암 표지자(Tumor markers) 에 대하여 - 논문 읽어야

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Tumor Markers

What are tumor markers?

Tumor markers are substances that are produced by cancer or by other cells of the body in response to cancer or certain benign (noncancerous) conditions. Most tumor markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumor tissue, or other tissues or bodily fluids of some patients with cancer. Most tumor markers are proteins. However, more recently, patterns of gene expression‎ and changes to DNA have also begun to be used as tumor markers.

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 two or more cancer types. No “universal” tumor marker that can detect any type of cancer has been found.

There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can 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. Moreover, tumor markers have not been identified for every type of cancer.

How are tumor markers used in cancer care?

Tumor markers are used to help detect, diagnose, and manage some types of cancer. Although an elevated level of a tumor marker may suggest the presence of cancer, this alone is not enough to diagnose cancer. Therefore, measurements of tumor markers are usually combined with other tests, such as biopsies, to diagnose cancer.

Tumor marker levels may be measured before treatment to help doctors plan the appropriate therapy. In some types of cancer, the level of a tumor marker reflects the stage (extent) of the disease and/or the patient’s prognosis (likely outcome or course of disease). More information about staging is available in the NCI fact sheet Cancer Staging.

Tumor markers may also be measured periodically during cancer therapy. A decrease in the level of a tumor marker or a return to the marker’s normal level may indicate that the cancer is responding to treatment, whereas no change or an increase may indicate that the cancer is not responding.

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

How are tumor markers measured? 

A doctor takes a sample of tumor tissue or bodily fluid and sends it to a laboratory, where various methods are used to measure the level of the tumor marker.

If the tumor marker is being used to determine whether treatment is working or whether there is a recurrence, the marker’s level will be measured in multiple samples taken over time. Usually these “serial measurements,” which show whether the level of a marker is increasing, staying the same, or decreasing, are more meaningful than a single measurement.

Does NCI have guidelines for the use of tumor markers? 

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

·         The American Society of Clinical Oncology (ASCO) has published clinical practice guidelinesExit Disclaimer 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 RequirementsExit Disclaimer, which focuses on the appropriate use of tumor markers for specific cancers.

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. 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. Tumor markers that are currently in common use are listed below.

ALK gene rearrangements and overexpression‎

·         Cancer types: Non-small cell lung cancer and anaplastic large cell lymphoma

·         Tissue analyzed: Tumor

·         How used: To help determine treatment and prognosis

Alpha-fetoprotein (AFP)

·         Cancer types: Liver cancer and germ cell tumors

·         Tissue analyzed: Blood

·         How used: To help diagnose liver cancer and follow response to treatment; to assess stage, prognosis, and response to treatment of germ cell tumors

Beta-2-microglobulin (B2M)

·         Cancer types: Multiple myeloma, chronic lymphocytic leukemia, and some lymphomas

·         Tissue analyzed: Blood, urine, or cerebrospinal fluid

·         How used: To determine prognosis and follow response to treatment

Beta-human chorionic gonadotropin (Beta-hCG)

·         Cancer types: Choriocarcinoma and germ cell tumors

·         Tissue analyzed: Urine or blood

·         How used: To assess stage, prognosis, and response to treatment

BRCA1 and BRCA2 gene mutations

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To determine whether treatment with a particular type of targeted therapy is appropriate

BCR-ABL fusion gene (Philadelphia chromosome)

·         Cancer type: Chronic myeloid leukemia, acute lymphoblastic leukemia, and acute myelogenous leukemia

·         Tissue analyzed: Blood and/or bone marrow

·         How used: To confirm‎ diagnosis, predict response to targeted therapy, and monitor disease status

BRAF V600 mutations

·         Cancer types: Cutaneous melanoma and colorectal cancer

·         Tissue analyzed: Tumor

·         How used: To select patients who are most likely to benefit from treatment with certain targeted therapies

C-kit/CD117

·         Cancer types: Gastrointestinal stromal tumor and mucosal melanoma

·         Tissue analyzed: Tumor

·         How used: To help in diagnosing and determining treatment

CA15-3/CA27.29

·         Cancer type: Breast cancer

·         Tissue analyzed: Blood

·         How used: To assess whether treatment is working or disease has recurred

