A liquid biopsy may soon be available to find early signs of cancer in asymptomatic patients when the disease is still treatable and even curable.
Picture this: At your annual doctor’s appointment when they draw your blood to check your cholesterol, thyroid and liver enzymes, they also run a test for cancer. That little vial of blood, however, doesn’t just screen for a few types of cancer but for all 100-plus of them — including hard-to-find forms like pancreatic and ovarian.
And if this blood draw leads to a scan or biopsy and if you receive a diagnosis of cancer, it is more likely to be in the asymptomatic, early stages when the tumor is treatable and more likely to be cured.
This was exactly how diagnosis played out for Rosemary Jemo of Hazle Township, Pennsylvania, in 2016, when she enrolled in the DETECT study being run by Johns Hopkins University and Geisinger Health. Jemo, who works as a hairdresser and exercise instructor, was one of 10,000 women ages 65 to 75 in the study with no prior history of cancer.
“I felt wonderful at the time,” Jemo says. “I always went to my doctor for my yearly checkups. Then I had the first blood test of the trial and a second blood test, and then they called me to get a PET scan. Then my doctor told me I had a tumor the size of a football on my ovary. I had no pain or (inkling) that I was even sick. They were able to remove the tumor in one piece. It’s been a year and a half since then, and everything looks good. I have no other signs of cancer, so I’m pretty happy.”
This is the promise of what a liquid biopsy can do. Such tests already exist, but they’re just beginning to make their way into mainstream care as a means to check for recurrence or lingering microscopic cancer in patients who have already been treated for the disease. Using them to find early signs of cancer in asymptomatic patients would be a new venture, but it may not be far off: Several liquid biopsy candidates are in clinical trials for this purpose.
If they prove effective, they could save lives and money, prompting a change in the medical system.
One of the first to imagine a cancer-screening blood test was Nick Papadopoulos, who holds a doctorate in biomedical sciences and is a professor of oncology and pathology at Johns Hopkins University School of Medicine and a member of the Sidney Kimmel Comprehensive Cancer Center there. Papadopoulos is a co-founder of Thrive Earlier Detection Corp., which has licensed the CancerSEEK test (formerly known as DETECT-A), a liquid biopsy designed to detect multiple types of cancer at the earliest stages possible, before noticeable symptoms.
“The majority of cancers are found when the person has symptoms, and many times by the time they see a doctor and are diagnosed, it’s hard to cure or even prolong the patient’s life,” Papadopoulos says. “We’re trying to detect cancers as early as we can.”
He says that for 30 or 40 years, scientists have known that some kind of signal must exist in the blood of someone with cancer to broadcast that the disease is there. It’s just taken decades to find it.
So what is that signal? Adam Buchanan, director of Geisinger Genomic Medicine Institute and principal investigator on the DETECT study, says the liquid biopsy looks for protein biomarkers and pieces of DNA that have been shed from a tumor and are circulating through the blood.
These biomarkers can be found in people with numerous cancer types, which means that testing the blood may reveal the presence of cancers that are difficult to detect any other way. In fact, of the more than 100 cancer types that exist, there are screening tests for only five: cervical, breast, prostate, lung and colon, says Sudhir Srivastava, who holds a doctorate in biological science and is senior scientific officer and chief of the Cancer Biomarkers Research Group at the National Cancer Institute.
The real power of these tests, then, lies in finding the remaining 95-plus cancers, says
Dr. Joshua Ofman, chief medical officer and head of external affairs for GRAIL, a health care company developing another liquid biopsy.
“Right now, about 71% of cancer deaths occur due to cancers that have no routinely recommended early detection testing,” Ofman says.
Pancreatic cancer is one of them and, as a result, it’s often diagnosed months after symptoms begin. By then, only about 15% to 20% of patients are eligible for surgery, and only 10% of those with the diagnosis live beyond five years.
