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INTRODUCTION
Cancer is the leading cause of death worldwide, second only to cardiovascular diseases; the lifetime risk of
[1]
developing cancer is nearly 40% and accounts for approximately 20% of deaths in the United States . Most
cancer diagnoses continue to be made at advanced stages and are associated with poor prognoses; this is in
part due to a lack of effective cancer screening programs. As early-stage cancer treatments are generally
more effective and less invasive, the diagnosis of cancer at earlier stages would significantly improve
[2]
treatment and survival outcomes for many patients .
Gold standard diagnostic testing for solid tumors involves imaging combined with pathology-based
assessments of biopsied tissues and other biological samples from or near the suspected malignant lesions.
Tumor tissue presence and stage of progression are evaluated based on a combination of morphological and
histological markers in the biopsied tissues. However, tissue biopsy is invasive and associated with
significant co-morbidities, including potential infection, pain, and bleeding. While diagnostic imaging is less
invasive, it is costly and the ability to detect early-stage tumors is limited. Some imaging modalities also
involve exposure to radiation, which limits their utility for a serial follow-up to detect recurrence. To
address these issues, the past decade has marked an acceleration in the discovery and development of
minimally invasive tests for tumor markers in easily collected patient samples, such as blood, which would
require only routine venipuncture or fingerstick.

The term “liquid biopsy” refers to the sampling and analysis of any non-solid biological materials sourced
[3]
from patients (e.g., blood, urine, saliva) . Similar to tissue biopsy, the goal of liquid biopsy is to gather
information about a potential lesion or a tumor that will inform a patient’s clinical care journey [Figure 1].
A particular advantage of liquid biopsy may be to aid in the earlier detection of cancers, prior to the
development of tumors and/or lesions large enough to detect by imaging or tissue biopsy. Liquid biopsy
may also help inform differential diagnosis through molecular phenotyping of tumors and allow for the
earlier detection of recurrent disease. In this review, we summarize the current use of liquid biopsy to detect
various types of tumor markers and their potential application in the early diagnosis of cancer. We highlight
the use of protein-based tumor markers in combination with other markers [e.g., circulating tumor cells
(CTCs), cell-free circulating tumor DNA (ctDNA)] into multi-analyte panels, as well as the integration of
liquid biopsy into comprehensive algorithms for cancer screening and diagnosis. The current advancement
of big data analytics, informatics, and artificial intelligence can be used to combine clinical data and liquid
biopsy results for more accurate diagnosis and tumor profiling . Finally, we discuss recent advances in the
[4,5]
application of liquid biopsy in the oncology field.

LIQUID BIOPSY FOR CANCER DIAGNOSIS
Types of cancer biomarkers utilized in liquid biopsy
Liquid biopsies can be used to test for various types of diagnostic, prognostic, or predictive tumor markers,
including CTCs and tumor cell fragments released into a patient’s circulation, ctDNA, and tumor cell
[6]
proteins and secreted factors [Figure 2] . Recent liquid biopsy research efforts have focused extensively on
the early detection of CTCs and on nucleic acid interrogations, including deep sequencing of ctDNA . For
[3,7]
the last three decades, a large body of work has also identified various circulating protein-based tumor-
associated biomarkers and their utility in liquid biopsy for noninvasive cancer screening and aiding in
diagnosis [Table 1]. These markers can help identify patients who are likely to have a malignancy and
require further diagnostic workup. Recent research has also described the potential use of liquid biopsy to
detect protein markers within extracellular vesicles derived from breast cancer cells and keratins as
[8]
[9]
candidate protein biomarkers .