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Table 1. Clinical indications for circulating protein-based tumor markers in blood-based liquid biopsies [27,45-47]
Clinical Protein tumor marker examples
indication
Differential • ProGRP is indicative of small cell lung cancer phenotype
diagnosis • SCCA is indicative of NSCLC squamous cell carcinoma phenotype
Prognosis and • AFP association and progression of HCC
staging • Free and total PSA for prostate cancer
Cancer monitoring • CEA for monitoring colorectal, gastric, breast, lung, prostate, pancreatic, and ovarian carcinomas
• CA 72-4 for monitoring upper GI and mucinous ovarian cancers
Treatment • CEA and Cyfra 21-1 signature predictive of improved survival in advanced NSCLC patients on linifanib treatment in an
prediction exploratory study

AFP: Alpha-fetoprotein; CA: cancer antigen; CEA: carcinoembryonic antigen; GI: gastrointestinal; HCC: hepatocellular carcinoma; NSCLC: non-
small cell lung cancer; ProGRP: pro-gastrin-releasing peptide; PSA: prostate-specific antigen; SCCA: squamous cell carcinoma antigen.

Figure 1. Clinical indications for liquid biopsy of tumor markers throughout the patient journey.

Improving cancer diagnosis with liquid biopsy multi-analyte panels
Historically, protein-based tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen
19-9 (CA 19-9), and cancer antigen 125 (CA 125) have been used to monitor cancer progression or
recurrence in previously diagnosed patients. While these protein biomarkers may be useful for follow-up of
patients with known diseases, none have been approved for screening or to aid in diagnosis, in part because
of their low clinical sensitivity or specificity [10-12] . A recent trend to combat this limitation is to combine
several tumor markers, which may include CTCs, proteins, and nucleic acid-based markers such as ctDNA
or methylated DNA, into multi-analyte panels that provide a more accurate composite result or risk score
[Table 2]. While individual tumor marker panel results alone are not sufficient for providing a definitive
diagnosis, they can be included in algorithms with other factors to provide an initial assessment of the
likelihood of malignancy and identify patients who need more extensive follow-up with more intensive
diagnostic procedures.

The combination of multiple markers can increase diagnostic accuracy by reducing the number of false
positives and false negatives [13,14] . Several studies have shown that the clinical sensitivity and specificity of
CTC and ctDNA tests can be considerably improved when coupled with protein-based markers for several
types of tumors. In a recent proof-of-concept study presented at the 2021 American Association for Cancer
Research (AACR) Conference on Pancreatic Cancer, Hsu et al. reported that an assay for both cell-free
DNA methylation and CA 19-9 protein in plasma samples had significantly greater sensitivity and
specificity for detecting pancreatic ductal adenocarcinoma than either marker alone, even for stage II
[15]
disease . Another recent study demonstrated the performance of a liquid biopsy assay that detects ctDNA
methylation and protein-based biomarkers for diagnosis and prognosis in patients with hepatocellular
[16]
carcinoma (HCC) . A liquid biopsy assay for liver cancer that combines two ctDNA methylation markers