Questions and Answers about MCD Tests

About Cancer Screening

What are cancer screening tests?

Cancer screening tests are used to check for cancer or signs of cancer risk before a person has symptoms. There are two kinds of benefits from cancer screening tests: detection of abnormal cells that can be removed or treated before they become cancer (precancers), and detection of cancer at an earlier stage when it may be more treatable, leading to improved survival.

Cancer screening is not a stand-alone test. The success of a cancer screening test depends on more than just how well the test works. It also depends on the accuracy and affordability of the test, on the diagnostic workup needed after initial testing, and on effective cancer care delivery.

What kind of tests are used to screen for cancer?

Tests to detect cancer or cancer risk come in many forms:

• Physical exams to check general signs of health. These exams can uncover visible signs of disease, such as lumps, abnormal moles, or enlarged organs.
• Imaging procedures, which take pictures of areas inside the body.
  • A mammogram is a screening test for breast cancer. This test is an x-ray picture of the breast. Mammography has been shown to decrease the risk of dying from breast cancer by detecting it earlier when it is usually easier to treat.
  • Low-dose computed tomography (CT) is used to screen for lung cancer. It has been shown to decrease the risk of dying from lung cancer in heavy smokers. The procedure makes a series of detailed pictures of the lungs using a type of x-ray machine.
• Direct observation tests, which involve visual examination of tissue for abnormal growths. A colonoscopy is a screening test for colorectal cancer. In this test, the rectum and colon are examined using a flexible lighted tube with a lens for viewing.
• Laboratory tests, which analyze samples of tissue, blood, urine, or other substances in the body. For example, health care professionals take a sample of cervical cells to screen for cervical cancer with a Pap test and to check for infection with human papillomavirus.

Additionally, standard screening methods for colon and cervical cancers can detect precancers that can be removed (for example, polyps), and thus prevent the development of a cancer in addition to detecting cancer early when it may be easier to treat successfully.

Does a positive cancer screening test mean I have cancer?

No. A screening test alone cannot diagnose cancer. A cancer screening test identifies something abnormal, and then more tests must be done to determine whether a person has cancer and what type. These are called diagnostic tests.

For example, a screening mammogram may find a change in breast tissue. This change may be a cancer or a precancer or something else. More tests need to be done to find out what that tissue change means and whether it requires treatment or if it is a false-positive result. These tests may include a biopsy, in which cells or tissues are removed by a needle or during a surgical procedure so a pathologist can check them under a microscope for signs of cancer.

Does a negative cancer screening test mean I do not have cancer?

No. A screening test can miss the presence of cancer, leading to a false-negative test result. For example, mammograms may appear normal even though breast cancer is present. Overall, screening mammograms miss about 20% of breast cancers that are present at the time of screening.

About Multi-Cancer Detection Tests

What are multi-cancer detection (MCD) tests?

Multi-cancer detection (MCD) tests, also referred to as MCD assays or liquid biopsy tests, measure biological substances that cancer cells may shed in blood and other body fluids – such as circulating tumor cells, tumor DNA, and other analytes – that may suggest the presence of cancer. An assay is a laboratory test to find and measure the amount of a specific substance in a sample such as a liquid biopsy (tests done on a sample of blood, urine, or other body fluids to look for cancer cells, or other molecular evidence of cancer). The biological signals that MCD assays test for are known as biomarkers or tumor markers.

MCD tests differ from other cancer screening tests in two main ways. First, they use a single blood test instead of x-rays or imaging tests (such as mammography) or other medical procedures (such as colonoscopy). Second, they check for many types of cancer from different organ sites at the same time—including some cancers that existing screening tests do not check for.

As a new tool for cancer screening, MCDs make a prediction about the presence of cancer, not a diagnosis.

Depending upon which biological signals the MCD test measures, it may screen for several different types of cancer.

Current MCD tests in development measure different biological signals in blood plasma, such as:

• Changes in DNA and/or RNA sequences
• Patterns of DNA methylation (a chemical change to DNA which changes how the gene product is expressed)
• Patterns of DNA fragmentation (how the DNA is broken into smaller pieces)
• Levels of protein biomarkers
• Antibodies that a person’s body may develop against components of growing cancer cells.

Research scientists continue to search for new technological approaches that may expand this list to measure even more biological signals (e.g., what a person’s immune cells are actively searching for).

To date, no professional medical societies nor the U.S. Preventive Services Task Force have issued recommendations on the use of MCD tests for cancer screening. Health insurance programs do not routinely cover MCD testing. (See below, "Are there Food and Drug Administration (FDA)-authorized MCD tests available in the United States?")

