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Tumor Markers

What are tumor markers?

A tumor marker is anything present in or produced by cancer cells or other cells of the body in response to cancer or certain benign (noncancerous) conditions that provides information about a cancer, such as how aggressive it is, what kind of treatment it may respond to, or whether it is responding to treatment.

Tumor markers have traditionally been proteins or other substances that are made at higher amounts by cancer cells than normal cells. These can be found in the blood, urine, stool, tumors, or other tissues or bodily fluids of some patients with cancer. Increasingly, however, genomic markers (such as tumor gene mutations, patterns of tumor gene expression, and nongenetic changes in tumor DNA) that are found in tumors themselves and in tumor fragments shed into bodily fluids are being used.

Many different tumor markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with multiple different cancer types

How are tumor markers used in cancer care?

There are two main types of tumor markers: circulating tumor markers and tumor tissue markers.

Circulating tumor markers can be found in the blood, urine, stool, or other bodily fluids of some patients with cancer. Circulating tumor markers are used to:

  • estimate prognosis
  • determine the stage of cancer
  • detect cancer that remains after treatment (residual disease) or that has returned after treatment
  • assess how well a treatment is working
  • monitor whether the treatment has stopped working

Although an elevated level of a circulating tumor marker may suggest the presence of cancer and can sometimes help to diagnose cancer, this alone is not enough to diagnose cancer. For example, noncancerous conditions can sometimes cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumor marker associated with that cancer. Therefore, measurements of circulating tumor markers are usually combined with the results of other tests, such as biopsies or imaging, to diagnose cancer.

Tumor markers may also be measured periodically during cancer therapy. Such “serial measurements,” which show how the level of a marker is changing over time, are usually more meaningful than a single measurement. For example, a decrease in the level of a circulating tumor marker may indicate that the cancer is responding to treatment, whereas an increasing or unchanged level may indicate that the cancer is not responding.

Circulating tumor markers may also be measured periodically after treatment has ended to check for recurrence (the return of cancer).

Examples of commonly used circulating tumor markers include calcitonin (measured in blood), which is used to assess treatment response, screen for recurrence, and estimate prognosis in medullary thyroid cancer; CA-125 (measured in blood), to monitor how well cancer treatments are working and if cancer has come back in ovarian cancer; and beta-2-microglobulin (measured in blood, urine, or cerebrospinal fluid), to estimate prognosis and follow response to treatment for multiple myeloma, chronic lymphocytic leukemia, and some lymphomas. Additional circulating tumor markers are described in the list of tumor markers in common use.

Tumor tissue (or cell) markers are found in the actual tumors themselves, typically in a sample of the tumor that is removed during a biopsy. Tumor tissue markers are used to:

  • diagnose, stage, and/or classify cancer
  • estimate prognosis
  • select an appropriate treatment (e.g., treatment with a targeted therapy)

Tumor tissue markers that indicate whether someone is a candidate for a particular targeted therapy are sometimes referred to as biomarkers for cancer treatment. Tests for these biomarkers are usually genetic tests that look for changes in genes that affect cancer growth. More information is available on the Biomarker Testing for Cancer Treatment page and the Targeted Therapy to Treat Cancer page. 

Examples of tumor tissue markers that are used as biomarkers for cancer treatment include estrogen receptor and progesterone receptor, which are tested for to determine whether someone with breast cancer should get treatment with hormone therapy; FGFR3 gene mutation analysis, to help determine treatment for patients with bladder cancer; and PD-L1, to see if people with any of a number of cancer types are candidates for treatment with an immune checkpoint inhibitor.

Because some tumors shed cells and genetic material into blood, it is sometimes possible to examine biomarkers in blood samples. Although these "liquid biopsies" are not yet routinely used, they have several potential advantages. Because they don’t involve surgery, they can be done more frequently than standard biopsies. They can also be performed when surgical biopsies cannot, such as when tumors are difficult to reach or patients can’t tolerate surgery.

Liquid biopsy tests can often detect multiple cancer-associated biomarkers. For example, the Foundation One Liquid CDx test is approved for the detection of genetic mutations in 324 genes and two genomic signatures in any solid tumor type. The test can also identify which patients with non-small cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer may benefit from 15 different FDA-approved targeted treatment options.

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Does NCI have guidelines for the use of tumor markers?

NCI does not have guidelines for the use of tumor markers. However, some national and international organizations have guidelines for the use of tumor markers for some types of cancer:

  • The American Society of Clinical Oncology (ASCO) has developed and published clinical practice guidelines on a variety of topics, including tumor markers for breast cancer, colorectal cancer, lung cancer, and others.
  • The National Academy of Clinical Biochemistry publishes laboratory medicine practice guidelines, including Use of Tumor Markers in Clinical Practice: Quality Requirements, which focuses on the appropriate use of tumor markers for specific cancers.

Because tumor markers are detected using biospecimens (tissue and blood samples), the National Cancer Institute publishes best practices for biospecimen collection, processing, and storage.

What tumor markers are currently being used, and for which cancer types?