CA19-9

·         Cancer types: Pancreatic cancer, gallbladder cancer, bile duct cancer, and gastric cancer

·         Tissue analyzed: Blood

·         How used: To assess whether treatment is working

CA-125

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To help in diagnosis, assessment of response to treatment, and eval‎uation of recurrence

Calcitonin

·         Cancer type: Medullary thyroid cancer

·         Tissue analyzed: Blood

·         How used: To aid in diagnosis, check whether treatment is working, and assess recurrence

Carcinoembryonic antigen (CEA)

·         Cancer types: Colorectal cancer and some other cancers

·         Tissue analyzed: Blood

·         How used: To keep track of how well cancer treatments are working or check if cancer has come back

CD20

·         Cancer type: Non-Hodgkin lymphoma

·         Tissue analyzed: Blood

·         How used: To determine whether treatment with a targeted therapy is appropriate

Chromogranin A (CgA)

·         Cancer type: Neuroendocrine tumors

·         Tissue analyzed: Blood

·         How used: To help in diagnosis, assessment of treatment response, and eval‎uation of recurrence

Chromosomes 3, 7, 17, and 9p21

·         Cancer type: Bladder cancer

·         Tissue analyzed: Urine

·         How used: To help in monitoring for tumor recurrence

Circulating tumor cells of epithelial origin (CELLSEARCH?)

·         Cancer types: Metastatic breast, prostate, and colorectal cancers

·         Tissue analyzed: Blood

·         How used: To inform clinical decision making, and to assess prognosis

Cytokeratin fragment 21-1

·         Cancer type: Lung cancer

·         Tissue analyzed: Blood

·         How used: To help in monitoring for recurrence

EGFR gene mutation analysis

·         Cancer type: Non-small cell lung cancer

·         Tissue analyzed: Tumor

·         How used: To help determine treatment and prognosis

Estrogen receptor (ER)/progesterone receptor (PR)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with hormone therapy and some targeted therapies is appropriate

Fibrin/fibrinogen

·         Cancer type: Bladder cancer

·         Tissue analyzed: Urine

·         How used: To monitor progression and response to treatment

HE4

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To plan cancer treatment, assess disease progression, and monitor for recurrence

HER2/neu gene amplification or protein overexpression‎

·         Cancer types: Breast cancer, gastric cancer, and gastroesophageal junction adenocarcinoma

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with certain targeted therapies is appropriate

Immunoglobulins

·         Cancer types: Multiple myeloma and Waldenström macroglobulinemia

·         Tissue analyzed: Blood and urine

·         How used: To help diagnose disease, assess response to treatment, and look for recurrence

KRAS gene mutation analysis

·         Cancer types: Colorectal cancer and non-small cell lung cancer

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with a particular type of targeted therapy is appropriate

Lactate dehydrogenase

·         Cancer types: Germ cell tumors, lymphoma, leukemia, melanoma, and neuroblastoma

·         Tissue analyzed: Blood

·         How used: To assess stage, prognosis, and response to treatment

Neuron-specific enolase (NSE)

·         Cancer types: Small cell lung cancer and neuroblastoma

·         Tissue analyzed: Blood

·         How used: To help in diagnosis and to assess response to treatment

Nuclear matrix protein 22

·         Cancer type: Bladder cancer

·         Tissue analyzed: Urine

·         How used: To monitor response to treatment

Programmed death ligand 1 (PD-L1)

·         Cancer type: Non-small cell lung cancer

·         Tissue analyzed: Tumor

·         How used: To determine whether treatment with a particular type of targeted therapy is appropriate

Prostate-specific antigen (PSA)

·         Cancer type: Prostate cancer

·         Tissue analyzed: Blood

·         How used: To help in diagnosis, assess response to treatment, and look for recurrence

Thyroglobulin

·         Cancer type: Thyroid cancer

·         Tissue analyzed: Blood

·         How used: To eval‎uate response to treatment and look for recurrence

Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To determine aggressiveness of cancer and guide treatment

5-Protein signature (OVA1?)

