EACH YEAR, millions of people in the U.S. undergo tissue biopsies to learn more about a mass or lesion that might be cancer. As part of the process, doctors remove all or part of the suspicious tissue and send it to a laboratory for analysis. Biopsy results are essential not only in confirming a cancer diagnosis, but also for uncovering genetic abnormalities that might guide treatment decisions. But what if doctors could get similar insights about the presence and nature of a cancer using a simple blood test?

Fueled by advances in DNA sequencing technology, that scenario has already started to take shape as the technology becomes so sensitive that it can analyze circulating cancer cells or traces of cancer DNA in the bloodstream. These liquid biopsies hold promise as a quick and less invasive way to detect, characterize and monitor cancers, but some practical questions remain about when these blood tests should be used.

Recent FDA Approvals

Blood tests that are manufactured and developed in a single laboratory don’t require Food and Drug Administration (FDA) approval to be used in clinical practice. However, in recent years, the FDA has approved a handful of liquid biopsy tests, called companion diagnostics, to help pair patients who have certain tumor characteristics with drugs that could effectively treat their cancer. The first liquid biopsy approval came in June 2016 with the Cobas EGFR Mutation Test v2, which looks for particular mutations in the EGFR gene within blood samples of patients with metastatic non-small cell lung cancer (NSCLC). The test identifies patients whose cancer might respond to a group of drugs that target these mutations. This liquid biopsy also provides an alternative for patients who are unable to give a tissue sample due to illness, location of the tumor near vital organs, or other reasons.

On Aug. 7, 2020, the FDA approved the Guardant360 CDx test, a liquid biopsy test that uses DNA sequencing technology to detect mutations in the EGFR gene to identify NSCLC patients who might benefit from Tagrisso (osimertinib). The test also received approval to detect abnormalities in 55 other cancer genes across multiple tumor types. On Aug. 26, the FDA approved another liquid biopsy test, FoundationOne Liquid CDx, which analyzes blood samples to identify patients who might benefit from specific prostate and lung cancer drugs, in addition to looking for more than 300 cancer-related genes for people with any kind of solid cancer. In October and November, the FDA expanded approvals for FoundationOne Liquid CDx as a companion diagnostic for certain drugs in patients with breast and ovarian cancer. Also, the FDA approved using the test to identify additional drugs to treat lung and metastatic prostate cancer.

Uses for Liquid Biopsies

Liquid biopsies can fulfill a variety of needs​.

Liquid vs. Tissue Biopsy

In clinical practice, liquid biopsies have been used most often to evaluate patients with advanced cancer to determine whether they might be candidates for targeted treatments or to better understand their prognosis, says Bert Vogelstein, a researcher and cancer geneticist at the Johns Hopkins Kimmel Cancer Center in Baltimore. That’s because patients with cancer that has spread to another part of the body are more likely to have genetic alterations present in their bloodstream.

Sometimes, a liquid biopsy may be the only way to get the genetic information. For example, a tumor may be in a part of the body that makes getting tissue difficult or, in cases of recurrence, there may not be a lot of cancerous tissue in the body to remove.

“In general, if there is tissue available, it’s preferable to look at tissue to identify genetic alterations rather than looking in the plasma,” Vogelstein says. He adds that important genetic alterations in a tumor sample are usually present in 100% of cancer cells, but those alterations are present at low concentrations in blood samples—especially in patients with early disease. “Sometimes, it’s not present at detectable levels at all,” Vogelstein says.

In other words, liquid biopsies may miss important genetic information. This is especially likely in patients who have a small amount of cancer in their bodies. However, a February 2019 study published in JAMA Oncology suggests that using both liquid and tissue biopsies together could improve the ability to detect important genetic alterations in people with stage IV NSCLC.

The study looked at 323 patients with metastatic NSCLC who had liquid biopsies, including 128 patients who received both plasma and tissue testing at the same time. In the study, tissue samples turned up mutations that could be matched to a targeted treatment in 47 patients. However, liquid biopsies, performed alone for those who could not provide adequate tissue samples or in combination with tissue samples, increased the number of patients with targetable mutations to 82. In addition, 36 of 42 patients who received targeted treatment based on their liquid biopsy results alone went on to show a partial or complete treatment response, or to have stable disease. These findings suggest that the routine use of liquid biopsies could increase the number of patients with advanced NSCLC who are eligible for targeted treatments, potentially leading to better outcomes.

Charu Aggarwal, who is an author of the study and a medical oncologist specializing in head and neck cancer and lung cancer at the Hospital of the University of Pennsylvania in Philadelphia, sees tissue and liquid biopsies as complementary. In fact, for advanced cancers, Aggarwal doesn’t see a reason to choose between them.

“Liquid and tissue biopsy both have pros and cons. In our clinic, we actually use both,” she says. “Tissue biopsy remains the gold standard. But we often find the turnaround time [for tissue biopsy] is much longer. Everyone is anxious to get started on the right treatment. Patients don’t want to wait for two to three weeks, during which time they may progress or develop more symptoms.” By comparison, liquid biopsy results often take a week or two.

