Update: Blood tests called liquid biopsies for cancer screening, monitoring and treatment

Contents

TOPIC AT A GLANCE

Use of liquid biopsies in cancer care

Cancer screening tests

There are only five established cancer screening tests for people at average risk for cancer: colonoscopy for colon cancer, mammography for breast cancer, Pap smears for cervical cancers, PSA (prostate serum antigen) for prostate cancer and low-dose CT (computer tomography) for those at high risk for lung cancer due to being a current or former smoker. People at high risk for cancer due to an inherited mutation may also have other types of cancer screening tests (e.g., breast MRI or endoscopic ultrasound to detect pancreatic cancer).

Because cancer screening tests are few and current screening tests are specific to a given organ, developing a reliable, simple test that could detect multiple cancers has been a goal of cancer research for decades.

Cell-free DNA

When cells in the body die, their contents are released into the blood. Cell-free DNA (cfDNA) is DNA that has left the nucleus of a cell and floats freely in the blood. While everyone has some amount of cfDNA in their blood from normal cells, the blood of people with cancer may have some abnormal cfDNA from cancer cells. This DNA is often called circulating tumor DNA or ctDNA.

In someone with cancer, the amount of ctDNA is very small—about 0.1 percent of their total cfDNA. However, ctDNA can be analyzed with advanced technologies to look for specific changes (mutations) found in cancer cells. When found, these mutations in the ctDNA from tumors may indicate the type of cancer and even suggest possible treatments.

Liquid biopsies

Liquid biopsies look for bits of ctDNA in the blood that are specific to cancer. An ideal liquid biopsy would accomplish all the following goals:

• detect a new or recurrent cancer at an earlier or more treatable stage than current screening
• have a low “false positive” rate (the test results is positive for cancer in a person who does not have cancer)
• reduce the need for surgical biopsies and other invasive screening procedures
• reveal the type of cancer or where it started
• provide information on how to treat the disease

No test currently performs all these actions.

Liquid biopsies for people who are diagnosed with cancer

The FDA has approved two liquid biopsy tests to help guide treatment decisions for patients who are already diagnosed with cancer and likely have a lot of cancer ctDNA in their blood. Guardant360 CDx, made by Guardant Health, is approved as a companion diagnostic for lung cancer therapy. FoundationOne Liquid CDx, made by Foundation Medicine, is approved as a companion diagnostic for ovarian, breast, lung and prostate cancer therapies.

Other liquid biopsy tests have been granted FDA breakthrough designations. These are Signatera from Natera and RaDaR from Inivata to detect cancer recurrence.  Another test from Blue Star Genomics is used to detect pancreatic cancer in patients with new-onset diabetes.

Liquid biopsies as a screening tool for those without cancer

Significant progress had been made in recent years on the development of liquid biopsies to screen for and diagnose cancer in people who are not known to have cancer. Currently, three liquid biopsy tests are available in the US for people who have not previously been diagnosed with cancer. None of these tests have been FDA approved or given breakthrough designations. The tests—CancerSEEK from Thrive, PanSeer from Siglera Genomics and Galleri from Grail—are being marketed as tests that can detect multiple types of cancer at early stages. However, research on these tests is still early. Importantly, these tests are not recommended in expert guidelines to detect cancer yet.

Liquid biopsy false positives and false negatives

One of the challenges with liquid biopsies is that they need to be shown to be very “sensitive,” meaning that they can find cancers more effectively than current screening methods. Tests that are not very sensitive will have many “false negatives.” This means that the test will fail to detect cancers in people.

Liquid biopsies must also be proven to be “specific.” Tests that are not very specific will have many “false positives.” This means that they will incorrectly report that people have cancer when they do not. People with a false positive test may have to undergo additional, invasive procedures to determine whether they do or do not have cancer.

The best way to know if a liquid biopsy is sensitive and specific enough to be clinically useful is through a large, randomized research study that shows the test can increase survival compared to standard screening. The biotechnology company Grail is beginning a large, randomized prospective study involving 140,000 participants in the United Kingdom. The study will look at whether Grail’s Galleri multi-cancer early detection test is beneficial when compared to standard cancer screening tests.

Earlier detection is not always better

Finding some cancers at an early stage has been shown to decrease the chance of dying from that cancer. In contrast, finding and treating some cancers early do not improve the chance of a cure or help a person to live longer. While ctDNA tests may eventually be able to detect more cancers at an early stage, early detection will not always mean fewer deaths.

In some cases, early cancer detection may do more harm than good. Some tumors may never grow enough to need treatment—any amount of treatment results in overtreatment. An ideal early detection test would distinguish aggressive tumors from slow-growing tumors.

These concerns highlight the need for careful evaluation of liquid biopsies and the tradeoff when it comes to current cancer screening methods, especially if screening many more healthy people identifies more cancers but at the likely emotional and financial cost of more false-positive cases in people who are cancer-free.

Health insurance coverage of liquid biopsies

Health insurance companies are most likely to cover the costs for tests that have solid evidence of improving outcomes and those that have been incorporated into national expert guidelines. Tests that are not part of guidelines may be available, but their benefits are unproven and out-of-pocket costs may be high.

What does this mean for me?

Liquid biopsy tests are playing an increasingly important role in cancer treatment. They may play a more prominent role in cancer screening as the research evolves.

If you are a person who has been diagnosed with cancer, ask your doctor if you might benefit from a liquid biopsy test. These tests are especially helpful for:

• advanced, recurrent or difficult-to-treat cancers.
• cancers that are hard to reach for a tissue biopsy.
• cancers for which treatment outcomes may be improved when recurrence is detected early.

If you are at high risk for cancer, it’s important to follow national expert guidelines for cancer screening and prevention. Talk with your healthcare professional about additional screening or whether you qualify for an early detection research study.

Read our related blog: Headline Hype: One simple blood test to detect 50 cancers? Not yet.

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Posted 9/29/2021

References

Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Annals of Oncology. 32(9):1167-1177. Published online June 24, 2021.

Nadauld LD, McDonnell CH III, Beer TM, et al. The PATHFINDER study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Cancers (Basel). 2021; June 13; 13(14):3501.

Chen X, Dong Z, Hubbell E, et al. Prognostic significance of blood-based multi-cancer detection in plasma cell-free DNA. Clinical Cancer Research. 2021; 27(15):4221-4229. Published online June 4, 2021.

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.