FIVE MILES INTO a 30-mile bike ride on a sunny Sunday morning in August 2019, Craig Schumpert ran into trouble. He hadn’t thought twice about getting on the bike for that ride. Schumpert, then 51, had previously completed long rides of 100 miles. But halfway up a steep hill in Rock Creek Park near his home in Washington, D.C., Schumpert lost his breath and had to turn around. Before then, he had noticed a cough when he accompanied his wife on long runs, but he’d always been quick to recover. This bout of breathlessness seemed more severe, and he made an appointment with his primary care doctor for the next day.
During the visit, Schumpert failed a lung function test, which measures how well a person is breathing. A chest X-ray revealed a large mass in his left lung. A biopsy and more imaging tests—a CT scan, an MRI and a PET scan—led to a diagnosis of stage IV non-small cell lung cancer (NSCLC). The scans showed metastases throughout his lungs and in his bones, brain and lymph nodes.
The results were devastating. Schumpert felt like he’d received a death sentence. On the advice of a family friend, he met with a thoracic medical oncologist at the Johns Hopkins Kimmel Cancer Center in nearby Baltimore to begin his care. The oncologist recommended radiation to treat the bone and brain lesions, which Schumpert started immediately. In addition, samples from Schumpert’s lung tumor were tested for genetic mutations that could guide treatment.
Over the last two decades, researchers have identified variants in nine genes found in lung cancer that can be targeted by medications. These medications tend to have fewer severe side effects than chemotherapy, and in many cases, therapies matched to a particular variant have supplanted chemotherapy as an initial treatment for NSCLC. Researchers estimate that 60% of people diagnosed with metastatic NSCLC have one or more of those variants, known as actionable mutations, in their tumors. If Schumpert’s tumor had a mutation with an associated approved treatment, his oncologist told him, he would be eligible to start a targeted therapy.
That possibility seemed promising, Schumpert recalls. The timeline didn’t. It takes about four to six weeks to get results from a tissue biopsy, the oncologist told Schumpert, which meant waiting a month or more to start treatment. “And when you get diagnosed with cancer, it’s like, get me on some kind of treatment,” Schumpert says.
But Schumpert’s doctor also ordered a blood test—called a liquid biopsy—that can detect molecules from cancer cells, including information about cancer mutations. Liquid biopsy results typically come back in about a week. In Schumpert’s case, the blood test results showed his tumor had a fusion in the ALK gene, an alteration that helps lung cancer cells grow and spread.
His doctor recommended he immediately start a drug called Alecensa (alectinib), which binds to the surface of cells with the ALK fusion, slowing or stopping tumor growth. Within weeks, scans showed the mass in his lung had begun shrinking, and his cough had nearly disappeared. Schumpert credits the liquid biopsy with both shortening his time to treatment and alleviating the stress of waiting for the test results.
Fast-tracking Treatment
Researchers have known for decades that cancer cells shed genetic information—bits of DNA, proteins and other molecules—into the blood. More recently, studies have verified that many of those genetic messages can reveal actionable biomarkers that can be targeted with treatment. As a result, liquid biopsies have become an important tool for several cancers, including breast, colorectal and lung cancers.
While tissue samples remain the gold standard for diagnosis and for determining treatment for cancer, liquid biopsies offer the advantage of faster access to test results with a simple blood draw—which means treatment can often start more quickly. “If a patient has an actionable mutation [detected through liquid biopsy], they can get fast-tracked,” says radiation oncologist Aadel Chaudhuri, who leads research on liquid biopsies at Mayo Clinic in Rochester, Minnesota.
In some cases, Chaudhuri notes, physicians order liquid and tissue biopsies at the same time, which can increase the likelihood that one or both tests will identify an actionable mutation. “We’re doing tumor tissue and plasma [testing] in parallel and then guiding our care accordingly,” says Chaudhuri. If one test doesn’t show a mutation, the other might catch it, he says.
