Liquid biopsies for early cancer detection and disease monitoring

Liquid biopsies detect tumor biomarkers in blood or other bodily fluids, such as urine and saliva, rather than in solid tissue samples. These tests most commonly detect circulating tumor DNA (ctDNA), but some also look at circulating tumor cells (CTCs), exosomes, or other biomarkers. Liquid biopsies have three main applications:

1. Treatment selection: Molecular profiling of tumor biomarkers to identify actionable mutations and match patients to appropriate therapies

2. Early cancer detection: Screening for individual cancer types or multiple cancers at once

3. Disease monitoring: Identifying molecular markers of treatment response and resistance, disease progression, and recurrence—most commonly minimal residual disease (MRD)

While the use of liquid biopsies for treatment selection is becoming more common, liquid biopsies for early cancer detection and disease monitoring are just now starting to be used in the clinical setting.

Why is it useful?

Liquid biopsies for early cancer detection and disease monitoring present several advantages for both patients and providers.

When it comes to cancer detection, primary and specialty care providers can use liquid biopsies to screen for many more types of cancer than traditional forms of cancer screening. These tests can be more convenient and less invasive for patients. They have the potential to detect cancer earlier, when it is more easily treatable and survival rates are higher. In doing so, they may also decrease cancer patients’ total cost of care.

Liquid biopsies for disease monitoring can help oncologists identify signs of treatment response and resistance as well as monitor for early signals of recurrence. Because they are non-invasive, liquid biopsies can be taken serially, allowing for more frequent biopsies with decreased risk of complication and a better patient experience. They also tend to have shorter turnaround times than tissue biopsies, enabling providers to quickly alter treatment plans based on test results. Liquid biopsies for disease monitoring can be especially useful in cases when there’s not enough tumor tissue for a traditional tumor biopsy or when cancer patients are not medically fit to undergo invasive tissue biopsy.

Who are the key players?

Companies with commercial liquid biopsies for early cancer detection

• Arquer Diagnostics
• Bio-Techne
• Epigenomics
• Exact Sciences
• GRAIL
• Immunovia
• Pacific Edge
• StageZero Life Sciences

Select companies with tests in development: Burning Rock Biotech, Delfi Diagnostics, Freenome, Guardant Health, Singlera Genomics

Companies with commercial liquid biopsies for disease monitoring

• Adaptive Biotechnologies
• Clinical Genomics
• Guardant Health
• Natera

Select companies with tests in development: Biovica, Exact Sciences, Foresight Diagnostics, Inivata, Invitae

The first liquid biopsies for early cancer detection and disease monitoring have entered the market, with many more life sciences companies racing to launch additional commercial tests in the near future. These new market entrants— combined with significant venture capital investor interest in non-invasive cancer diagnostics, a growing pool of patients at risk for cancer, and an increasing body of evidence establishing analytical validity and clinical utility—all contribute to rapid projected growth in the U.S. liquid biopsy market over the next decade.

The path to reimbursement for these types of tests is becoming clearer, as demonstrated by Medicare’s coverage of a liquid biopsy for MRD detection in 2019 and its recent decision to cover all FDA-approved blood-based colorectal cancer screening tests that meet sensitivity and specificity thresholds. These changes to the reimbursement landscape are creating a more favorable environment for these liquid biopsy applications.

Application: Early cancer detection

When the first liquid biopsies for MCED became available in the first half of 2021, health systems grappled with how to make them accessible to their patients. One of these tests, the Galleri test by GRAIL, can detect more than 50 types of cancer in asymptomatic patients from a simple blood draw.

In March 2021, Providence announced a partnership with GRAIL to integrate the Galleri test into the clinical setting, making it the first health system to do so. Providence has begun rolling out the test in its California, Washington, and Oregon locations, with the possibility of eventually offering it at all its hospitals and health clinics across seven states.

As the first health system to offer the Galleri test, Providence has enabled its patients to have early access to this new technology and has the benefit of receiving GRAIL’s support in the implementation process. At the same time, partnering with Providence has allowed GRAIL to gain recognition, drive adoption across a large geographic area, and conduct crucial implementation research. Over time, Providence and GRAIL will gain insight into how to best support providers who order the Galleri test and ensure positive patient experiences.

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Application: Early cancer detection

AccessHope, a City of Hope subsidiary that provides cancer expertise to employers and their health care partners, is also partnering with GRAIL around early cancer detection. Rather than providing access to the Galleri test directly, AccessHope supports patients and providers by giving them guidance and information about the test and helping them determine next steps following a positive test result. The partnership enables large, self-funded employers to offer their employees expert guidance about the latest technology in multi-cancer early detection.

Application: Disease monitoring

After recognizing that liquid biopsies can be useful in predicting and monitoring for relapse, researchers at MGH decided to use Natera’s Signatera liquid biopsy for ctDNA detection in a clinical trial involving early-stage breast cancer patients. The trial is testing the ability of a targeted therapy to reduce relapse among patients with a high risk of recurrence after surgery. The researchers are using Signatera to determine which patients have a high risk of relapsing and to measure whether that risk declines in response to the drug being tested. Though this is a novel use of a liquid biopsy in a clinical trial, some cancer care providers are similarly using Signatera and other liquid biopsies in the clinical setting to monitor treatment response and determine patients’ risk of recurrence.

Despite the promise of liquid biopsies to transform cancer detection and monitoring, these applications are still too novel for most providers to adopt immediately. Most organizations should wait for further evidence of utility or clear industry-wide utilization guidelines before implementing these tests.