Sue Friedman, founder and executive director of Facing Our Risk of Cancer Empowered (FORCE), a national nonprofit focused on hereditary cancers, is a 23-year breast cancer survivor who has a BRCA gene mutation that puts her at high risk of developing pancreatic cancer.
“Right now, the testing that’s available for pancreatic cancer is not usually covered by insurance for people who do not have a family history, even if they’re at high risk,” Friedman says. “There’s a certain specialized MRI or endoscopic ultrasound, but both tests are expensive, and my health plan won’t cover them.”
In addition to screening for cancers that are otherwise hard to detect, liquid biopsies could supplement the effectiveness of other tests and help determine when those tests are necessary — for example, the prostate-specific antigen (PSA) blood test used to screen for prostate cancer.
“If men have a PSA between 4 ng/mL and 10 ng/mL, there is only a 20% to 30% chance that they will have biopsy-positive prostate cancer, but even so, the doctor may advise the patient to undergo biopsy,” Srivastava says. Perhaps a liquid biopsy test could identify which men with PSAs at that level could benefit from biopsy, he says, allowing doctors to spare the others from the unnecessary procedure and to place them under active surveillance.
Figuring out how liquid biopsies might fit into the diagnostic process is something that researchers on the DETECT study hoped to find out.
According to the study’s results, 96 of the 10,000 enrolled women received diagnoses of cancer during the trial. Of those, 26 were identified by the blood test, 24 by standard screening methods
and 46 after they developed symptoms.
Of the patients diagnosed by the blood test, 14 had hard-to-find cancers in organs such as ovaries, kidneys or the lymphatic system. Nine of these tumors had not yet spread beyond their original sites.
“One of the things we wanted to see with this trial was if we were competing with the standard of care, or if the test is additive and synergistic,” Papadopoulos says. “We detected 26 cancers with our blood tests within the population that we tested. And then (24 cancers were) detected with the standard of care. So the blood test doubled the screen-detected cancers, which was a very good result.”
According to Buchanan, the goal of the trial was primarily to assess the test’s feasibility and safety. Researchers wanted to know how well it worked, but also if it could be used to minimize negative outcomes like false positives that would lead people to have additional medical tests.
“We want to encourage participants to continue standard-of-care screening that is already known to be helpful,” Buchanan says. “We’re trying not to discourage people from doing the useful stuff, and we don’t want results to lead to unnecessary emotional, medical or financial cost.”
In the case of the CancerSEEK test, a positive result does not tell a clinician where the cancer is located, so those results must be followed by a full body PET/ CT scan to identify the tumor’s origin. This could add unnecessary testing and radiation for those with false positives. But, according to Buchanan, the trial found that the test’s false positive rate was under 1%.
However, not all liquid biopsies work the same way. While Srivastava says CancerSEEK looks for any of approximately 16 mutated genes, some blood tests, such as GRAIL’s, measure the patterns of gene methylation. Buchanan describes methylation as an on/off switch on DNA. It happens when methyl groups, made up of one carbon and three hydrogen atoms, attach themselves to DNA, modifying the expression of genes.
“We found methylation patterns to be the most effective method of finding cancer because methylation is a signature,” Ofman says. “They’re these tiny molecules that attach to the DNA in groups that are abnormal in cancer. They also contain information about where the tissues originated from. It’s a very rich signal. So our test is detecting the cancer signal and then localizing the signal to a specific tissue or organ.”
That’s why the GRAIL test can tell the clinician not only if the patient likely has a tumor but also what type of cancer it is likely to be. In a clinical trial of the test, researchers detected more than 50 cancer types with 93% accuracy.
But not all liquid biopsies are conducted using blood. Other trials are being done with saliva and cerebrospinal fluid.
David Wong is a professor and an associate dean for research at the University of California Los Angeles (UCLA) School of Dentistry and part of a project looking at saliva for “fingerprints” of lung cancer malignancy.
