Liquid Biopsy: A Pathway To Earlier And Less Invasive Cancer Detection

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  • Liquid biopsies provide hope for quicker and more accurate early-stage cancer detection across a wider range of cancer types with a simple blood test.
  • Using current standard of care, only about 25% of cancers are detected via screening. The remaining 75% are detected when the patient is symptomatic, and most likely in a later stage of cancer.
  • Largely as a result, cancer accounts for 609,000 deaths a year in the United States, making it the second leading cause of death.3 Liquid biopsies, however, provide hope.
  • This approach can be particularly beneficial for detecting cancers that currently do not have proven screening methods and thus require invasive tissue biopsies.

Blood samples for Liquid biopsy blood test to detect cancer cells

Md Babul Hosen/iStock via Getty Images

Liquid biopsies provide hope for quicker and more accurate early-stage cancer detection across a wider range of cancer types with a simple blood test. Using current standard of care, only about 25% of cancers are detected via screening.1 The remaining 75% are detected when the patient is symptomatic, and most likely in a later stage of cancer.2

Largely as a result, cancer accounts for 609,000 deaths a year in the United States, making it the second leading cause of death.3 Liquid biopsies, however, provide hope.

This approach can be particularly beneficial for detecting cancers that currently do not have proven screening methods and thus require invasive tissue biopsies. In this piece, we introduce liquid biopsy technology and examine what it will take for it to become a prominent standard of care.

Key Takeaways:

  • Liquid biopsy offers a screening option to diagnose early-stage cancers via a single blood test.
  • To drive clinical adoption, multi-omic approaches will help improve test accuracy.
  • Industry winners will address the entire cancer diagnostic continuum, from diagnosis to remission.

Biomarkers at the Heart of Liquid Biopsy’s Potential

Biomarkers are biological molecules found in a patient’s sample that serve as medical signs to specific illnesses.4 For a long time, finding biomarkers for solid tumors was limited to tissue samples, collected via a tissue biopsy.

Tissue biopsies can be particularly challenging when a tumor is difficult to access, such as a tumor in the brain or lung. New methods, however, now allow scientists to use biomarkers in non-invasive liquid samples, like blood or urine, to detect cancer. The most studied biomarkers so far for liquid biopsy include:

  • Circulating Tumor Cells (CTC): CTCs are cancer cells that split away from a tumor and circulate in the bloodstream.5 CTCs can sometimes exit the bloodstream and enter other organs, growing into new, metastatic tumors.6 This tumor shedding in the blood can be measured to determine if a patient has cancer. The more shedding found in the blood, the higher the likelihood of the patient having late-stage cancer. As a result, CTC-based tests can have lower specificity in early-stage settings.7
  • Circulating Tumor DNA (ctDNA): ctDNA is DNA that circulates in the bloodstream and derives from cancerous cells and tumors. As tumors grow, cancerous cells die and are replaced by new ones. The dead cells get broken down and their contents, including DNA, are released into the bloodstream. Like CTCs, ctDNA can be measured in a patient sample to determine if a patient has cancer. ctDNA is known for its higher sensitivity relative to alternative biomarkers, though noise from normal cell shedding is a potential disadvantage to this method.8
  • Exosomes: Exosomes are extracellular vesicles responsible for cell-to-cell communication and the transmission of diseases.9 Exosomes are particularly useful as a basis for liquid biopsy, as they are secreted by living cells rather than secreted during cell death. As a result, exosome-based assays offer a more comprehensive real-time window into the patient’s health and have higher sensitivity. They also offer logistical benefits because exosomes are highly stable and easy to obtain and distinguish.

The genetic information obtained from these biomarkers spans multiple uses and can aid in patient care across their diagnostic and treatment journey.

Liquid biopsy applications

Liquid biopsy applications (Author)

Tumor-Specific and Multi-Cancer Assays Show Promise

For early cancer detection, tumor-specific assays solely focus on diagnosing one type of cancer. Exact Sciences’ (EXAS) Cologuard, for example, is a Food and Drug Administration (FDA)-approved test that can help detect colon cancer via cancerous particles in stool.