After Schumpert started taking Alecensa, he learned that results from his tissue biopsy were inconclusive. Without the liquid biopsy, he likely would have needed another tissue biopsy or a new analysis of his original tissue sample. Either option would have delayed the start of treatment for weeks.
Noting that some research suggests up to 40% of people with cancer have insufficient or inadequate tumor tissue samples to receive conclusive test results to guide care, medical oncologist Natasha Leighl at Princess Margaret Cancer Centre in Toronto has focused her research on analyzing liquid biopsies as an alternative that can reduce wait times and provide more information about cancer. “People were waiting weeks and even months,” she says. “And the pathologist said, ‘This sample is too small. We can’t get this done.’”
Liquid biopsies can also provide other advantages compared with traditional tissue biopsies. When cancer spreads throughout the body, for example, a liquid biopsy can offer snapshots of multiple cancerous growths and reveal mutations from any of them. In other cases, a liquid biopsy may be preferable to a tumor biopsy if the tumor tissue is in an area where it is too dangerous to safely get a tissue sample. “Where the tumor tissue is inaccessible, we’ll do plasma only,” Chaudhuri says.
A Snapshot of Treatment Response
Oncologists typically use liquid biopsies after diagnosis to help find actionable mutations that can be targeted with drugs, “but there are also some really exciting emerging roles” for liquid biopsies, says Chaudhuri. Recent and ongoing clinical trials have been examining how liquid biopsies might confirm the absence of disease after initial surgery or radiation to avoid unnecessary treatment.
A study presented at the American Society of Clinical Oncology Annual Meeting in May 2024 showed a type of liquid biopsy known as ctDNA testing in people with stage II colon cancer could help determine whether they could safely skip chemotherapy after surgery. In the study, people in the experimental group did not receive chemotherapy after surgery unless the liquid biopsy indicated the presence of ctDNA. In the control group, physicians made treatment recommendations based on traditional factors, like tumor size. After five years of follow-up, researchers found comparable overall and recurrence-free survival rates in the two groups, supporting the utility of liquid biopsy in pointing to treatment. If that ctDNA test is negative, says Chaudhuri, the patient can safely forgo chemotherapy and the unwelcome side effects that accompany it.
Multi-cancer detection tests could help find cancers often diagnosed at later stages.
The last few years have brought several new liquid biopsy tests that promise to detect multiple cancers.
In July 2024, the Food and Drug Administration (FDA) approved Shield, a blood test that can help detect new cases of colorectal cancer by identifying free-floating fragments of cancerous DNA. In a study published March 14, 2024, in the New England Journal of Medicine, Shield identified colorectal cancer in 83.1% of people who were later diagnosed with colorectal cancer through colonoscopy.
Other liquid biopsies purport to use blood samples to screen for multiple cancers. These tests, called multi-cancer early detection tests, are not yet approved by the FDA, but physicians can order these tests for patients since they are laboratory-developed tests, which have different regulatory oversight.
One test called Galleri can detect the genetic signatures of more than 50 cancers, which could make it useful in screening for cancers often diagnosed at later stages, like pancreatic or ovarian cancers. Another test, called Signatera, uses genetic information from a person’s tumor biopsy to produce a customized blood test that searches for circulating tumor DNA in people who have completed treatment to find cancer recurrence. Although this test is not FDA approved, some people say they get peace of mind from the test’s ability to find the earliest signs of a cancer’s return. Oncologists, however, typically recommend caution, as these tests may miss certain cancers and carry the risk of producing false positive results, which can cause unnecessary anxiety for patients.
Liquid biopsies can also detect early signs of cancer progression before scans can and prior to the appearance of troubling symptoms. In addition, several genetic mutations could indicate early signs of treatment resistance, which can help guide an oncologist to recommend a treatment change.
“Once you’ve had cancer and you’ve been on treatment, it is hard to go back for repeat biopsies” because they’re invasive and time-consuming, Leighl says. “These blood tests might help identify new genetic variants that are starting to emerge.”
Still, even as liquid biopsies are being used in the clinic for some cancers, not all cancers shed the same amount of tumor DNA in the blood. Liquid biopsies may not be able to detect variations if the concentration of DNA from the tumor is too low, which could be an issue with early-stage cancers.
