What if a single blood test could determine whether you had one of 14 types of cancer?
That’s the question posed by a study published in November in the journal Cancer. Conducted by researchers at the cancer detection-test company Exact Sciences, the paper models how cancer care for five million U.S. adults might be changed by easy access to blood tests designed to spot many cancers — known as multicancer early detection (MCED) liquid biopsy tests.
But for now, liquid biopsies that test for multiple cancers still have unacceptably high false-positive rates. And even when they don’t, there aren’t clear guidelines for how to integrate them into the standard-of-care. That means they aren’t going to make their way into the clinic in the near term, experts told Live Science.
Before the transformative effect predicted by the Cancer paper can be borne out, doctors will need to figure out how to best use these tests in the clinic.
The pitch for liquid biopsy
The idea behind liquid biopsy tests is that they enable clinicians to look for cancer without going anywhere near the tumor itself, Dr. Carolina Reduzzi, an oncologist and director of the liquid-biopsy platform at Weill Cornell Medicine, told Live Science.
“It’s like translating a tissue biopsy into the blood,” said Reduzzi, who was not involved in the Cancer report. These tests can detect various signs of cancer, including individual circulating tumor cells (CTCs), chunks of tumor genetic material floating in the bloodstream, and even tiny fragments of tumor cells.
Because they do not direct tumor sampling, liquid biopsy tests are comparatively simpler and less invasive. Additionally, the hope is that if clinicians regularly repeat liquid biopsies, they could build up a picture of how a tumor changes in response to treatment.
If a patient’s tumors contain many genetically distinct cells, tissue biopsies that only sample one portion of the tissue may provide a biased view of their disease, said Reduzzi. Liquid biopsy, in contrast, should provide a broader picture of a patient’s cancer by making it easier to analyze cells from multiple tumor sites.
Which tests are in use now?
To date, the U.S. Food and Drug Administration (FDA) has approved five liquid biopsy diagnostic tests, each for single types of cancer. These tests have been validated via assays that compared their ability to detect signs of cancer against tests that sample tumor tissue.
No MCED tests are currently approved or available through routine clinical care, although some, like Exact’s Cancerguard and GRAIL’s Galleri, are available in the United States as “laboratory-developed tests” (LDTs). LDTs exist in a regulatory gray area in which they are not formally approved by the FDA but are available to patients through their clinicians or independent telemedicine providers.
Dr. Iseult Browne, a clinical oncologist based at the Royal Marsden Hospital in London and the U.K. Institute of Cancer Research, said that progress in Europe is patchier. The U.K.’s National Health Service is conducting a trial of Galleri, called PATHFINDER 2, based on data from 140,000 participants. That data will be released next year.
Browne and Reduzzi noted that inertia in the field of oncology could delay the further rollout of liquid biopsies. Oncologists have, for decades, built diagnostic and treatment plans based on data from tissue-biopsy analyses. Shaking these entrenched practices, even with data showing the utility of liquid biopsies, is difficult.
Even with single-cancer tests, Browne says that standardization is an issue. “Everyone is using a different assay,” so making head-to-head comparisons to decide which test is best can be confusing. Different trials have been analyzing different markers of cancer, at various timepoints in disease progression, she said.
‘Less optimistic’ predictions
Ruth Etzioni, a biostatistician at Fred Hutch cancer center in Seattle, leads a multi-institute effort to review emerging cancer treatment and diagnostics. Similar to the Cancer report, Etzioni’s team has modeled the impact of MCEDs and predicts that they would allow cancers to be detected at earlier stages.
However, she added, “our numbers are a little less optimistic.”
The tests’ helpfulness varies by cancer type, because it hinges on how long different cancers remain in each stage of progression. If a cancer lingers longer in stage I and II, then MCED tests would be well-placed to diagnose it early. But if a cancer rapidly progresses to stage IV, then the test will be less useful, Etzoni explained.
The question of how long different cancers stay in each stage is still a matter of debate. The “dwell times” used in the recent Cancer report leaned more optimistic, assuming that cancers would progress slowly enough for an annual MDEC test to make a difference.
Another reason MCED tests are not ready to replace existing diagnostics is that some analyses will always require a tissue biopsy, and current medical guidelines advise doctors to make some clinical decisions based on tumor-tissue samples.
I don’t think we have a test that is there. But I think we will. With time.
Dr. Carolina Reduzzi, Weill Cornell Medicine
“Immunotherapy is given in some cases based on how much your tumor has leukocytes [immune cells] infiltrating the tumor,” Reduzzi said. “You cannot get that in the blood.” All the researchers interviewed for this article agreed that a positive on a liquid biopsy test would need to be followed up with further testing before any cancer treatment was initiated.
So, multicancer tests may diagnose cancer earlier, but whether that early diagnosis will lead to lower death rates will depend on whether those confirmation tests happen quickly, Etzioni said. And those follow-up tests also have to be up to the task of identifying early-stage cancer, she noted.
Fixing false positives
Emerging MCEDs also have issues with false positives, Browne said. Early, non-peer reviewed data from the PATHFINDER 2 trial shows that Galleri was extremely good at identifying people without cancer — correctly identifying people without the disease 99.6% of the time. But meanwhile, roughly 40% of the patients that the test diagnosed with cancer were actually cancer-free.
A false-positive rate of that magnitude puts unnecessary worry on the patient, said Browne, and each false-positive could trigger follow-up tests that people would not have gotten otherwise. If scaled up to the millions of people at elevated risk of cancer, it would significantly burden any health system that adopted the tests.
To reduce false-positive rates, future studies will need to find more reliable signals of cancer to detect. Detecting information from other cell types, like immune cells, has been shown to improve test specificity. Improvements to laboratory standardization could also help cut the false-positive rate.
Browne hopes that liquid biopsy could someday help patients avoid the sapping side effects that were once unavoidable parts of cancer treatment. For instance, an ongoing trial at the Royal Marsden Hospital is assessing whether a test could identify breast cancer patients who don’t need post-operative chemotherapy. The test enables the doctors to assess a patient’s risk even after their tumor has been removed because it looks for tumor DNA in the blood.
Reduzzi believes that optimized multicancer tests — which would identify a large fraction of people who have cancer while having a low false-positive rate — will transform cancer diagnostics, and that such tests are on the horizon.
“I don’t think we have a test that is there,” she said. “But I think we will. With time.”
This article is for informational purposes only and is not meant to offer medical advice.