Though colonoscopies remain the standard of care for colon cancer diagnosis, a liquid biopsy test such as Cologuard can help rule out colon cancer. Exact states that 84% of Cologuard patients test negative, with a 99.94% negative predictive value.10

If Cologuard patients test positive, it indicates potential signs of colon cancer and the patient should schedule a colonoscopy. Ruling out patients is valuable, particularly now, as the COVID-19 pandemic resulted in patients putting off elective procedures that resulted in a years-long backlog of colonoscopy procedures.11

Recent work in the multi-cancer early detection (MCED) space looks for a wider net of cancer-derived biomarkers. MCED tests, sometimes also referred to as pan-cancer early detection tests, simultaneously screen for and localize multiple cancers.

Meant to be used to complement with existing diagnostic options, MCEDs signal that the patient requires more in-depth examination. Illumina’s (ILMN) Grail launched the first commercially available MCED in 2021.12 The test detects 50 types of cancer with 99.5% specificity and 89% cancer signal origin accuracy.13

Overall sensitivity for the test was 51.5%, with a steady improvement in detection across cancer stages: 17% at stage I, 40% at stage II, 77% at stage III, and 90% at stage IV.14

Firms Seek Increased Test Accuracy Using Omics, Combined Approaches

The liquid biopsy space is still quite nascent compared to other cancer screening alternatives and firms continue to pursue improved test accuracy. Two possibilities are multi-omic and combined biomarker approaches. Omics are used to better understand the roles, relationships, and actions of different types of molecules that make up human cells.15

Combining approaches is expected to lead to increased insights gathered from a single liquid biopsy assay and improved accuracy rates. For pan-cancer tests, combined approaches could also improve the accuracy rate for detecting cancer origin.

Firms also want to provide multiple sample options for tumor-specific assays. Exact Sciences is developing a blood-based test for colon cancer that would complement its stool-based Cologuard test.16 For detection or monitoring of other cancer types, sample types like urine and saliva might be in play.

For example, urine might be an appropriate sample for detecting kidney cancer due to increased tumor shedding in the sample compared to blood.17 In instances where multiple tests come to market with different sample options, we expect adoption to be largely determined by test accuracy and patient preference.

Establishing Clinical Guidelines Key to Liquid Biopsy Adoption

The Centers for Disease Control and Prevention (CDC) recently found that cancer deaths decreased 27% from 2000 to 2020, given more effective and widely available cancer screening options for asymptomatic patients.18 Overwhelming evidence shows that earlier detection of colon cancer will improve patient outcomes significantly.

As a result, firms used colon cancer to validate liquid biopsy and forge a pathway towards FDA approval and reimbursement coverage for tests. Crucial questions, however, remain unanswered about how expanded use of liquid biopsy will be implemented and what clinical best practices should be followed after a positive test result.

In our view, establishing robust downstream guidelines for diagnostic and post-diagnostic care is essential to ensure increased adoption of liquid biopsies. Currently, it’s customary for specialists to perform cancer screening, if available, and diagnosis.

For example, when a patient is screened for cervical cancer, an OB-GYN most likely makes the diagnosis via a Pap test. Conversely, MCEDs, could serve as a screening aid as a part of annual blood work. Physicians will need a clear workflow, which must be built from the ground up.

Robust downstream guidelines can ensure that patients have a seamless experience with the product and aid in the medical community embracing liquid biopsy’s clinical utility. For example, the commercial strategy should include ideal patient characteristics. Illumina’s GRAIL suggests that patients with an elevated risk of cancer and those over 50 are the ideal group to benefit from such a test.19

Competition Grows, Firms Look to Address the Full Cancer Care Continuum

The more late-stage clinical trial data and commercial adoption continue to validate liquid biopsy technology, the more companies enter the market. In our view, test accuracy and result comprehensibility will be the primary determinants of success for any company or test. Other factors, like reimbursement level and company reputation within the physician community, will also play important roles.

In this increasingly competitive market, firms are taking steps to differentiate themselves. Guardant Health (GH), for example, recently announced that it formed a partnership with electronic health records (EHR) firm Epic. The partnership will integrate Guardant’s portfolio of cancer tests into the Epic system. Epic is one of the two major EHR providers in the United States.20

In our view, the firms best positioned to drive test adoption will be those that have comprehensive portfolios with diagnostic options at each step along the entire cancer care continuum, from diagnosis through remission.

In addition, we believe having both tissue and liquid-based diagnostic options will help validate the benefit of this new diagnostic approach and drive long-term adoption. Breadth of portfolio will also aid firms in gaining reimbursement coverage, which will ultimately make the technology accessible to a greater patient population.