It might make sense for your organization to implement liquid biopsies for early cancer detection now if you:

• Have patients that express interest in using them and would be willing to pay out-of-pocket
• Have the capacity for increased patient volumes (due to more patients being referred to the cancer program with positive test results), including the ability to provide additional diagnostic imaging services, education, and other forms of patient support
• Serve a patient population with historically low cancer screening rates or higher than average rates of late-stage diagnoses

It might make sense for your organization to implement liquid biopsies for disease monitoring now if you:

• Have experts who could set organizational standards for when and how liquid biopsies for disease monitoring should be used
• Have a physician champion and buy-in from other physicians and staff who are willing to alter workflows to support more frequent disease monitoring
• Have strong relationships with IT and internal or external lab partners to allow you to simplify test ordering and integrate lab data into the EHR

Along with implementing liquid biopsies for cancer detection and disease monitoring into clinical practice, health care organizations can become involved in liquid biopsy development in two main ways. First, many clinical research programs partner with manufacturers to study their liquid biopsies in clinical trials. Second, some cancer programs participate in the early-stage research and development of liquid biopsies, either in partnership with manufacturers or on their own.

For example, Mayo Clinic collaborated with Exact Sciences on developing its OncoGuard Liver test for detecting liver cancer, and Stanford University researchers developed a liquid biopsy for MRD detection and have spun out a company to commercialize it. Cancer programs that employ researchers with extensive expertise in cancer genomics and diagnostics or who are interested in engaging with life sciences companies to study their liquid biopsy tests might be best poised to pursue these opportunities.

Life sciences companies

Since only a few liquid biopsies for early cancer detection and disease monitoring are currently on the market, there is still a significant opportunity for life sciences companies to develop their own tests. However, there is substantial competition in both applications.

Whether or not a life sciences company develops a liquid biopsy test, it can still benefit from the technology. As demonstrated by MGH, companies developing cancer therapies can use liquid biopsies to monitor patients more easily and frequently throughout their trials and evaluate trial endpoints. Companies whose drugs are most effective in patients with molecular markers of recurrence could consider collaborating with liquid biopsy developers to get their tests approved as companion diagnostics to increase the number of patients who are tested for treatment eligibility. Pursuing approval would also help the liquid biopsy manufacturers gain reimbursement and drive adoption.

Payers

Though few payers currently cover liquid biopsies for early cancer detection or disease monitoring, both applications have the promise of increasing efficiency and lowering total cost of care for cancer patients. When it comes to cancer detection, payers will need to weigh the benefits of catching cancers earlier with the cost of reimbursing these tests for a potentially larger patient population than is eligible for standard cancer screenings. As more data on the clinical utility of liquid biopsies for disease monitoring becomes available, payers must consider whether possible increases in care efficiency and downstream savings will offset the expense of testing cancer patients more frequently throughout treatment.

Payers must stay updated on the latest data about the utility and cost-effectiveness of liquid biopsies. They should also view liquid biopsies as an opportunity to collaborate with providers, perhaps through including liquid biopsy utilization in value-based care contracts.

Labs

Liquid biopsies for early cancer detection and disease monitoring represent a potential source of revenue for labs, especially as adoption grows.

For liquid biopsies that are designed to be sold to labs in test kits, such as Epigenomics’ Epi proColon blood test for colorectal cancer screening, health system and third-party labs can run the tests themselves and receive reimbursement directly.

Other liquid biopsies are considered laboratory-developed tests, which can be run only in the lab that manufactures them. However, these tests still offer the possibility for third-party labs to partner with manufacturers around patient access and marketing. For example, Quest Diagnostics receives funding from GRAIL to provide phlebotomy services for the Galleri test, enabling patients around the country who are interested in the test to easily access blood collection services. Similarly, Labcorp partnered with Adaptive Biotechnologies to increase access to its clonoSEQ test for MRD detection. In addition to collecting blood samples, Labcorp’s oncology salespeople promote the test to oncologists and hematologists around the country.

Liquid biopsies for early cancer detection and disease monitoring are moving toward commercialization. Labs with large geographic footprints should consider partnering with manufacturers to provide services that could bring the tests to more patients while generating revenue for the lab. And all labs should stay up-to-date on the latest liquid biopsy test kits available and assess which are most valuable to offer to patients and providers. To do so, labs will need to consider the reimbursement landscape and investments needed to perform the tests.

Right now, adoption of liquid biopsies for both early cancer detection and disease monitoring is limited primarily by the lack of evidence that these tests can significantly impact patient outcomes and corresponding payer hesitancy to reimburse them. However, new data is quickly surfacing that could drive payer coverage and provider adoption over the next few years.

Things that change the calculus:

• Conclusive clinical data demonstrating analytical validity and clinical utility for individual liquid biopsies
• FDA clearance or approval of individual liquid biopsies or inclusion in NCCN guidelines
• Passage of legislation that would require CMS to cover liquid biopsies
  • For example, the proposed Medicare Multi-Cancer Early Detection Screening and Coverage Act of 2021 would require CMS to cover MCED tests upon FDA approval
• Regulatory action that would require automatic coverage for liquid biopsies
  • For example, a test receiving an A or B rating from the USPSTF would automatically be covered by both Medicare and private insurers under the Affordable Care Act
• Increased patient interest and comfort in using liquid biopsies for cancer detection

Whether these changes happen soon or many years from now, cancer care providers should be prepared for the potential disruption liquid biopsies could cause. For now, providers should pay attention to the liquid biopsy market and keep track of how patients, regulators, and payers respond as new clinical data becomes available.