A number of tumor markers are currently being used for a wide range of cancer types. See the list of tumor markers in common use for more information. Although most of these can be tested in laboratories that meet standards set by the Clinical Laboratory Improvement Amendments, some cannot be and may therefore be considered experimental.

Can tumor markers be used in cancer screening?

Because tumor markers can be used to predict the response of a tumor to treatment and for prognosis, researchers have hoped that they might also be useful in screening tests that aim to detect cancer early, before there are any symptoms.

However, studies to see whether circulating tumor markers can be used to screen for cancer have generally found that these markers don’t identify everyone with the disease (they are not sensitive enough) or that they indicate the possible presence of cancer in people who don’t have it (they are not specific enough). When a test has low specificity, people have to have further testing to determine whether cancer is present. And some screening tests based on tumor markers have been shown to lead to overdiagnosis, which happens when people are diagnosed with cancers that would never have affected them during their lifetimes. 

For example, the prostate-specific antigen (PSA) test was used routinely in the past to screen men for prostate cancer. However, as more was learned about the limitations of the test (including relatively low specificity), medical groups began to recommend against using it for routine population screening.

Several liquid biopsy–based assays that test for multiple tumor markers to detect cancer early, in people without symptoms, are in development:

  • PapSEEK identifies ovarian and endometrial cancer–related alterations in DNA obtained from fluids collected during a routine Pap test. In a study that included women already diagnosed with cancer, the test was able to detect some endometrial and ovarian cancers at early, more treatable stages.
  • CancerSEEK is a blood test that detects DNA mutations and protein biomarkers linked to multiple types of cancer. In a large trial of women with no history of cancer that combined the blood test with whole-body PET imaging, 65% of cancers that were detected were at an early stage.
  • UroSEEK is a urine-based test that detects the most common alterations in 11 genes linked to bladder and upper tract urothelial cancers. In a study that included patients not yet diagnosed with bladder cancer but at high risk of the disease because of symptoms, UroSEEK identified 83% of those who developed bladder cancer.

Although these tests are able to detect early cancers, it is not yet known whether treating those cancers would actually reduce deaths from these cancers. 

What research is under way to develop additional tumor markers?

NCI’s Early Detection Research Network (EDRN), a collaborative consortium of academic and private-sector investigators, has focused on the systematic discovery, development, and validation of biomarkers and imaging methods to detect early-stage cancers and to assess risk for developing cancer. One goal of EDRN is to develop biomarkers that can distinguish aggressive early-stage cancers from slow-growing cancers that would never cause symptoms to reduce overtreatment

Cancer researchers are turning to proteomics (the study of protein structure, function, and patterns of expression) and proteogenomics (the integration of proteomics with genomics and gene expression analysis, or transcriptomics) with the hope of developing novel biomarkers that can be used to identify cancer in its early stages, to predict the effectiveness of treatment, and to predict the chance of cancer recurrence.

NCI’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) is using a proteogenomic approach for tumor marker discovery for a growing number of cancers, including colorectal, breast, and ovarian cancers. By systematically identifying proteins (and associated biological processes) that originate from alterations in cancer genomes, CPTAC researchers have discovered new tumor subtypes, tumor microenvironment variations, and new potential proteins for targeted drug therapy. Recent innovations have suggested that these analyses could be done on a microscale using very small amounts of tumor tissue obtain from a biopsy.

NCI’s Molecular Applications for Therapy Choice (NCI-MATCH) and NCI-COG Pediatric MATCH clinical trials are using a precision medicine approach to assign patients to treatment by gene mutations in their tumors rather than by the type of cancer they have. By analyzing the response of patients to these targeted agents, and the underlying genomic alterations associated with these responses, researchers are identifying potentially new molecular targets for cancer therapy. Companion studies associated with these trials will also allow researchers to identify new biomarkers for determining response to therapies and for predicting treatment resistance. 

The NCI Cancer MoonshotSM Biobank is working with patient participants at community hospitals around the country to encourage them to donate tissue and blood samples over the course of their cancer treatment. The samples are sent to researchers who use them to better understand cancer and potentially identify tumor markers.  

More information on NCI’s role in supporting research on novel tools and methods for diagnosing cancer is available on the Cancer Diagnosis Research page.

Selected References
  1. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Science Translational Medicine 2014; 6(224):224ra24.

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  2. Duffy MJ. Clinical uses of tumor markers: a critical review. Critical Reviews in Clinical Laboratory Sciences 2001; 38(3):225–262.

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  3. Duffy MJ. Tumor markers in clinical practice: A review focusing on common solid cancers. Medical Principles and Practice 2013; 22(1):4–11.

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  4. Lennon AM, Buchanan AH, Kinde I, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science 2020; 369(6499):eabb9601.

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  5. Springer SU, Chen CH, Rodriguez Pena MDC, et al. Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. Elife 2018; 7:e32143.

    [PubMed Abstract]
  6. Wang Y, Li L, Douville C, et al. Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers. Science Translational Medicine 2018; 10(433):eaap8793.

    [PubMed Abstract]
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