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The study authors concluded that CancerSEEK and liquid biopsy, combined with imaging, hold promise for
screening and detection of early-stage cancer, but require further optimization to improve the positive
predictive value.

Another liquid biopsy assay, Galleri from GRAIL, measures methylated ctDNA markers in more than 50
types of cancer. A recent study of almost 6700 individuals with and without cancer reported 67% sensitivity
for detecting a set of 12 cancer types with the highest mortality in the US and 44% sensitivity for detecting
all cancer types . The utility of the assay as a screening tool is currently being tested in the SUMMIT study
[40]
of 13,000 adults with no known cancer diagnosis (NCT03934866).

Freenome has developed a multi-omic blood test of ctDNA methylation markers for early detection of
[41]
CRC . The test detects DNA methylation signatures of both tumor-related and immune-related genes. In a
recent multi-site study including 122 patients with advanced adenomas and 420 controls, the test had a 41%
sensitivity, higher than blood tests for mSEPT9 or stool-based markers, and 90% specificity . The
[42]
prospective Prevention of Colorectal Cancer Through Multiomics Blood Testing (PREEMPT CRC) study is
currently enrolling individuals at “average risk” for CRC to validate the ctDNA-based liquid biopsy test
(NCT04369053). Freenome is also investigating blood-based assays of ctDNA to detect changes in
transcription factors associated with tumorigenesis .
[43]

CONCLUSION
The role of liquid biopsy of circulating tumor markers in the early diagnosis of cancer will continue to
evolve. Improving technology and decreasing costs could allow liquid biopsy to serve as a highly sensitive
and specific tool for aiding in earlier diagnosis of cancer in the near future. Liquid biopsy could one day be
used for general population screening and surveillance through preventive health or “wellness checks.”
Incorporation of multi-analyte panels into preventive health screening may detect multiple cancer
biomarkers simultaneously and move a patient to further workup faster. Screening protocols will need to
consider the best ways to incorporate liquid biopsy to benefit patient care, including whether to target
specific patient populations or cancer types, how and when results are integrated with other clinical
[44]
information, and how often testing is needed to benefit patient care . Further studies are needed to not
only clinically validate liquid biopsy panels but also understand barriers to their widespread
implementation, such as cost, resource use, and feasibility.

DECLARATIONS
Acknowledgments
The authors would like to thank Stacey Tobin, Ph.D., for editorial support in the preparation of this
manuscript.

Authors’ contributions
Reviewed the draft manuscript and made substantial revisions: Gawel SH
Conceived of the manuscript topic, wrote the first draft, and revised the manuscript: Davis GJ
Reviewed the draft manuscript and made substantial revision: Jackson L
Reviewed the draft manuscript and made substantial revisions: Jeanblanc N
Approved: Gawel SH, Davis GJ, Jackson L, Jeanblanc N

Availability of data and materials
Not applicable.