Why a liquid biopsy?
Liquid biopsies are diagnostic tests designed to detect cancer biomarkers in the blood (or other bodily fluids) rather than traditional solid tissue samples. Due to the shedding of biomarkers—such as cells, DNA, or exosomes—by tumors into the bloodstream, it is possible to use a simple blood draw to gather a large amount of information about a patient's cancer, or lack thereof.
Liquid biopsies are cheaper, safer, and much less invasive than traditional biopsies, making them a prime area for investment by cancer programs. However, the tests' current limitations (including low sensitivity and specificity) have constrained commercial applications of liquid biopsies to only one of their two potential applications: molecular profiling of tumor biomarkers to identify actionable mutations and match patients with late-stage cancers to appropriate therapies—but the second application, cancer detection and screening, received a major boon with the publication of a study this past April from Thrive Earlier Detection, a liquid biopsy test maker.
A large step forward
Thrive partnered with Geisinger Health System and Johns Hopkins University to conduct a study of more than 10,000 women between the ages of 65 and 75, marking the first time doctors have used the results of a liquid biopsy test to detect and treat cancer in those who are otherwise healthy.
For the study, scientists used an earlier version of Thrive's CancerSEEK blood test, which looks both for copies of specific genes, as well as high levels of several proteins, to double the rate of cancers detected by screening (when compared to the rate of cancers detected by patient-reported symptoms). Participants in the study had to be flagged twice by the CancerSEEK test for potential blood abnormalities for a cancer diagnosis to be considered, which was then confirmed with an imaging test that locates tumors. Of the participants, 96 women developed cancer during the study: 26 identified by CancerSEEK, 24 through traditional screenings, and 46 through symptoms.
Again, this study is a huge boon for liquid biopsies. It shows that providers at Geisinger were measurably aided by this technology, especially in the detection of cancers that do not currently have a screening test—of the 10 different organs the tests assessed for cancers, seven do not have standard-of-care screenings. Even with these positive results, however, it is important to assess where this technology still falls short of being a safe commercial option for screening.
Still some distance to go
Liquid biopsies are normally limited by a few factors, so below we'll look at how CancerSEEK addressed these issues:
The cells, DNA, and exosomes emitted by tumors are rare when compared to the number of normal molecules in a blood sample, limiting the sensitivity of current testing. A low sensitivity will lead to a higher number of false negatives, possibly leading to a false sense of security for patients.
Now, while there have been improvements here, this current study reported a sensitivity rate of only 27.1% (generally a test around 90% would be considered to have good diagnostic performance) when performed alone. And although the founder of Thrive makes the point that this is better than nothing for cancers where screening tools don't exist, such as thyroid cancer, a false negative can potentially cause more issues for patients because it can lengthen the amount of time they go without proper care.
Considering the opposite problem, it's also important to avoid the potential for false positives by being able to consistently identify the source of the biomarker as well as the malignancy of the source; a low specificity will lead to a higher number of false positives.
While liquid biopsies normally underperform in this regard, here CancerSEEK excelled in the study, offering a rate of 98.9% specificity on its own. And given that false positives can lead to overdiagnosis or misdiagnosis, unnecessary treatments, and the worsening of other health concerns due to treatment side effects, these findings are an exciting discovery for not just Thrive but all liquid biopsy proponents.
Even with high sensitivity and specificity, increasing the ability to accurately detect these signatures in the blood does not automatically possess clinical utility, or the ability to create better outcomes or set a clinical threshold that impels a doctor to act. To provide that metric, there must be more of these types of studies, with results specifically matching results of the testing to improved outcomes.
This study is a great first step, showing that a test of this kind can be used to detect cancer in those previously unknown to have cancer (at least in a subset of individuals). However, even the authors concluded that it is unclear whether the test truly led to improved outcomes for any participant. Considering the current concerns over PSA testing for prostate cancer and even late-in-life breast mammograms, it is clear that without proper evaluation, provider and patient education, and consistent clinical evidence, there is a chance that this could lead to worsened patient outcomes due to overdiagnoses and unnecessary treatment. When investing in liquid biopsies, assessing the actual utility will be key to protecting your patients and your program.
Keep a sharp eye on the horizon
It is apparent that liquid biopsies will have an impact on the current diagnostic market sooner than later. The test used in this study is itself out of date, as Thrive has already launched a new 3,000-person study with a more sophisticated test, including a machine learning technique to help more reliably detect cancer. Numerous other companies, such as Grail and Guardant, are also making strides with their own versions of liquid biopsies, expanding testing to more diverse populations and gathering the clinical evidence necessary for eventual FDA approval.
Keeping that in mind, cancer program leaders must consider the potential impact that a pan-cancer screening test can have on their own programs, including the:
1. Financial impact
Generally, the financial outlook for the future of these tests is positive for most stakeholders. Liquid biopsies are significantly less expensive than traditional surgical biopsies, will lead to fewer complications and thus lower unforeseen costs, and most likely can be done at a higher volume due to their ease of use and potential speed. However, while traditional biopsies are typically well reimbursed, reimbursement for liquid biopsies will likely be a limiting factor as payers can be slow to provide coverage for new technologies, even once they're FDA-approved.
2. Operational impact
In addition, because of their simplicity, liquid biopsies done for screening purposes could potentially be handled by primary care providers (PCPs) in the future, shifting that revenue away from the cancer program and into the primary care space.
If this is the case, there will be no guarantee that the eventual uptick in cancer diagnoses from a multiple-cancer screening test will increase your program's volumes for downstream services unless you have a solid relationship with your referring providers. Cancer programs should also consider how a comprehensive test of this kind may impact the current patient pathway and corresponding workflows, perhaps by replacing more intensive or less efficient procedures, and plan to modify their staffing models accordingly.