Beyond traditional points along the cancer care continuum, we anticipate that hereditary cancer testing and real-world evidence (RWE) will increasingly converge with the segments of traditional oncology diagnostics that liquid biopsy addresses:

  • Hereditary Cancer Testing: This blood-based test searches for specific genetic mutations that can help identify patients at a higher risk of developing cancer in their lifetime.21 For example, if a patient has a BRCA mutation, physicians might recommend more frequent screening tests, such as mammograms and MRIs.22 One in eight cancer patients has an inherited gene mutation.23
  • Real World Evidence (RWE): RWE can take the shape of robust databases offered by healthcare companies that can be used to accelerate research and development (R&D) of cancer medications. Liquid biopsy companies are increasingly partnering with pharmaceutical and biotech firms to offer de-identified clinical information and genomic data collected from their liquid biopsy tests. These partnerships give drug developers insights into tumor evolution, treatment resistance, and anti-cancer therapy use.24 In practice, these insights can help pharmaceutical firms prioritize development of cancer drugs by level of unmet need, shape the design of clinical trials to better determine drug effectiveness, and evaluate success of approved drugs.25

Creating an end-to-end cancer diagnostics operation

Creating an end-to-end cancer diagnostics operation (Author)


Liquid biopsy technology has momentum as an increasingly viable early-stage cancer detection tool. We’re seeing that momentum play out as firms expand their portfolios and established life sciences companies enter the space.

Increased acquisition activity is another telltale sign of liquid biopsy’s growth potential, including Exact Sciences’ $2.15 billion acquisition of Thrive Earlier Detection, Illumina’s $8 billion re-acquisition of Grail, and Agilent’s (A) $550 million acquisition of Resolution Sciences.26, 27, 28

In our view, these developments can accelerate research in the industry and shift the oncology landscape as patients and providers begin to experience the benefits.