How are MCDs and MCEDs different?

NCI uses the term “Multi-Cancer Detection (MCD) tests,” while some researchers and businesses prefer “Multi-Cancer Early Detection (MCED) tests.” Both acronyms refer to the same type of assay intended to detect cancer in people with no symptoms of cancer.

How are MCD tests different from genetic tests?

While MCD tests analyze molecules released by tumor cells, genetic tests for cancer risk look for specific inherited patterns in a person’s genes, including healthy cells. Genetic variants can have harmful, beneficial, neutral (no effect), unknown, or uncertain effects on the risk of developing diseases. Harmful variants in certain genes are known to be associated with an increased risk of developing cancer. These inherited variants are thought to contribute to about 5% to 10% of all cancers.

Genetic tests are usually requested by a person’s genetic counselor, doctor, or other health care professional who has reviewed the individual’s personal and family history. The genetic test options from which a health professional may select include those that look at a single gene and those that look for harmful variants in multiple genes at the same time. Genetic testing is done on a small sample of bodily fluid or tissue—usually blood, but sometimes saliva, cells from inside the cheek, or skin cells. The sample is then sent to a laboratory that specializes in genetic testing. The laboratory returns the test results to the doctor or genetic counselor who requested the test.

Are there Food and Drug Administration (FDA)-authorized MCD tests available in the United States?

No. The FDA authorizes devices and tests differently from how it approved medicines. No MCD tests have been authorized by the FDA. However, some companies are offering the tests to physicians and consumers as laboratory developed tests (LDTs). LDTs are tests that are designed, manufactured, and used within a single laboratory. Laboratories offering LDTs are required to show that they measure what they say they can measure. The federal regulation of LDTs does not require evidence that they provide a clinical benefit to patients, such as diagnosing cancer early.

A few MCD tests have received a Breakthrough Device Designation from the FDA, but this does not mean they have gone through the FDA’s rigorous premarket review process.

What MCD tests are available to the public in the United States?

This is a rapidly evolving emerging technology. There is no comprehensive centralized listing of MCD tests available to the public.

There are some MCD tests available to the public as laboratory developed tests (LDTs). However, no MCD tests have been authorized by the FDA. LDTs are regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The federal regulation of LDTs under CLIA does not require evidence that they provide a clinical benefit to patients, such as diagnosing cancer early. (See above, “Are there FDA-authorized MCD tests available in the United States?”)

We do not know if using the current MCD tests available to the public to detect possible cancers is more likely to cause harm than benefit. Randomized clinical trials are needed to assess the risk/benefit ratio of MCDs.

Do health insurance plans pay for MCD tests?

No. Currently, no MCD tests are recommended for reimbursement by the Centers for Medicare & Medicaid Services. Health insurance plans typically will not pay for MCD tests. Most people will have to pay out-of-pocket for the tests, and some people may also have to pay for the follow-up diagnostic procedures out-of-pocket. The cost for MCD tests varies but could cost around $900. There is little known about whether the cost of a diagnostic workup for a positive MCD result would be covered by insurance.

What kinds of cancers can each MCD test potentially find?

Most MCD tests measure different biological signals that may be shed by cancer cells. Depending on what is measured, the cancers that may be detected will vary. Currently, no MCD tests screen for every type of cancer. Tests typically include cancers for which effective screening is already available, such as colorectal cancer and breast cancer, as well as other cancers for which screening is not available. Some MCD tests include highly lethal cancers such as ovarian and pancreatic cancer. One MCD test may screen for colorectal cancer, bladder cancer, and prostate cancer, while another may screen for a different group of cancer types. To date, each MCD test under development looks for a different group of cancers.

Does a positive result on an MCD test mean that a person has cancer?

No. A positive result on an MCD test is just a signal that a person might have cancer. If a person gets a positive MCD result, more tests will be needed (which may include invasive tests and/or biopsies) to confirm a diagnosis of cancer. We do not know if MCD tests will only find cancers that will require treatment or may also identify slow-growing cancers that might never affect a person’s health.

Will an MCD test say what type of cancer a person has?

No. Some MCD tests indicate the likely organ site of the cancer (e.g., lung). Like other cancer detection tests, the MCD test only provides a signal for a possible cancer.

Additional testing, such as imaging, tissue biopsy, and/or surgery is required to diagnose if someone has cancer and if so, which kind of cancer. The type or sequence of additional testing that should be used following a positive MCD test is not yet known.

How many follow-up tests might be needed if an MCD test is positive for cancer?

