerase Chain Reaction (dPCR), real-time Polymerase Chain Reaction (qPCR), mass spectrometry, and detection of hypermethylation.

Benefits of Liquid Biopsy

Current next-generation sequencing reaches a specificity of around 80% and sensitivity close to 100%, allowing early detection of cancer. Early detection of the tumor is essential. Cancer that has not yet metastasized can be surgically removed or treated with milder drug regimens than at later stages of the disease, dramatically improving survival rates for cancer patients with early-stage discovery.

The minimally invasive nature of liquid biopsy and the high specificity and sensitivity makes the technology very suitable for screening populations at risk of developing cancer. Additionally, liquid biopsy can be used in determining success after surgery, chemotherapy or radiotherapy. Regular liquid biopsies could become commonplace for monitoring people at risk for relapse.

FDA Approvals — Validation and Momentum

In August 2020, the FDA approved the first next-generation system-based liquid biopsy product, Guardant360 CDx. The companion diagnostic test from Guardant Health, Inc. requires only a simple blood draw to identify non-small cell lung cancer (NSCLC) patients who might benefit from Tagrisso®. The Guardant test also received approval to detect 55 other cancer genes across multiple tumor types. Notably, Guardant360 CDx was the first approval combining both next-generation sequencing (NGS) and liquid biopsy technology in one diagnostic test in order to guide treatment decisions.

In addition, on August 26, 2020, the FDA approved a liquid biopsy test from FoundationOne that analyzes blood samples to identify patients who might benefit from specific prostate and lung cancer drugs. FoundationOne's companion diagnostic test looks at more than 300 cancer-related genes for genomic alterations in people with any solid cancer. Results are then reported out, identifying these alterations and matching them to FDA-approved therapies. In the United States, the test is covered across all solid tumors for eligible Medicare and Medicare Advantage beneficiaries.

Momentum in this exciting space is significant. Guardant, FoundationOne and other companies continue to work with pharma companies to expand the approved menus for these companion diagnostics tests, further enabling and accelerating their development of precision therapeutics.

Liquid Biopsy Challenges and Limitations

Yet there continues to be important considerations before the full clinical utility of liquid biopsy in cancer patients can be realized, including potential variability in analyte concentration, sequencing errors, analytical sensitivity and limit of detection challenges.

Next-generation sequencing processes are complex, with several steps involved, such as DNA extraction, library preparation, quality control and bioinformatic analysis. The tests are carried out by the assay developed within their verified and validated laboratories. The turn-around time from sample collection to the result is one to two weeks. For some patients, even this short time period can be critical. Days, let alone weeks, feel like a long time to someone with a potentially life-threatening, serious disease. Therefore, PCR technologies are used when the oncologist has a clear hypothesis and knows what mutations to test. In all other cases, NGS must be used.

Next-Generation Systems and Liquid Biopsy in Clinical Trials

As a tool for maximizing both insight and efficiency, liquid biopsy technology has tremendous value for clinical trials administrators. Biomarker-driven oncology research and development is enriching the study of new targeted drugs based on a tumor's molecular profile. A report from 2019, published in conjunction with the Personalized Medicine Coalition (PMC), determined that 55% of all oncology trials in 2018 involved the use of biomarkers, compared with 15% in 2000.

A simple blood test identifies study participants who possess the mutation of interest for inclusion in a trial. Throughout the study, liquid biopsy can be used to better assess dynamic molecular changes within the tumor and determine if a drug candidate is acting in ways that align with the study hypothesis.

A Promising Future for Cancer Treatment

The future of cancer care is expected to be profoundly influenced by the use of biomarkers, guiding researchers and physicians at every stage from drug development to disease management. In addition to applications within clinical trials, several different improvements within the industry are taking place, promising wider and more consistent use of next-generation system-based liquid biopsy in oncology.

While costs for sequencing continues to decrease, so too has its footprint requirements, such that smaller sequencers are enabling workflow integration into a single device. This closes the distance between the patient and the lab, compressing turnaround times. Meanwhile, improved detections from a single test (so that more genes and potential mutations are identified) will provide further insight into the tumor.

On a macro, population-level scale, the simplicity and increased prevalence of these non-invasive tests supports a dramatically expanding data set. Harnessing these insights together with AI-enhanced bioinformatic algorithms leads to ever increasing disease-state insights, which in turn provides a more precise and informed roadmap to help guide the caregiver in their delivery of more personalized treatments for the patient.

Next-generation sequencing and liquid biopsy are poised to deliver a vital one-two punch in the battle against cancer — improving outcomes while lowering costs. As the genomics field advances and oncology diagnostics technologies continue to evolve, Jabil is proud to be at the forefront of these exciting developments, dedicated to supporting our customers with capabilities for bringing innovative new liquid biopsy products to market.