“You can find this fingerprint in blood too,” Wong says. “But it is easier to access in saliva. You may not realize it, but we produce three soda cans of saliva every day.”
According to Ofman, the risk of cancer increases significantly after age 50, so if the GRAIL liquid biopsy was available to complement standard-of-care screening for everyone older than 50, it could avert many deaths by earlier detection of up to 75% of all the cancers that have less than a 50% five-year survival rate.
These tests could potentially save hundreds of thousands of lives, but Srivastava says some questions need to be answered before they become widely available.
• How specific (false-positive rate) and how sensitive (false-negative rate) are they?
• Do these tests shift stage of cancer diagnosis to an earlier one?
• Do they help reduce unnecessary diagnostic work-ups or biopsies?
• Do randomized trials show that these tests reduce cancer mortality?
The DETECT study showed that the test was feasible and safe, and the results provided helpful information to patients and their doctors. Papadopoulos says the next phases of testing will include a more diverse population of varying ages, genders, races and ethnicities. While the testing process has been slowed by COVID-19 restrictions, he thinks that the CancerSEEK test will be available in the next four or five years.
Buchanan, however, thinks CancerSEEK will come to market faster, becoming available to some health systems and insurers within the next year or two — although he doesn’t expect it to have Food and Drug Administration (FDA) approval at that point.
He noted that the FDA will wait to review clinical trial outcomes before granting the test approval, and that will be key to it being covered through Medicare and private insurance.
Ofman says the timeline for GRAIL will be shorter still, with the test possibly being introduced in the next year. He notes that the FDA has already given the test a breakthrough device designation, meaning that it will get an expedited review, with the company fulfilling some “evidence-generation requirements in the post-approval setting.”
As for the saliva test out of UCLA, Wong says it is in its second year of a trial that aims to accrue 360 participants.
Once a test is available, clinicians will need to determine how often it should be used and on what populations.
Papadopoulos thinks CancerSEEK should be used every two or three years, but he says the details of who gets it and how often will be determined based on each person’s risk profile. Patients who are worried about a recurrence of cancer or, like Friedman, face genetic risk, may be tested earlier and more often.
Testing for recurrence may be slightly different for GRAIL because, in those individuals,
the goal will be to look for methylation patterns that may have been altered by treatment. Other tests for recurrence, such as one developed by a company called Natera, uses the DNA sequence of the original tumor to develop a customized test that detects tiny amounts of the DNA in the blood if the tumor is recurring but before it is detectable by scans.
“We’re doing research right now to understand how well our test performs in different populations,” Ofman says, “and whether chemotherapy or surgery affect it.”
While Friedman is enthusiastic about the possibility of a liquid biopsy to detect cancer, she cautions others to be careful about using tests that have not yet been validated through rigorous research studies.
“On the one hand, there is the unmet need of the community,” Friedman says. “On the other hand, an unvalidated test doesn’t necessarily benefit people. We’ve seen this several times over the past 20 years, especially with ovarian cancer — blood tests that are put on the market and then taken off.”
To help speed the process along, Friedman recommends that people enroll in clinical trials. Those interested can find a list of trials that are enrolling on FORCE’s website.
If these liquid biopsies work like they’re designed to, doctors will find more cancers — and find them earlier. Ofman says this could reduce the cancer-related five-year mortality rate by 15% to 24%. Given that an estimated 600,000 Americans will die of cancer this year, if Ofman is right, this technology could save 144,000 lives per year in the United States alone.
“Furthermore, treating cancer early is about half the cost of treating it in the late stages,” Ofman says. Since Americans are projected to spend $158 to $207 billion this year on cancer care, the savings could be significant.
Srivastava says liquid biopsies could also save Americans billions of dollars in unnecessary diagnostic work-ups. “So you’ll reduce the cost of treating cancer dramatically, and then, given all the false positives that are generated by single-cancer screening tests, you’ll reduce it even more.”
For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.