How much additional testing a person may need after an MCD test to determine if they have cancer, where that cancer is located, and what to do if those additional tests do not show a cancer, is unknown. In published research about people who had a positive MCD test, more than half the time, no cancer could be found.

In addition, follow-up diagnostic tests needed after a positive MCD result may lead to invasive procedures to check all the possible cancer sites that could be involved. There may be complications from those procedures, time spent away from work and family, and anxiety and uncertainty about the testing process. To date, information is too limited to know how frequently to check on these patients and the extent to which patient anxiety and concern about costs will affect adherence to follow-up testing. (See below, “What are the potential harms of MCD tests?”)

Does a negative MCD test mean that a person does not have cancer?

There is limited data. However, patients have been diagnosed with cancer despite having a negative MCD test. As yet, no MCD tests are so accurate or broad that a negative result means that a person does not have cancer.

For example, a person may have a cancer that a MCD test does not detect. A person may have an early stage cancer that a MCD test screens for, but the cancer is missed by the test.

Each MCD test has a different cut-point for determining what constitutes a negative or positive test result. The cut-point is based on a proprietary algorithm (a set of rules for making a prediction) developed using machine learning or artificial intelligence.

Are regular standard-of-care cancer screenings needed if a person has an MCD test?

Yes. Standard-of-care cancer screenings are recommended regardless of whether or not a person has an MCD test. The following standard-of-care screening tests are considered effective and recommended by expert groups: breast cancer screening, cervical cancer screening, colorectal cancer screening, and lung cancer screening. These screening tests are recommended because they have been proven to find these specific cancers early, reduce the chances that someone screened regularly will die from these specific cancers, and provide more potential benefits than harms.

Risks, Benefits, and Needed Research

What are the potential benefits of MCD tests for cancer screening?

It is not known whether, and to what extent, the benefits of screening with MCD tests will outweigh the harms for the population in which these tests would be used. In at least one study, half the patients who had a positive MCD test went through diagnostic testing with no cancer detected at one year.

Understanding the benefits and harms of MCD-based screening requires a randomized controlled trial. Potential benefits of MCD screening might include:

• Screening at organ sites currently without a screening test. MCD tests may potentially detect cancers at organ sites where currently no screening is available, and perhaps save lives.
• Earlier detection. MCD tests may potentially detect cancers that are hard to identify when those cancers are in an early stage. Finding cancer at an earlier stage may improve the chance of cure or allow for less invasive treatments.
• Screening for multiple cancers at the same time. MCD tests can potentially identify cancers from many different organ sites with only a single test.
• Less invasive procedures. Most MCD tests rely on a blood draw, which may be more acceptable to patients than other forms of cancer screening tests.

What are the potential harms of MCD tests?

The potential harms of MCDs include:

• Negative results. Participation in MCD testing may provide a false sense of confidence that leads people to skip standard-of-care screening, such as regular mammograms.
• False-negative results. An MCD test may report a negative result when the person has a cancer. This could lead to a delay in cancer treatment if the MCD results provide a false sense of confidence that leads a person to ignore symptoms.
• False-positive results. An MCD test may report a positive result, but further diagnostic procedures do not find a cancer.
• Overdiagnosis and overtreatment. Like other screening tests, MCD tests may not be able to tell the difference between cancers that grow slowly and may never require treatment from those that lead to illness or death.
• Early detection of some types of cancer may not make a difference in a person’s treatment options, survival, or chance of dying from the disease.
• Uncertainty and potential harms from procedures needed to diagnose the cancer. Some companies producing MCD tests provide a list of potential organ sites for cancer to support a health care provider in starting a diagnostic workup. However, a positive MCD test could potentially result in multiple follow-up tests, leading to a prolonged process to find out if any cancer is present. This prolonged process can cause patient anxiety, require time, and lead to financial expense. These follow-up procedures each carry their own risks and have the potential to cause physical harm.
• MCD tests may increase medical mistrust if test characteristics and/or results are not adequately explained or appropriately understood by the public.
• MCD tests could make existing health disparities worse. Not all individuals may have access to health care to have follow-up diagnostic/screening tests after a positive MCD result. This unequal access to cancer screening and necessary health services may worsen existing health disparities. Only randomized controlled trials that follow people over time and consider the complex set of factors involved in testing for multiple different kinds of cancers can determine how the potential benefits of MCD tests stack up against potential harms.

Do MCD tests address health disparities?

The impact of MCD-based cancer screening on healthcare disparities is unknown. More research is needed to understand whether MCD tests improve access or worsen health care disparities. Clinical trials to determine the benefits and harms of MCD tests should enroll a broad and diverse range of population groups, so that we can determine whether all communities will benefit or be harmed by these tests.