Seeing the Big Picture

Physicians at Moores Cancer Center at the University of California, San Diego have been using liquid biopsies extensively for about five years for almost every type of advanced cancer, says Razelle Kurzrock, a researcher and medical oncologist who is the director of the Center for Personalized Cancer Therapy.

“It’s much easier to get a blood sample than tissue,” Kurzrock says. She notes that liquid biopsy tests are not as comprehensive as tissue tests at this point in time, but liquid biopsies still have the potential to capture useful and unique information about advanced cancers.

“When there are metastases, there can be heterogeneity,” she says. For instance, metastases that have spread from a primary lung tumor to other parts of the lung, the liver or other areas in the body may have different types of abnormalities in a single patient. “There will be overlap, but there may be differences as well because tumors evolve. When you do a biopsy of the liver, you only know what’s in that piece of liver. When you do liquid, you get DNA shed from multiple sites. You may get a bigger picture of what’s going on.”

For these reasons, liquid and tissue biopsy results can differ, but Kurzrock believes this variability is a strength since liquid biopsies can expand the view to all cancer in the body instead of the cancer at one site. Liquid biopsies also open the door to other possibilities, including the ability to do a series of blood draws over time to monitor a cancer’s response to treatment or to pick up on emerging treatment resistance as new genetic alterations arise.

Kurzrock typically orders liquid biopsy tests for patients when there is a suspicious area on a scan that may indicate a relapse but is either too small or too hard to reach for a tissue biopsy. “We’ve seen sometimes that new resistant alterations emerge months before we see a change on a CT scan,” Kurzrock says. “It’s a glimpse into what will happen in the future.”

Higher Stakes

“If liquid biopsies can help find targetable mutations, they have a lot of potential, so many people including myself have adopted them” for use in patients with metastatic disease, says Daniel Catenacci, a gastrointestinal medical oncologist at the University of Chicago Medicine. “On the other hand, if you are looking at stage II or III cancers where cure is more likely, the stakes are higher. If you get it wrong, you could do significant harm.”

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Patients with advanced gastrointestinal cancer who had liquid biopsies got results faster than patients who had tissue biopsies. The liquid biopsy patients were also more likel​y to enroll in clinical trials.

For example, Catenacci expresses concern over a liquid biopsy test, which has received breakthrough designation to help expedite its FDA review. The test uses circulating tumor DNA (ctDNA), which is DNA from tumor cells found in the bloodstream​. The company that makes the test has reported that the liquid biopsy detects relapses, on average, more than eight months earlier than scans for patients with stage II and stage III colorectal cancer. But Catenacci worries that some doctors may assume the absence of ctDNA after surgery means that patients require less aggressive treatment. “If the ctDNA test is negative, are you going to withhold therapy? I think that’s dangerous,” he says.

Before such a leap can be made, Catenacci is calling for clinical studies designed to determine how liquid biopsies might inform treatment decisions. Vogelstein also emphasizes a need for more clinical trials to define the applications for liquid biopsies. He adds that an ongoing trial in Australia called Dynamic-III is testing how the use of ctDNA could inform doctors’ decisions about chemotherapy treatment for patients with stage III colon cancer.

While many oncologists and researchers are optimistic about the promise of liquid biopsies in general, Vogelstein says, much of the science is still early. In fact, Vogelstein is involved in the development of a liquid biopsy test called CancerSEEK​ that he hopes will one day detect cancers earlier when they are more treatable. But at this point, he says, the benefits of liquid biopsies as a screening tool or to guide treatment in most cases are “more of a hope than something that has been rigorously demonstrated [in the clinic].”

For now, decisions about whether and when to order one of the available liquid biopsy tests will have to be made by doctors and patients together, Vogelstein says. Health insurance may or may not cover their cost. (However, many of the companies offering the tests provide financial assistance for those who need help to reduce out-of-pocket costs.)

Meanwhile, some patients have already made up their minds. One of them is Kelly Shanahan, who learned she had metastatic breast cancer in 2013, years after she was first diagnosed with stage IIB breast cancer in 2008. After her advanced cancer diagnosis, Shanahan was no longer able to work as an obstetrician-gynecologist in private practice because of issues related to her treatment. She is now a patient advocate who has provided input to researchers at the Ohio State University Comprehensive Cancer Center in Columbus for a clinical trial on liquid biopsies. The researchers are designing a study to test serial liquid biopsies, which are repeated over time to quickly determine whether a new treatment is working. Shanahan has had no evidence of disease since 2014. When asked whether she would consider a liquid biopsy if she needed to undergo more treatment, she doesn’t need to think hard about the answer.

“Believe me,” she says, “when I have progression—because I will [have progression]—I will have a liquid biopsy and perhaps a tissue biopsy too, depending on where the progression is, and my oncologists know that.”

Kendall K. Morgan is a health and science writer based in Durham, North Carolina.

A previous version of this article stated that a liquid biopsy test for detecting colorectal cancer relapses was approve​d by the FDA for use. The updated version of the article notes that the test has expedited status for FDA review but is not yet approved for general use.