What You Need to Know About Liquid Biopsies

Posted by ALCF Staff on August 15th, 2018

by Janet Freeman-Daily, Founder of ROS1ders and lung cancer patient/activist, and Lecia V. Sequist, MD, MPH, The Landry Family Associate Professor of Medicine, Harvard Medical School

The term “liquid biopsy” is appearing with increasing frequency in the news and lung cancer community discussions. Hundreds of presentations about liquid biopsies were offered this spring at major oncology conferences. The tidal wave of data can be confusing for many patients and caregivers.

Let’s take a look at liquid biopsies, how they are used, and the benefits and challenges of this technology.

What is a liquid biopsy?
A liquid biopsy is a cancer test done on a bodily fluid, usually a blood sample (although other fluids such as urine or saliva might be used). A liquid biopsy collects either whole tumor cells or materials shed from tumor cells, like fragments of tumor DNA. Whole tumor cells collected from the blood are called circulating tumor cells (CTCs). Fragments of DNA in the blood are called cell-free DNA (cfDNA). If analysis has determined the DNA fragments came from a tumor, those fragments are called circulating tumor DNA (ctDNA).

Why use a liquid biopsy instead of a tumor tissue biopsy?
Liquid biopsies have several theoretical advantages over tissue biopsies:

  1. A blood draw is easier, less invasive and less risky than a biopsy of a tumor in the lung or a site of metastatic disease. Some patients are not healthy enough to undergo a tissue biopsy.
  2. An invasive needle biopsy might not collect enough tumor tissue to run all the desired tests or might miss the tumor altogether. If either of those happens, the only way to get more tissue is to do another invasive biopsy. A liquid biopsy can be easily repeated to obtain more DNA if the material collected in the first attempt is insufficient.
  3. Lung cancer tumors can be heterogeneous, meaning the tissue in tumor is not uniform. Relevant mutations can be clustered in only one area of a tumor or in only one location in the body. Circulating tumor DNA could potentially reflect a more diverse sampling of tumor genetics compared to a needle biopsy of a single tumor.
  4. Blood biopsies often provide results faster than tissue biopsies because less processing is required to extract DNA from the sample.

How are liquid biopsies used in patient care?
As of July 1, 2018, only one liquid biopsy test has been approved by the U.S. Food and Drug Administration (FDA). The cobas® EGFR Mutation Test is approved for use with lung cancer patients to identify those who may be candidates for EGFR-targeted therapy drugs like osimertinib (Tagrisso). The cobas test evaluates ctDNA in the blood and can detect 42 gene mutations in EGFR exons 18, 19, 20, and 21, including the T790M resistance mutation. Since the test may produce a false negative (meaning it might not detect a treatable EGFR mutation even though one may be present), the FDA recommends a tissue biopsy if the liquid biopsy test is negative.

Other liquid biopsy tests are commercially available, although their accuracy has not been validated sufficiently to earn FDA approval. Some of these are being used in patient care by oncologists at academic cancer centers when a tissue biopsy cannot collect enough tumor tissue for testing. The March 2018 Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors recommends “the use of cell free DNA to ‘rule in’ targetable mutations when tissue is limited or hard to obtain.” The document, published jointly by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP), does NOT recommend liquid biopsy as a replacement for a diagnostic tissue biopsy.

Some liquid biopsy tests are covered by select health insurance plans. If your doctor orders a liquid biopsy test that isn’t covered by your health insurance, talk to your doctor or the test’s manufacturer about financial assistance to cover the cost of the test.

Note that even if a liquid biopsy (or a tissue biopsy) indicates that a patient does have a targetable genomic alteration, there is no guarantee that a targeted therapy will work for that patient.

What are the challenges associated with liquid biopsies?
While using liquid biopsy technology sounds very attractive, it has major challenges. The issue is accuracy. The results of some ctDNA liquid biopsies do not reliably match the results of tissue biopsies. For example, liquid biopsies are more reliable in determining that a patient DOES have a treatable genomic alteration like EGFR than determining a patient does NOT have a treatable genomic alteration. Why is that?

Biology is a big factor. The quantity of available ctDNA fragments may be insufficient to analyze or may not reflect the presence of every type of tumor cell (some cells might not be actively shedding DNA). A patient with a known EGFR mutation who is taking a targeted therapy may test negative for EGFR on a liquid biopsy, even though a tissue biopsy shows the EGFR mutation is still present (researchers think this situation may indicate the targeted therapy is effectively controlling the cancer). Recent research suggests that liquid biopsies become more accurate as the volume of cancer tumors (known as tumor burden) increases. Also, accuracy is affected by the way the cancer tumor’s DNA breaks apart to create ctDNA as well as the chemical stability of the ctDNA fragments.