·         Cancer type: Ovarian cancer

·         Tissue analyzed: Blood

·         How used: To pre-operatively assess pelvic mass for suspected ovarian cancer

21-Gene signature (Oncotype DX?)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To eval‎uate risk of recurrence

70-Gene signature (Mammaprint?)

·         Cancer type: Breast cancer

·         Tissue analyzed: Tumor

·         How used: To eval‎uate risk of recurrence

Can tumor markers be used in cancer screening? 

Because tumor markers can be used to assess 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. For a screening test to be useful, it should have very high sensitivity (ability to correctly identify people who have the disease) and specificity (ability to correctly identify people who do not have the disease). If a test is highly sensitive, it will identify most people with the disease—that is, it will result in very few false-negative results. If a test is highly specific, only a small number of people will test positive for the disease who do not have it—in other words, it will result in very few false-positive results.

Although tumor markers are extremely useful in determining whether a tumor is responding to treatment or assessing whether it has recurred, no tumor marker identified to date is sufficiently sensitive or specific to be used on its own to screen for cancer.

For example, the prostate-specific antigen (PSA) test, which measures the level of PSA in the blood, is often used to screen men for prostate cancer. However, an increased PSA level can be caused by benign prostate conditions as well as by prostate cancer, and most men with an elevated PSA level do not have prostate cancer. Initial results from two large randomized controlled trials, the NCI-sponsored Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the European Randomized Study of Screening for Prostate Cancer, showed that PSA testing at best leads to only a small reduction in the number of prostate cancer deaths. Moreover, it is not clear whether the benefits of PSA screening outweigh the harms of follow-up diagnostic tests and treatments for cancers that in many cases would never have threatened a man’s life.

Similarly, results from the PLCO trial showed that CA-125, a tumor marker that is sometimes elevated in the blood of women with ovarian cancer but can also be elevated in women with benign conditions, is not sufficiently sensitive or specific to be used together with transvaginal ultrasound to screen for ovarian cancer in women at average risk of the disease. An analysis of 28 potential markers for ovarian cancer in blood from women who later went on to develop ovarian cancer found that none of these markers performed even as well as CA-125 at detecting the disease in women at average risk.

What kind of research is under way to develop more accurate tumor markers? 

Cancer researchers are turning to proteomics (the study of protein structure, function, and patterns of expression‎) in hopes of developing new biomarkers that can be used to identify disease in its early stages, to predict the effectiveness of treatment, or to predict the chance of cancer recurrence after treatment has ended.

Scientists are also eval‎uating patterns of gene expression‎ for their ability to help determine a patient’s prognosis or response to therapy. For example, results of the NCI-sponsored Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx , showed that for women recently diagnosed with lymph node–negative, hormone receptor–positive, HER2-negative breast cancer who had undergone surgery, those with the lowest 21-gene (Oncotype Dx?) recurrence scores had very low recurrence rates when given hormone therapy alone and thus can be spared chemotherapy. The trial is ongoing to see whether women at intermediate risk of recurrence, based on the 21-gene test, do better with chemotherapy in addition to hormone therapy than with hormone therapy alone.

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

Selected References

1.      Bigbee W, Herberman RB. Tumor markers and immunodiagnosis. In: Bast RC Jr., Kufe DW, Pollock RE, et al., editors. Cancer Medicine. 6^th ed. Hamilton, Ontario, Canada: BC Decker Inc., 2003.

2.      Andriole G, Crawford E, Grubb R, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine 2009; 360(13):1310–1319. [PubMed Abstract]

3.      Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine 2009; 360(13):1320–1328. [PubMed Abstract]

4.      Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 2011; 305(22):2295–2303. [PubMed Abstract]

5.      Cramer DW, Bast RC Jr, Berg CD, et al. Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prevention Research 2011; 4(3):365–374. [PubMed Abstract]

6.      Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression‎ assay in breast cancer. New England Journal of Medicine 2015; First published online September 28, 2015. doi: 10.1056/NEJMoa1510764Exit Disclaimer.

Related Resources

·         Cancer Staging

·         Prostate-Specific Antigen (PSA) Test

·         Targeted Cancer Therapies

·         Understanding Cancer Prognosis

·         Understanding Laboratory Tests

·         Reviewed: November 4, 2015

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