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Gawel et al. J Cancer Metastasis Treat 2022;8:26 https://dx.doi.org/10.20517/2394-4722.2022.13 Page 7 of 11

USE OF LIQUID BIOPSY TO DETECT CANCER RECURRENCE
Early clinical studies have demonstrated that liquid biopsy can detect molecular residual disease as well as
recurrent disease that is not yet evident by imaging. The protein markers CEA, CA 19-9, CA 125, and CA
15-3 are used to monitor progression or postoperative recurrence for several cancer types [27,28] . As in
screening, liquid biopsy could be used to monitor patients following surgery or other local-regional therapy
to detect residual disease prior to imaging. Patients with a positive liquid biopsy test may then be referred to
advanced imaging with sensitive modalities such as positron emission tomography/computed tomography
(PET/CT) to localize residual or metastatic disease. Large clinical studies are needed to determine if serial
monitoring using liquid biopsy can replace routine imaging surveillance in patients without evidence of
molecular residual disease.

APPLICATION OF LIQUID BIOPSY IN LUNG CANCER
Lung cancer is the deadliest cancer worldwide, accounting for almost 20% of cancer-related fatalities. Lung
tumors are typically asymptomatic in their early stages and are often diagnosed at later stages with poorer
prognoses, resulting in low treatment success. Considering that the 5-year survival for patients with stage IA
lung cancer is greater than 70%, advances in early detection are crucial to enable timely curative surgery .
[29]
LDCT is currently used for lung cancer screening in patients considered to be at high risk based on various
factors and family history. The feasibility of LDCT-based screening is limited by cost and availability,
however, making liquid biopsy an exciting possible alternative or complementary approach to detect early-
stage lung cancer.

Higher levels of ctDNA have been shown to correlate with worse prognosis for lung cancer [30-32] . ctDNA
[33]
levels are also associated with tumor volume as measured with CT and PET/CT and may help distinguish
between residual disease and treatment-related changes, as well as provide earlier treatment response
assessment compared with radiographic approaches [34,35] . Several studies are currently investigating the value
of combining noninvasive biomarker tests for risk stratification with LDCT to improve the cost-benefit
ratio of screening and possibly reduce mortality. MicroRNAs (miRNAs) are small non-coding RNAs that
have been associated with a variety of physiological processes and diseases including cancer. A recent
analysis of 84 patients with lung cancer identified in large LDCT screening cohorts utilized a miRNA
[36]
signature classifier (MSC) risk profile to stratify patients according to their survival. The MSC risk profile
was able to refine prognosis within specific clinicopathological groups: 20 out of 24 (83%) patients who died
were classified as high-risk based on the MSC test, as were 63% of stage II-IV patients. Conversely, patients
classified as having low or intermediate risk by the MSC test had mostly stage I disease (71%) with better
survival rates. MSC testing could be integrated into patient care algorithms prior to LDCT to reduce
unnecessary imaging in those found to be at low risk.

RECENT ADVANCES IN LIQUID BIOPSY OF CANCER BIOMARKERS
The potential benefits of liquid biopsy for cancer screening and aiding in cancer diagnosis have led to the
development of several new multi-analyte tests that can detect multiple cancers simultaneously [37,38] .
CancerSEEK, as previously mentioned, detects a combination of 16 ctDNA mutations and 8 protein
[20]
markers associated with various types of cancer in blood specimens . The diagnostic accuracy of
[39]
CancerSEEK was assessed in a large study of more than 10,000 women with no history of cancer . Women
with positive tests underwent PET imaging to confirm the diagnosis and localize the tumor if possible.
CancerSEEK detected 26 of 96 incident cancers during the 12-month study; of these, 15 also had a positive
PET result. Nine women underwent surgery based on the combined results of the blood test and imaging
results. The test detected cancers in 10 different organs, many of which have no available screening test. In
22 patients who developed lung cancer, 9 were detected by the blood test, and 3 were detected by LDCT.