Accuracy can be significantly affected by technology, such as the method used to collect and process the ctDNA, or the technique used to distinguish ctDNA fragments from the DNA fragments of healthy cells. Also, blood cells can develop mutations that are a natural sign of aging or an early sign of a blood disorder; analyses of ctDNA from these cells might wrongly assume these mutations originated in a solid cancer tumor.

Some tests that are routinely run on tissue biopsies cannot technically be performed via liquid biopsies, so liquid biopsies need to employ different techniques to find these variants. Liquid biopsies cannot support FISH analyses (to identify gene rearrangements like ALK or ROS1) or PDL-1 immunohistochemistry (a biomarker for immunotherapy drugs).

Identifying targetable mutations using liquid biopsies is also complicated by genomic variations. A liquid biopsy requires a unique chemical to “label” each specific ctDNA fragment of interest. This is doable for EGFR cancer mutations, which have a limited number of genomic variations and one predominant resistance mutation (T790M). However, other targetable mutations like ROS1 gene rearrangements have MANY possible variants and resistance mutations. For a liquid biopsy to detect all known variations and resistance mutations, a large number of unique chemical labels will be required, which might not be practical.

Clinicians and researchers are still debating the appropriate role of liquid biopsies. A March 2018 position paper from the American Society for Clinical Oncology (ASCO) stated there is insufficient evidence for the use of most ctDNA assays outside of clinical trials. In the summer of 2018, the International Association for the Study of Lung Cancer (IASLC) published a paper titled “IASLC Statement Paper: Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC)” that discusses technical details and processes that help ensure reliable liquid biopsies for lung cancer patients.

How are liquid biopsies being studied by cancer researchers?
Cancer research is exploring many ways to use liquid biopsies. Researchers hope one day that liquid biopsies will be useful in a range of applications:

  • Early diagnosis – detect cancer during screening or post-treatment surveillance, even before it can be detected by scans
  • Therapy selection – assist in selecting the best treatment option for a patient (targeted therapy, immunotherapy, or chemotherapy),
  • Prognostic – assess the likelihood of progression or recurrence for cancer patients, and
  • Therapy monitoring – determine how well a treatment is working and/or whether the cancer has acquired resistance to a given therapy.

Figure 1. Cancer cell materials detectable in blood (image credit: Jia et al, Oncotarget 2017)

In addition to ctDNA, cancer cells shed other materials into the blood stream that can provide information about a cancer’s biology (Figure 1, which shows a colon cancer example). Circulating tumor RNA can be collected from blood plasma and used to assess response to treatment. Some liquid biopsies are looking for exosomes, which are thought to be one of the ways cells deliver messages to other nearby cells. Exosomes are little packets spawned from the cancer cell that contain DNA, RNA, proteins, metabolites, and other materials (even viruses) surrounded by a lipid membrane.

Liquid biopsies that detect these materials may be able to tell us more about how the cancer cell is reacting to treatment. Researchers are evaluating liquid biopsies that might someday be used for early detection by identifying combinations of proteins in the blood that might indicate whether a patient has lung cancer before it is detectable on scans. Some clinical trials have found that circulating tumor cells (CTCs) detected by liquid biopsies can indicate a cancer patient’s risk of recurrence after treatment. A breakout session at a recent National Cancer Institute workshop on post-treatment surveillance discussed using liquid biopsies in clinical trials to determine when a lung cancer patient could stop treatment with a low risk of recurrence.

So, are we there yet?
Liquid biopsies aren’t quite ready for prime time (except for one that is FDA approved for lung cancer patients), but they have a promising future. Expect to see lots of research findings published about them in the coming months.

If you’d like to learn more about liquid biopsies, check out the resources below.

Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer. Website. National Cancer Institute. Accessed 4-Jul-2018 at https://www.cancer.gov/news-events/cancer-currents-blog/2017/liquid-biopsy-detects-treats-cancer .

Rolfo, Christian et al. IASLC Statement Paper: Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC). Journal of Thoracic Oncology, article in press. Accessed 4-Jul-2018 at https://www.jto.org/article/S1556-0864(18)30680-4/fulltext

Turner, N. What Are Liquid Biopsies and How Are They Used? Podcast 5-Mar-2018. American Society for Clinical Oncology. Accessed 4-Jul-2018 at https://www.cancer.net/blog/2018-03/what-are-liquid-biopsies-and-how-are-they-used

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