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  1. Exact Sciences. (2022, April 26). Making earlier cancer detection a routine part of medical care: First quarter 2022 earnings call [PowerPoint slides].
  2. Ibid.
  3. Ibid.
  4. Strimbu, K., & Tavel, J. A. (2010, November). What are biomarkers? Current Opinion in HIV and AIDS, 5(6), 463-466. doi: 10.1097/COH.0b013e32833ed177
  5. Zhang, H., Lin, X., Huang, Y., Wang, M., Cen, C., Tang, S., Dique, M.R., Cai, L., Luis, M. A., Smollar, J., Wan, Y., & Cai, F. (2021, June 2). Detection methods and clinical applications of circulating tumor cells in breast cancer. Frontiers in Oncology, 11(652253). doi: 10.3389/fonc.2021.652253
  6. Micalizzi, D. S., Maheswaran, S., & Haber, D. A. (2017, September 15). A conduit to metastasis: Circulating tumor cell biology. Genes & Development, 31(18), 1827-1840. doi: 10.1101/gad.305805.117
  7. Zhang, J., Quadri, S., Wolfgang, C., & Zheng, L. (2018, August). New development of biomarkers for gastrointestinal cancers: From neoplastic cells to tumor microenvironment. Biomedicines, 6(3), 87. doi: 10.3390/biomedicines6030087
  8. Ibid.
  9. Edgar, J. R., 2016, June 13). Q&A: What are exosomes exactly? BMC Biology, 14(46). doi: 10.1186/s12915-016-0268-z
  10. Cologuard. (2022, May). High sensitivity in a noninvasive colorectal cancer (CRC) screening option. Exact Sciences Corporation. Clinical Offer | Cologuard® For HCPs | Risk Info
  11. Newitt, P. (2021, August 13). Colonoscopy backlog could take ‘years to recover from,’ CFO says. Becker’s GI & Endoscopy. Colonoscopy backlog could take 'years to recover from,' CFO says
  12. Grail. (2021, January 11). GRAIL confirms Q2 2021 introduction of Galleri, first-of-kind multi-cancer early detection blood test [Press release]. GRAIL Confirms Q2 2021 Introduction of Galleri, First-of-Kind Multi-Cancer Early Detection Blood Test - GRAIL
  13. Galleri. (2022). Clinical impact. GRAIL. Clinical Evidence | Galleri® for HCPs
  14. Ashford, M. (2021, April 15). Grail cancer early detection test performance holds steady as Q2 launch approaches. GenomeWeb. Grail Cancer Early Detection Test Performance Holds Steady as Q2 Launch Approaches
  15. Add Health. (n.d.) Omics. Accessed on May 11, 2022 from Omics
  16. Staff Reporter. (2022, February 22). Exact Sciences Q4 revenues up 2 percent; non-COVID-19 revenues rise 16 percent. GenomeWeb. Exact Sciences Q4 Revenues up 2 Percent; Non-COVID-19 Revenues Rise 16 Percent
  17. Oshi, M., Murthy, V., Takahashi, H., Huyser, M., Okano, M., Tokumaru, Y., Rashid, O. M., Matsuyama, R., Endo, I., & Takabe, K. (2021, June). Urine as a source of liquid biopsy for cancer. Cancers (Basel), 13(11), 2652. doi: 10.3390/cancers13112652
  18. Division of Cancer Prevention and Control. (2022, February 28). An update on cancer deaths in the United States. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Atlanta, GA. Accessed on April 5, 2022 from An Update on Cancer Deaths in the United States
  19. Nadauld, L. (2021). Multi-cancer early detection: Implementation considerations for health systems [PowerPoint slides]. Intermountain Healthcare US-GA-2100171-1.
  20. Staff Reporter. (2022, April 4). Guardant Health inks partnership with Epic for EHR integration of cancer tests. GenomeWeb. Guardant Health Inks Partnership with Epic for EHR Integration of Cancer Tests
  21. American Cancer Society. (2022). Understanding genetic testing for cancer. Understanding Genetic Testing for Cancer
  22. National Cancer Institute. (n.d.) BRCA gene mutations: Cancer risk and genetic testing. Accessed on May 11, 2022 from BRCA Gene Mutations: Cancer Risk and Genetic Testing Fact Sheet
  23. Natera. (2022). EmpowerTM. Empower Overview | Empower Overview| Natera
  24. Guardant. (2020, June 23). Guardant Health launches real-world clinical-genomic platform to accelerate precision oncology drug development [Press release]. Guardant Health Launches Real-World Clinical-Genomic Platform to Accelerate Precision Oncology Drug Development
  25. Ibid.
  26. Al Idrus, A. (2020, October 27). Exact Sciences snaps up liquid biopsy company Thrive in $2.15B deal. Fierce Biotech. Exact Sciences snaps up liquid biopsy company Thrive in $2.15B deal
  27. Hale, C. (2020, September 21). Illumina to pay $8B to reacquire cancer blood test maker Grail, with all eyes on 2021. Fierce Biotech. Illumina to pay $8B to reacquire cancer blood test maker Grail, with all eyes on 2021
  28. Hale, C. (2021, March 4). Agilent to pick up cancer blood tester Resolution Bio in $695M deal. Fierce Biotech. Agilent to pick up cancer blood tester Resolution Bio in $695M deal
  29. van Niel, G., D’Angelo, G., & Raposo, G. (2018, January 17). Shedding light on the cell biology of extracellular vesicles. Nature Reviews Molecular Cell Biology, 19, 213-228. doi: 10.1038/nrm.2017.125
  30. Vailati-Riboni, M., Palombo, V., & Loor, J. J. (2017, August 11). What are omics sciences? In B. Ametaj (Ed.), Periparturient Diseases of Dairy Cows (1-7). Springer. doi: 10.1007/978-3-319-43033-1_1
  31. Add Health. (n.d.) Omics. Accessed on May 11, 2022 from Omics
  32. Division of Cancer Prevention and Control. (2021, September 27). Hereditary breast cancer and BRCA genes. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Atlanta, GA. Hereditary Breast Cancer and BRCA Genes


Specificity: A test’s ability to correctly identify people without the disease, i.e., the true negativity rate.

Sensitivity: A test’s ability to correctly identify patients with the disease, i.e., the true positivity rate.

Extracellular Vesicles: A group of cell-derived structures involved in key biological processes. They are a part of intracellular communication, allowing cells to exchange proteins, lipids, and genetic material.29

Cancer Signal Origin: A test’s ability to currently identify the origin of the signal, i.e., what cancer type the patient has.

Omics: A field of study in biological sciences that ends with -omics, such as genomics, transcriptomics, proteomics, or metabolomics. Refers to the collective technologies used to explore the roles, relationships, and actions of molecules that make up the cells of an organism.30, 31

BRCA: BRCA1 and BRCA2 are tumor suppressor genes important to fighting cancer. A change or mutation in these genes can prevent them from working normally and might raise a patient’s risk for breast, ovarian, and/or other cancer.32

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