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Table 2. Examples of multi-analyte tumor marker tests to aid in early detection of cancers (approved or under clinical development)
Test indication & clinical Test description References
utility
Multi-analyte panels of nucleic acid-based markers
Multicancer early detection test CancerSEEK is in clinical development. It detects 8 common cancers at early stages. CancerSEEK utilizes multiplexed PCR ctDNA test for mutations with protein Lennon et al.,
[11]
(CancerSEEK) biomarker tests to aid in detecting tumors, including 5 types for which there is currently no clinically available screening test. Clinical Investigators & Thrive 2020
Corporation have received FDA breakthrough device designation Cohen et al.,
[20]
2019
Galleri multicancer early This NGS-based test measures ctDNA methylation patterns to aid in detection of many solid tumors. Clinical investigators & Grail Corporation have FDA Liu et al.,
[40]
detection test breakthrough device designation 2020
Epi proColon test for aiding in Real-time PCR test detects methylated cytosines in the SEPTIN9 gene for detection of CRC. Epigenomics Corporation’s test was FDA-approved in 2016 and is in Lamb et al.,
[48]
early detection of CRC clinical use 2017
Cologuard test for early Identifies DNA mutations and altered methylation in stool (FIT), associated with the possibility of colon cancer or precancer. Cologuard was FDA-approved for Imperiale et al.,
detection of CRC clinical use in 2015 2014 [49]
Bluestar test for detection of Detects 5-hydroxymethylcytosine alterations in cell-free DNA of genes involved in pancreatic cancer Guler et al.,
pancreatic cancer 2020 [50]
Multi-analyte panels that include protein-based markers
EarlyCDT-Lung test for aiding in The EarlyCDT-Lung test from Oncoimmune Holdings detects 7 autoantibodies and was approved in the EU in 2018 Macdonald et al.,
early detection of lung cancer 2017 [51]
Freenome multi-omic test for Freenome’s in-research multi-analyte test measures a combination of cell-free nucleic acids and plasma protein-based markers to more accurately detect CRC Kleif et al.,
[22]
early detection of CRC 2020
Wan et al.,
[41]
2019
Liquid biopsy for detection of Two independent groups are developing assays that combine ctDNA methylation signatures and protein-based markers AFP and DCP Cai et al., 2021 [16]
early-stage HCC Guo et al.,
2021 [17]
Incorporation of protein-based markers into clinical algorithms
Emerging algorithms for early ASAP, Random Forest, and GALAD algorithms are in clinical development that combine patient factors such as age and sex with biomarkers including AFP, Hemken et al.,
[52]
detection of HCC DCP, PIVKA-II, and AFP-L3 2019
Yang et al.,
[53]
2019
Yang et al.,
2019 [54]
AFP: Alpha-fetoprotein; AFP-L3: lens culinaris agglutinin-reactive AFP; CRC: colorectal cancer; ctDNA: cell-free circulating tumor DNA; DCP: des-gamma-carboxyprothrombin; EU: European Union; FDA: US Food &
Drug Administration; FIT: fecal immunochemical test; HCC: hepatocellular carcinoma; NGS: next-generation sequencing; PCR: polymerase chain reaction; PIVKA-II: protein induced by vitamin K absence-II.

and two protein-based markers [alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP)] had a sensitivity of 96.6% for HCC and 86.2% for
intrahepatic cholangiocarcinoma (ICC) and high sensitivity for detecting early-stage HCC .
[17]