In 2016, the Food and Drug Administration (FDA) approved the first liquid biopsy test that could identify actionable mutations traditionally found in tumor tissue samples. The test can find two mutations in the EGFR gene in people diagnosed with NSCLC to identify which patients could benefit from an EGFR inhibitor called Tarceva (erlotinib). Research leading to the approval showed the test detected the same mutations as tumor tissue biopsies 76.7% of the time.
In Schumpert’s case, his doctor ordered a biomarker test made by the company Guardant Health. Although the liquid biopsy test hadn’t yet been approved by the FDA for diagnostic purposes, Schumpert’s insurance agreed to cover the cost. In August 2020, the FDA approved the test, which scanned for cancer-related variants in 55 genes. (It now covers 74.) The approval heralded the first liquid biopsy test to use next-generation sequencing, which can simultaneously analyze multiple genes at the same time. In the same month, the FDA approved another liquid biopsy test by Foundation Medicine that detects multiple genes in solid tumors.
Since then, the FDA has approved several liquid biopsy tests that use a variety of methods to identify targetable mutations. Tests like Guardant360 look for circulating DNA from the tumor, but other tests look for other circulating markers, including tumor cells, proteins or genetic fragments like RNA.
Enthusiasm Builds
Leighl, in Toronto, describes herself as a liquid biopsy enthusiast. She has been actively involved in clinical trials analyzing the utility of liquid biopsies for nearly a decade.
In 2016, she was an investigator on a clinical trial called NILE, and the results bolstered her confidence in the reliability of liquid biopsies in assessing tumors. The trial involved 282 people with newly diagnosed advanced NSCLC who all received liquid and tissue biopsies as part of their care.
The liquid biopsy identified the same actionable mutations as tissue biopsy and even uncovered a few that tissue biopsy missed. “It showed that doing biomarker testing in blood for all known genetic abnormalities was at least as good as doing it in tissue,” Leighl says.
In 2021, Leighl helped launch the ACCELERATE (Accelerating Lung Cancer Diagnosis Through Liquid Biopsy) trial, which enrolled 150 people with suspected advanced lung cancer who received both tissue and liquid biopsies. Those people whose liquid biopsy revealed an actionable mutation started therapy on average in 33 days. Researchers, who examined medical records of those previously treated for advanced lung cancer, found people who received only tumor testing typically started therapy more than 60 days after referral. Additionally, in 12% of the 90 study participants who were found to have advanced NSCLC, liquid biopsy identified actionable mutations that otherwise would have been missed.
Still, even as liquid biopsies guide treatment decisions in cancers, Leighl worries these tests may not always be presented to patients during the initial diagnostic workup. She encourages patients to ask their doctors about using liquid biopsy, particularly if they are waiting for results from tumor sample testing to begin treatment. People who have already finished treatment can also ask about clinical trials for liquid biopsy tests that monitor progression or look for signs of treatment resistance.
For five years, Schumpert’s cancer showed no signs of progression in his lungs and bones while he continued to take Alecensa. But in the summer of 2024, scans revealed the unwelcome return of the disease in his lungs and a new spot in his brain. His oncologist at the University of Texas MD Anderson Cancer Center in Houston told Schumpert about a clinical trial for an experimental drug called NVL-665, a targeted drug that shows activity in the brain and is indicated for people whose tumors have developed resistance to ALK inhibitors. After starting the medication, the new growth in his lungs began to shrink, he says. Other scans showed small growths in his brain, which also shrank on the medication and will be treated with radiation.
Schumpert says his perspective has changed dramatically since those first scans in 2019 that showed tumors in his lungs, bones and brain. “When you find out you have a tumor in your brain, it is really hard to take that,” he says. But with his treatment guided, in part, by liquid biopsy, he continues to move forward with drugs designed to target the unique molecular features of his cancer. “I’m still working, talking and having fun. It’s obviously serious. But it’s very treatable,” he says.
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