If MCD tests and follow-up procedures needed to make a diagnosis are not widely available and affordable, inequities for minority, underserved, and vulnerable populations could increase. Plus, a screening test cannot address the availability and affordability of appropriate treatments if a cancer diagnosis is ultimately made.

MCD screening might also help narrow the disparities gap in cancer clinical care by increasing the participation rate with available cancer screening programs through improvement in access to screening of underserved and socioeconomically disadvantaged populations.

What is not yet known about MCD tests?

MCDs have the potential to transform how we think about and implement cancer screening. More than half of cancer deaths involve cancers that have no recommended screening tests, including highly deadly cancers like ovarian and pancreatic cancer. The potential risks and benefits for using emerging technologies such as MCD tests for cancer screening are unknown.

Currently, data indicate that MCD tests are better at detecting later-stage cancer than early stage disease. Therefore, it is critical to determine whether using these tests will reduce deaths due to cancer compared with not using such tests.

There are many unanswered questions about the use of MCD tests to screen for multiple cancers. Other unanswered questions include:

• What kind and how many diagnostic tests will be needed following an MCD test to make a cancer diagnosis?
• What happens if following a positive MCD test, a cancer is not found?
• How many people will receive unnecessary invasive procedures and suffer from various complications of those procedures following positive MCD tests?
• Will people stop standard-of-care screening, such as mammograms and colonoscopies, if they get a negative MCD test?
• Do MCD tests work equally well in all populations?
• Will MCD tests make screening more accessible or increase health disparities?
• Will MCD tests lead to overdiagnosis of slow-growing cancers that would not have caused illness or death?

Despite these unknowns, healthcare professionals and patients are faced with a marketing tsunami of MCD tests in various stages of development. To date, there is not enough information available about MCDs for doctors to adequately inform their patients.

Rigorous clinical trials are needed to determine whether using MCD tests to screen asymptomatic people will reduce cancer deaths without causing substantial harms, such as suffering and anxiety from inconclusive or negative diagnostic workups triggered by a positive result on a MCD test. To date, there are no definitive clinical trials showing that use of MCD tests for cancer screening will reduce overall cancer mortality.

What research and clinical trials are underway to develop MCD tests?

There are several studies in development to evaluate the effectiveness of MCD tests in detecting cancers in individuals without cancer symptoms. The National Health Service in the United Kingdom, for example, is enrolling people to a randomized controlled trial to see whether screening with a MCD test (along with standard screening) reduces the occurrence of late-stage cancers, and possibly death, compared to standard screening alone. Companies that make MCD tests and research groups are continuing to investigate additional approaches to develop new MCD tests.

What research is NCI doing on MCD tests?

The potential of MCD tests is exciting. If found to be useful, these new blood tests could provide the opportunity for less invasive tools for the early detection of cancer. No clinical trials have been conducted to determine whether using these tests to screen for cancer will lower the burden of cancer within populations.

Clinical trials of MCD tests are needed to understand whether their use can save lives. Only a clinical trial that follows many people over time can determine if the potential benefits outweigh the potential harms. Answering this question is an urgent matter; some of these tests are already available to the public, although none have been proven to reduce mortality from cancer.

NCI is working on a broad template for how to conduct a clinical trial with this new type of screening test. A key feature of such a trial is determining the clinical utility of MCD tests by measuring whether the tests result in fewer cancer deaths in the population of screened individuals compared to a control population. There are many MCD tests in development by a variety of companies, all of which will need clinical trials to understand their potential benefit.

NCI is setting up a network of researchers to find the best ways to test MCDs in clinical trials. In June 2022, the NCI Board of Scientific Advisors approved a proposal to create a Cancer Screening Research Network (CSRN), a new network of organizations that includes health care systems, military healthcare and academic institutions, federally qualified health centers, and at least one tribal nation . The CSRN will conduct rigorous, multi-center cancer screening trials and studies with large and diverse populations in a variety of health care settings with the ultimate goal of reducing the number of cancer-related deaths and illnesses.

In 2025, the CSRN will begin enrolling up to 24,000 healthy people aged 45-70 in a Vanguard study to assess the feasibility and finalize the design and logistics for a later, larger study. The Vanguard study will explore the best way to study MCDs and lay the groundwork for future large-scale clinical trials and other studies to assess multiple different technologies for cancer screening.

In addition, NCI is funding the collection of blood samples from patients with cancer and healthy persons to establish a large bank of case-control samples to use in evaluating MCD tests in future studies.

Selected Publications